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  • 1.
    Abacan, MaryAnn
    et al.
    Univ Philippines Manila, Inst Human Genet, NIH, Manila, Philippines.
    Alsubaie, Lamia
    KASCH, King Abdulaziz Med City, Riyadh, Saudi Arabia.
    Barlow-Stewart, Kristine
    Univ Sydney, Fac Med & Hlth, Northern Clin Sch, Sydney, NSW, Australia.
    Caanen, Beppy
    Maastricht Univ, Dept Clin Genet, Med Ctr, Maastricht, Netherlands.
    Cordier, Christophe
    SYNLAB Genet, Dept Genet, Lausanne, Switzerland.
    Courtney, Eliza
    Natl Canc Ctr, Div Med Oncol, Canc Genet Serv, Singapore, Singapore.
    Davoine, Emeline
    Lausanne Univ Hosp CHUV, Lausanne, Switzerland.
    Edwards, Janice
    Univ South Carolina, Genet Counseling Program, Transnat Alliance Genet Counseling, Columbia, SC USA.
    Elackatt, Niby J.
    Cloudnine Hosp, Org Rare Dis India, Bangalore, Karnataka, India.
    Gardiner, Kate
    LifeLabs Genet, Toronto, ON, Canada.
    Guan, Yue
    Emory Univ, Rollins Sch Publ Hlth, Atlanta, GA USA.
    Huang, Lian-Hua
    China Med Univ, Sch Nursing, Taichung, Taiwan;Natl Taiwan Univ, Coll Med, Sch Nursing, Taipei, Taiwan.
    Ingvoldstad, Charlotta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Lifestyle and rehabilitation in long term illness. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health. Karolinska Univ Hosp, Ctr Fetal Med & Clin Genet, Stockholm, Sweden;Karolinska Inst, Dept Clin Sci Intervent & Technol, Stockholm, Sweden.
    Kejriwal, Sahil
    Univ Washington, Inst Publ Hlth Genet, Seattle, WA USA.
    Kim, Hyon J.
    Ajou Univ, Med Sch, Suwon, South Korea;Konyang Univ, Grad Sch, Suwon, South Korea.
    Lambert, Deborah
    Natl Rare Dis Off, Dublin, Ireland.
    Lantigua-Cruz, Paulina Araceli
    Univ Med Sci Havana, Havana, Cuba.
    Lee, Juliana M. H.
    Natl Univ Malaysia, Kuala Lumpur, Malaysia.
    Lodahl, Marianne
    Copenhagen Univ Hosp, Rigshosp, Dept Clin Genet, Copenhagen, Denmark.
    Lunde, Ashild
    Univ Bergen, Dept Global Publ Hlth & Primary Care, Bergen, Norway.
    Macaulay, Shelley
    Univ Witwatersrand, Fac Hlth Sci, Div Human Genet, Johannesburg, South Africa;Natl Hlth Lab Serv, Johannesburg, South Africa.
    Macciocca, Ivan
    Victorian Clin Genet Serv, Melbourne, Vic, Australia.
    Margarit, Sonia
    Clin Alemana Univ Desarrollo, Fac Med, Ctr Genet & Genom, Santiago, Chile.
    Middleton, Anna
    Soc & Eth Res Connecting Sci, Wellcome Genome Campus, Cambridge, England;Univ Cambridge, Fac Educ, Cambridge, England.
    Moldovan, Ramona
    Babes Bolyai Univ, Dept Psychol, Cluj Napoca, Romania.
    Ngeow, Joanne
    Natl Canc Ctr, Div Med Oncol, Canc Genet Serv, Singapore, Singapore.
    Obregon-Tito, Alexandra J.
    Univ Arkansas Med Sci, Little Rock, AR 72205 USA.
    Ormond, Kelly E.
    Stanford Univ, Sch Med, Dept Genet, Stanford, CA USA;Stanford Univ, Sch Med, Stanford Ctr Biomed Eth, Stanford, CA USA;Stanford Univ, Sch Med, 300 Pasteur Dr,MC 5208, Stanford, CA USA.
    Paneque, Milena
    Univ Porto, CGPP Ctr Predict & Prevent Genet, I3S, Porto, Portugal;Univ Porto, IBMC Inst Mol & Cell Biol, Porto, Portugal.
    Powell, Karen
    Cone Hlth Canc Ctr, Greensboro, NC USA.
    Sanghavi, Kunal
    Jackson Lab Genom Med, Farmington, CT USA.
    Scotcher, Diana
    Manchester Univ Hosp NHS Fdn Trust, St Marys Hosp, Manchester Ctr Genom Med, Manchester, Lancs, England.
    Scott, Jenna
    Univ British Columbia, Vancouver, BC, Canada.
    Juhe, Clara Serra
    Univ Pompeu Fabra, Dept Ciencies Expt & Salut, Inst Hosp Mar Invest Med, Ctr Invest Biomed Red Enfermedades Raras, Barcelona, Spain.
    Shkedi-Rafid, Shiri
    Hadassah Hebrew Univ, Med Ctr, Jerusalem, Israel.
    Wessels, Tina-Marie
    Univ Cape Town, Div Human Genet, Cape Town, South Africa.
    Yoon, Sook-Yee
    Natl Univ Malaysia, Kuala Lumpur, Malaysia;Canc Res, Subang Jaya, Malaysia;Univ Malaya, Med Ctr, Kuala Lumpur, Malaysia.
    Wicklund, Catherine
    Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA.
    The Global State of the Genetic Counseling Profession2019In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 27, no 2, p. 183-197Article, review/survey (Refereed)
    Abstract [en]

    The profession of genetic counseling (also called genetic counselling in many countries) began nearly 50 years ago in the United States, and has grown internationally in the past 30 years. While there have been many papers describing the profession of genetic counseling in individual countries or regions, data remains incomplete and has been published in diverse journals with limited access. As a result of the 2016 Transnational Alliance of Genetic Counseling (TAGC) conference in Barcelona, Spain, and the 2017 World Congress of Genetic Counselling in the UK, we endeavor to describe as fully as possible the global state of genetic counseling as a profession. We estimate that in 2018 there are nearly 7000 genetic counselors with the profession established or developing in no less than 28 countries.

  • 2.
    Ameur, Adam
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Natl Genom Infrastruct, Sci Life Lab, Stockholm, Sweden..
    Dahlberg, Johan
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Natl Genom Infrastruct, Sci Life Lab, Stockholm, Sweden.
    Olason, Pall
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology. Natl Bioinformat Infrastruct, Sci Life Lab, Stockholm, Sweden..
    Vezzi, Francesco
    Natl Genom Infrastruct, Sci Life Lab, Stockholm, Sweden.;Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Stockholm, Sweden..
    Karlsson, Robert
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Martin, Marcel
    Natl Bioinformat Infrastruct, Sci Life Lab, Stockholm, Sweden.;Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Stockholm, Sweden..
    Viklund, Johan
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics. Natl Bioinformat Infrastruct, Sci Life Lab, Stockholm, Sweden..
    Kähäri, Andreas
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics. Natl Bioinformat Infrastruct, Sci Life Lab, Stockholm, Sweden..
    Lundin, Par
    Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Stockholm, Sweden..
    Che, Huiwen
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Thutkawkorapin, Jessada
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden..
    Eisfeldt, Jesper
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden..
    Lampa, Samuel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Natl Bioinformat Infrastruct, Sci Life Lab, Stockholm, Sweden.
    Dahlberg, Mats
    Natl Bioinformat Infrastruct, Sci Life Lab, Stockholm, Sweden.;Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Stockholm, Sweden..
    Hagberg, Jonas
    Natl Bioinformat Infrastruct, Sci Life Lab, Stockholm, Sweden.;Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Stockholm, Sweden..
    Jareborg, Niclas
    Natl Bioinformat Infrastruct, Sci Life Lab, Stockholm, Sweden.;Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Stockholm, Sweden..
    Liljedahl, Ulrika
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Natl Genom Infrastruct, Sci Life Lab, Stockholm, Sweden.
    Jonasson, Inger
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Natl Genom Infrastruct, Sci Life Lab, Stockholm, Sweden..
    Johansson, Åsa
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Feuk, Lars
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Lundeberg, Joakim
    Natl Genom Infrastruct, Sci Life Lab, Stockholm, Sweden.;Royal Inst Technol, Div Gene Technol, Sch Biotechnol, Sci Life Lab, Stockholm, Sweden..
    Syvänen, Ann-Christine
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Natl Genom Infrastruct, Sci Life Lab, Stockholm, Sweden.
    Lundin, Sverker
    Royal Inst Technol, Div Gene Technol, Sch Biotechnol, Sci Life Lab, Stockholm, Sweden..
    Nilsson, Daniel
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden..
    Nystedt, Björn
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution. Natl Bioinformat Infrastruct, Sci Life Lab, Stockholm, Sweden..
    Magnusson, Patrik K. E.
    Natl Genom Infrastruct, Sci Life Lab, Stockholm, Sweden.;Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Gyllensten, Ulf B.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    SweGen: a whole-genome data resource of genetic variability in a cross-section of the Swedish population2017In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 25, no 11, p. 1253-1260Article in journal (Refereed)
    Abstract [en]

    Here we describe the SweGen data set, a comprehensive map of genetic variation in the Swedish population. These data represent a basic resource for clinical genetics laboratories as well as for sequencing-based association studies by providing information on genetic variant frequencies in a cohort that is well matched to national patient cohorts. To select samples for this study, we first examined the genetic structure of the Swedish population using high-density SNP-array data from a nation-wide cohort of over 10 000 Swedish-born individuals included in the Swedish Twin Registry. A total of 1000 individuals, reflecting a cross-section of the population and capturing the main genetic structure, were selected for whole-genome sequencing. Analysis pipelines were developed for automated alignment, variant calling and quality control of the sequencing data. This resulted in a genome-wide collection of aggregated variant frequencies in the Swedish population that we have made available to the scientific community through the website https://swefreq.nbis.se. A total of 29.2 million single-nucleotide variants and 3.8 million indels were detected in the 1000 samples, with 9.9 million of these variants not present in current databases. Each sample contributed with an average of 7199 individual-specific variants. In addition, an average of 8645 larger structural variants (SVs) were detected per individual, and we demonstrate that the population frequencies of these SVs can be used for efficient filtering analyses. Finally, our results show that the genetic diversity within Sweden is substantial compared with the diversity among continental European populations, underscoring the relevance of establishing a local reference data set.

  • 3.
    Blom, Elin Susanne
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Viswanathan, Jayashree
    Kilander, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Helisalmi, Seppo
    Soininen, Hilkka
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Glaser, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Hiltunen, Mikko
    Low prevalence of APP duplications in Swedish and Finnish patients with early onset Alzheimer's disease2008In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 16, no 2, p. 171-5Article in journal (Refereed)
    Abstract [en]

    Familial early-onset Alzheimer's disease with cerebral amyloid angiopathy (EOAD/CAA) was recently associated with duplications of the gene for the amyloid-beta precursor protein (APP). In this study, we have screened for duplications of APP in patients with EOAD from Sweden and Finland. Seventy-five individuals from families with EOAD and 66 individuals with EOAD without known familial inheritance were screened by quantitative PCR. On the basis of the initial results, a portion of the samples was also investigated with quantitative multiplex PCR. No duplications of APP were identified, whereby we conclude that this is not a common cause of EOAD in the Swedish and Finnish populations, at least not in our collection of families and cases.

  • 4.
    Bondeson, Marie-Louise
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Malmgren, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Dahl, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Carlberg, Britt-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Pettersson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Presence of an IDS-related locus (IDS2) in Xq28 complicates the mutational analysis of Hunter syndrome1995In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 3, no 4, p. 219-227Article in journal (Refereed)
    Abstract [en]

    A deficiency of the enzyme iduronate-2-sulfatase (IDS) is the cause of Hunter syndrome (mucopolysaccharidosis type II). Here, we report a study of the human IDS locus at Xq28. An unexpected finding was an IDS-related region (IDS2) which is located on the telomeric side of the IDS gene within 80 kb. We have identified sequences in this locus that are homologous to exons 2 and 3 as well as sequences homologous to introns 2, 3 and 7 of the IDS gene. The exon 3 sequences in the IDS gene and in the IDS2 locus showed 100% identity. The overall identities of the other identified regions were 96%. A locus for DXS466 was also found to be located close to IDS2. The existence of the IDS2 locus complicates the diagnosis of mutations in genomic DNA from patients with Hunter syndrome. However, information about the IDS2 locus makes it possible to analyze the IDS gene and the IDS2 locus separately after PCR amplification.

  • 5. Borry, Pascal
    et al.
    van Hellemondt, Rachel E
    Sprumont, Dominique
    Jales, Camilla Fittipaldi Duarte
    Rial-Sebbag, Emmanuelle
    Spranger, Tade Matthias
    Curren, Liam
    Kaye, Jane
    Nys, Herman
    Howard, Heidi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Centre for Research Ethics and Bioethics.
    Legislation on direct-to-consumer genetic testing in seven European countries.2012In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 20, no 7, p. 715-21Article in journal (Refereed)
    Abstract [en]

    An increasing number of private companies are now offering direct-to-consumer (DTC) genetic testing services. Although a lot of attention has been devoted to the regulatory framework of DTC genetic testing services in the USA, only limited information about the regulatory framework in Europe is available. We will report on the situation with regard to the national legislation on DTC genetic testing in seven European countries (Belgium, the Netherlands, Switzerland, Portugal, France, Germany, the United Kingdom). The paper will address whether these countries have legislation that specifically address the issue of DTC genetic testing or have relevant laws that is pertinent to the regulatory control of these services in their countries. The findings show that France, Germany, Portugal and Switzerland have specific legislation that defines that genetic tests can only be carried out by a medical doctor after the provision of sufficient information concerning the nature, meaning and consequences of the genetic test and after the consent of the person concerned. In the Netherlands, some DTC genetic tests could fall under legislation that provides the Minister the right to refuse to provide a license to operate if a test is scientifically unsound, not in accordance with the professional medical practice standards or if the expected benefit is not in balance with the (potential) health risks. Belgium and the United Kingdom allow the provision of DTC genetic tests.

  • 6.
    Carrieri, Daniele
    et al.
    Univ Exeter, Egenis, England.
    Howard, Heidi Carmen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Centre for Research Ethics and Bioethics.
    Benjamin, Caroline
    Univ Cent Lancashire UCLan, Sch Community Hlth & Midwifery, Preston, Lancs, England;Liverpool Womens NHS Hosp Trust, Merseyside & Cheshire Clin Genet Serv, Liverpool, Merseyside, England.
    Clarke, Angus J.
    Cardiff Univ, Sch Med, Cardiff, S Glam, Wales.
    Dheensa, Sandi
    Univ Southampton, Fac Med, Clin Eth & Law, Southampton, Hants, England.
    Doheny, Shane
    Cardiff Univ, Sch Med, Cardiff, S Glam, Wales.
    Hawkins, Naomi
    Univ Exeter, Law Sch, Exeter, Devon, England.
    Halbersma-Konings, Tanya F.
    Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands.
    Jackson, Leigh
    Univ Exeter, Sch Med, Egenis, England.
    Kayserili, Hulya
    Koc Univ KUSoM, Sch Med, Med Genet Dept, Istanbul, Turkey.
    Kelly, Susan E.
    Univ Exeter, Egenis, England.
    Lucassen, Anneke M.
    Univ Southampton, Fac Med, Clin Eth & Law, Southampton, Hants, England;Univ Hosp Southampton NHS Fdn Trust, Wessex Clin Genet Serv, Southampton, Hants, England.
    Mendes, Alvaro
    Univ Porto, I3S, IBMC Inst Mol & Cell Biol, UnIGENe, Porto, Portugal;Univ Porto, I3S, IBMC Inst Mol & Cell Biol, CGPP Ctr Predict & Prevent Genet, Porto, Portugal.
    Rial-Sebbag, Emmanuelle
    Univ Paul Sabatier Toulouse III, INSERM, UMR 1027, Toulouse, France.
    Stefansdottir, Vigdis
    Natl Univ Hosp Iceland, Dept Genet & Mol Med, Landspitali, Reykjavik, Iceland.
    Turnpenny, Peter D.
    Royal Devon & Exeter NHS Fdn Trust, Clin Genet, Exeter, Devon, England.
    van El, Carla G.
    Vrije Univ, Amsterdam UMC, Sect Community Genet, Dept Clin Genet, Amsterdam, Netherlands;Vrije Univ, Amsterdam UMC, Amsterdam Publ Hlth Res Inst, Amsterdam, Netherlands.
    van Langen, Irene M.
    Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands.
    Cornel, Martina C.
    Vrije Univ, Amsterdam UMC, Sect Community Genet, Dept Clin Genet, Amsterdam, Netherlands;Vrije Univ, Amsterdam UMC, Amsterdam Publ Hlth Res Inst, Amsterdam, Netherlands.
    Forzano, Francesca
    Guys & St Thomas NHS Fdn Trust, Clin Genet Dept, London, ON, Canada.
    Recontacting patients in clinical genetics services: recommendations of the European Society of Human Genetics2019In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 27, no 2, p. 169-182Article in journal (Refereed)
    Abstract [en]

    Technological advances have increased the availability of genomic data in research and the clinic. If, over time, interpretation of the significance of the data changes, or new information becomes available, the question arises as to whether recontacting the patient and/or family is indicated. The Public and Professional Policy Committee of the European Society of Human Genetics (ESHG), together with research groups from the UK and the Netherlands, developed recommendations on recontacting which, after public consultation, have been endorsed by ESHG Board. In clinical genetics, recontacting for updating patients with new, clinically significant information related to their diagnosis or previous genetic testing may be justifiable and, where possible, desirable. Consensus about the type of information that should trigger recontacting converges around its clinical and personal utility. The organization of recontacting procedures and policies in current health care systems is challenging. It should be sustainable, commensurate with previously obtained consent, and a shared responsibility between healthcare providers, laboratories, patients, and other stakeholders. Optimal use of the limited clinical resources currently available is needed. Allocation of dedicated resources for recontacting should be considered. Finally, there is a need for more evidence, including economic and utility of information for people, to inform which strategies provide the most cost-effective use of healthcare resources for recontacting.

  • 7.
    Carrieri, Daniele
    et al.
    Univ Exeter, Egenis, Exeter, Devon, England.
    Howard, Heidi Carmen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Centre for Research Ethics and Bioethics. Wellcome Genome Campus, Soc & Eth Res, Connecting Sci, Cambridge, England.
    Clarke, Angus J.
    Cardiff Univ, Sch Med, Cardiff, S Glam, Wales.
    Stefansdottir, Vigdis
    Landspitali Natl Univ Hosp Iceland, Dept Genet & Mol Med, Reykjavik, Iceland.
    Cornel, Martina C.
    Vrije Univ Amsterdam, Amsterdam Publ Hlth Res Inst, Sect Community Genet, Amsterdam UMC,Dept Clin Genet, Amsterdam, Netherlands.
    van El, Carla G.
    Vrije Univ Amsterdam, Amsterdam Publ Hlth Res Inst, Sect Community Genet, Amsterdam UMC,Dept Clin Genet, Amsterdam, Netherlands.
    Forzano, Francesca
    Guys & St Thomas NHS Fdn Trust, Clin Genet Dept, London, England.
    Reply to Bombard and Mighton2019In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 27, no 4, p. 507-508Article in journal (Other academic)
  • 8.
    Cornel, Martina C.
    et al.
    Vrije Univ Amsterdam, Amsterdam UMC, Clin Genet & Amsterdam Publ Hlth Res Inst, Sect Community Genet, Boelelaan 1117, Amsterdam, Netherlands.
    Howard, Heidi Carmen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Centre for Research Ethics and Bioethics.
    Lim, Daniel
    Kirkland & Ellis Int LLP, London, England.
    Bonham, Vence L.
    NHGRI, Social & Behav Res Branch, NIH, Bethesda, MD 20892 USA.
    Wartiovaara, Kirmo
    Univ Helsinki, Helsinki Univ Hosp, Clin Genet, Meilahdentie 2, Helsinki 00290, Finland.
    Moving towards a cure in genetics: what is needed to bring somatic gene therapy to the clinic?2019In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 27, no 3, p. 484-487Article in journal (Refereed)
    Abstract [en]

    Clinical trials using somatic gene editing (e.g., CRISPR-Cas9) have started in Europe and the United States and may provide safe and effective treatment and cure, not only for cancers but also for some monogenic conditions. In a workshop at the 2018 European Human Genetics Conference, the challenges of bringing somatic gene editing therapies to the clinic were discussed. The regulatory process needs to be considered early in the clinical development pathway to produce the data necessary to support the approval by the European Medicines Agency. The roles and responsibilities for geneticists may include counselling to explain the treatment possibilities and safety interpretation.

  • 9.
    Danielsson, Marcus
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Halvardson, Jonatan
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Davies, Hanna
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Moghadam, Behrooz Torabi
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Mattisson, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Rychlicka-Buniowska, Edyta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab. Faculty of Pharmacy and 3P Medicine Laboratory, International Research Agendas Programme, Medical University of Gdańsk, Gdańsk, Poland.
    Jaszczyński, Janusz
    Department of Urology, Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, Kraków Branch, Kraków, Poland.
    Heintz, Julia
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Giedraitis, Vilmantas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Dumanski, Jan P.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Faculty of Pharmacy and 3P Medicine Laboratory, International Research Agendas Programme, Medical University of Gdańsk, Gdańsk, Poland.
    Forsberg, Lars A.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Beijer Laboratory of Genome Research, Uppsala, Sweden.
    Longitudinal changes in the frequency of mosaic chromosome Y loss in peripheral blood cells of aging men varies profoundly between individuals2019In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438Article in journal (Refereed)
    Abstract [en]

    Mosaic loss of chromosome Y (LOY) is the most common somatic genetic aberration and is associated with increased risk for all-cause mortality, various forms of cancer and Alzheimer's disease, as well as other common human diseases. By tracking LOY frequencies in subjects from which blood samples have been serially collected up to five times during up to 22 years, we observed a pronounced intra-individual variation of changes in the frequency of LOY within individual men over time. We observed that in some individuals the frequency of LOY in blood clearly progressed over time and that in other men, the frequency was constant or showed other types of longitudinal development. The predominant method used for estimating LOY is calculation of the median Log R Ratio of probes located in the male specific part of chromosome Y (mLRRY) from intensity data generated by SNP-arrays, which is difficult to interpret due to its logarithmic and inversed scale. We present here a formula to transform mLRRY-values to percentage of LOY that is a more comprehensible unit. The formula was derived using measurements of LOY from matched samples analysed using SNP-array, whole genome sequencing and a new AMELX/AMELY-based assay for droplet digital PCR. The methods described could be applied for analyses of the vast amount of SNP-array data already generated in the scientific community, allowing further discoveries of LOY associated diseases and outcomes.

  • 10. De Wert, G.
    et al.
    Heindryckx, B.
    Pennings, G.
    Clarke, A.
    Eichenlaub-Ritter, U.
    van El, Carla G.
    Forzano, F.
    Goddijn, M.
    Howard, Heidi C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Centre for Research Ethics and Bioethics.
    Radojkovic, D.
    Rial-Sebbag, E.
    Dondorp, W.
    Tarlatzis, B. C.
    Cornel, M. C.
    Responsible innovation in human germline gene editing: Background document to the recommendations of ESHG and ESHRE2018In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 26, no 4, p. 450-470Article in journal (Refereed)
    Abstract [en]

    Technological developments in gene editing raise high expectations for clinical applications, including editing of the germline. The European Society of Human Reproduction and Embryology (ESHRE) and the European Society of Human Genetics (ESHG) together developed a Background document and Recommendations to inform and stimulate ongoing societal debates. This document provides the background to the Recommendations. Germline gene editing is currently not allowed in many countries. This makes clinical applications in these countries impossible now, even if germline gene editing would become safe and effective. What were the arguments behind this legislation, and are they still convincing? If a technique could help to avoid serious genetic disorders, in a safe and effective way, would this be a reason to reconsider earlier standpoints? This Background document summarizes the scientific developments and expectations regarding germline gene editing, legal regulations at the European level, and ethics for three different settings (basic research, preclinical research and clinical applications). In ethical terms, we argue that the deontological objections (e.g., gene editing goes against nature) do not seem convincing while consequentialist objections (e.g., safety for the children thus conceived and following generations) require research, not all of which is allowed in the current legal situation in European countries. Development of this Background document and Recommendations reflects the responsibility to help society understand and debate the full range of possible implications of the new technologies, and to contribute to regulations that are adapted to the dynamics of the field while taking account of ethical considerations and societal concerns.

  • 11.
    de Wert, Guido
    et al.
    Department of Health, Ethics and Society, Research Institutes GROW and CAPHRI, Fac. of Health, Medicine and the Life Sciences, Maastricht University, Maastricht, The Netherlands.
    Pennings, Guido
    Bioethics Institute Ghent, Department of Philosophy and Moral Science, Ghent University, Ghent, Belgium.
    Clarke, Angus
    School of Medicine, Cardiff University, Cardiff, UK.
    Eichenlaub-Ritter, Ursula
    Institute of Gene Technology/Microbiology, Faculty of Biology, University of Bielefeld, Bielefeld, Germany.
    van El, Carla G.
    Department of Clinical Genetics, Section Community Genetics, and Amsterdam Public Health research institute, VU University Medical Center, Amsterdam, The Netherlands.
    Forzano, Francesca
    Clinical Genetics Department, Guy’s Hospital, Guy’s and St Thomas’ NHS Foundation Trust, London, UK.
    Goddijn, Mariëtte
    Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Academic Medical Center, Amsterdam-Zuidoost, The Netherlands.
    Heindryckx, Björn
    Ghent-Fertility and Stem cell Team (G-FaST), Department for Reproductive Medicine, Ghent University Hospital, Ghent, Belgium.
    Howard, Heidi C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Centre for Research Ethics and Bioethics.
    Radojkovic, Dragica
    Laboratory for Molecular Biology, Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade, Serbia.
    Rial-Sebbag, Emmanuelle
    University Paul Sabatier Toulouse, Toulouse, France.
    Tarlatzis, Basil C.
    1st Department of Obstetrics & Gynecology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece.
    Cornel, Martina C.
    Department of Clinical Genetics, Section Community Genetics, and Amsterdam Public Health research institute, VU University Medical Center, Amsterdam, The Netherlands.
    Human germline gene editing: Recommendations of ESHG and ESHRE2018In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 26, no 4, p. 445-449Article in journal (Refereed)
    Abstract [en]

    Technological developments in gene editing raise high expectations for clinical applications, first of all for somatic gene editing but in theory also for germline gene editing (GLGE). GLGE is currently not allowed in many countries. This makes clinical applications in these countries impossible now, even if GLGE would become safe and effective. What were the arguments behind this legislation, and are they still convincing? If a technique can help to avoid serious genetic disorders, in a safe and effective way, would this be a reason to reconsider earlier standpoints? The European Society of Human Reproduction and Embryology (ESHRE) and the European Society of Human Genetics (ESHG) together developed a Background document and Recommendations to inform and stimulate ongoing societal debates. After consulting its membership and experts, this final version of the Recommendations was endorsed by the Executive Committee and the Board of the respective Societies in May 2017. Taking account of ethical arguments, we argue that both basic and pre-clinical research regarding GLGE can be justified, with conditions. Furthermore, while clinical GLGE would be totally premature, it might become a responsible intervention in the future, but only after adequate pre-clinical research. Safety of the child and future generations is a major concern. Future discussions must also address priorities among reproductive and potential non-reproductive alternatives, such as PGD and somatic editing, if that would be safe and successful. The prohibition of human germline modification, however, needs renewed discussion among relevant stakeholders, including the general public and legislators.

  • 12. Demirkan, Ayse
    et al.
    Amin, Najaf
    Isaacs, Aaron
    Jarvelin, Marjo-Riitta
    Whitfield, John B.
    Wichmann, Heinz-Erich
    Kyvik, Kirsten Ohm
    Rudan, Igor
    Gieger, Christian
    Hicks, Andrew A.
    Johansson, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Hottenga, Jouke-Jan
    Smith, Johannes J.
    Wild, Sarah H.
    Pedersen, Nancy L.
    Willemsen, Gonneke
    Mangino, Massimo
    Hayward, Caroline
    Uitterlinden, Andre G.
    Hofman, Albert
    Witteman, Jacqueline
    Montgomery, Grant W.
    Pietilainen, Kirsi H.
    Rantanen, Taina
    Kaprio, Jaakko
    Doering, Angela
    Pramstaller, Peter P.
    Gyllensten, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    de Geus, Eco J. C.
    Penninx, Brenda W.
    Wilson, James F.
    Rivadeneria, Fernando
    Magnusson, Patrik K. E.
    Boomsma, Dorret I.
    Spector, Tim
    Campbell, Harry
    Hoehne, Birgit
    Martin, Nicholas G.
    Oostra, Ben A.
    McCarthy, Mark
    Peltonen-Palotie, Leena
    Aulchenko, Yurii
    Visscher, Peter M.
    Ripatti, Samuli
    Janssens, A. Cecile J. W.
    van Duijn, Cornelia M.
    Genetic architecture of circulating lipid levels2011In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 19, no 7, p. 813-819Article in journal (Refereed)
    Abstract [en]

    Serum concentrations of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (TGs) and total cholesterol (TC) are important heritable risk factors for cardiovascular disease. Although genome-wide association studies (GWASs) of circulating lipid levels have identified numerous loci, a substantial portion of the heritability of these traits remains unexplained. Evidence of unexplained genetic variance can be detected by combining multiple independent markers into additive genetic risk scores. Such polygenic scores, constructed using results from the ENGAGE Consortium GWAS on serum lipids, were applied to predict lipid levels in an independent population-based study, the Rotterdam Study-II (RS-II). We additionally tested for evidence of a shared genetic basis for different lipid phenotypes. Finally, the polygenic score approach was used to identify an alternative genome-wide significance threshold before pathway analysis and those results were compared with those based on the classical genome-wide significance threshold. Our study provides evidence suggesting that many loci influencing circulating lipid levels remain undiscovered. Cross-prediction models suggested a small overlap between the polygenic backgrounds involved in determining LDL-C, HDL-C and TG levels. Pathway analysis utilizing the best polygenic score for TC uncovered extra information compared with using only genome-wide significant loci. These results suggest that the genetic architecture of circulating lipids involves a number of undiscovered variants with very small effects, and that increasing GWAS sample sizes will enable the identification of novel variants that regulate lipid levels.

  • 13.
    Di Stazio, Mariateresa
    et al.
    Univ Trieste, Dept Med Surg & Hlth Sci, Trieste, Italy.
    Collesi, Chiara
    Univ Trieste, Dept Med Surg & Hlth Sci, Trieste, Italy;Int Ctr Genet Engn & Biotechnol ICGEB, Mol Med Lab, I-34149 Trieste, Italy.
    Vozzi, Diego
    IRCCS Burlo Garofolo, Med Genet, Trieste, Italy;Qatar Fdn, Sidra Med & Res Ctr, Div Expt Genet, POB 26999, Doha, Qatar.
    Liu, Wei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Myers, Mike
    Int Ctr Genet Engn & Biotechnol ICGEB, Mol Med Lab, I-34149 Trieste, Italy.
    Morgan, Anna
    Univ Trieste, Dept Med Surg & Hlth Sci, Trieste, Italy.
    D' Adamo, Pio Adamo
    Univ Trieste, Dept Med Surg & Hlth Sci, Trieste, Italy.
    Girotto, Giorgia
    Univ Trieste, Dept Med Surg & Hlth Sci, Trieste, Italy.
    Rubinato, Elisa
    Univ Trieste, Dept Med Surg & Hlth Sci, Trieste, Italy.
    Giacca, Mauro
    Univ Trieste, Dept Med Surg & Hlth Sci, Trieste, Italy;Int Ctr Genet Engn & Biotechnol ICGEB, Mol Med Lab, I-34149 Trieste, Italy.
    Gasparini, Paolo
    Univ Trieste, Dept Med Surg & Hlth Sci, Trieste, Italy.
    TBL1Y: a new gene involved in syndromic hearing loss2019In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 27, no 3, p. 466-474Article in journal (Refereed)
    Abstract [en]

    Hereditary hearing loss (HHL) is an extremely heterogeneous disorder with autosomal dominant, recessive, and X-linked forms. Here, we described an Italian pedigree affected by HHL but also prostate hyperplasia and increased ratio of the free/ total PSA levels, with the unusual and extremely rare Y-linked pattern of inheritance. Using exome sequencing we found a missense variant (r.206A>T leading to p.Asp69Val) in the TBL1Y gene. TBL1Y is homologous of TBL1X, whose partial deletion has described to be involved in X-linked hearing loss. Here, we demonstrate that it has a restricted expression in adult human cochlea and prostate and the variant identified induces a lower protein stability caused by misfolded mutated protein that impairs its cellular function. These findings indicate that TBL1Y could be considered a novel candidate for HHL.

  • 14.
    Dondorp, Wybo
    et al.
    Maastricht Univ, Res Sch CAPHRI, Dept Hlth Eth & Soc, NL-6200 MD Maastricht, Netherlands.;Maastricht Univ, Res Sch GROW, Dept Hlth Eth & Soc, NL-6200 MD Maastricht, Netherlands..
    de Wert, Guido
    Maastricht Univ, Res Sch CAPHRI, Dept Hlth Eth & Soc, NL-6200 MD Maastricht, Netherlands.;Maastricht Univ, Res Sch GROW, Dept Hlth Eth & Soc, NL-6200 MD Maastricht, Netherlands..
    Bombard, Yvonne
    Univ Toronto, Fac Med, Li Ka Shing Knowledge Inst, St Michaels Hosp, Toronto, ON, Canada.;Univ Toronto, Fac Med, Inst Hlth Policy Management & Evaluat, Toronto, ON, Canada..
    Bianchi, Diana W.
    Tufts Univ, Sch Med, Dept Pediat Obstet & Gynecol, Boston, MA 02111 USA..
    Bergmann, Carsten
    Ctr Human Genet Biosci, Ingelheim, Germany.;Univ Freiburg, Med Ctr, Dept Med, D-79106 Freiburg, Germany..
    Borry, Pascal
    Leuven Univ, Ctr Biomed Eth & Law, Dept Publ Hlth & Primary Care, Louvain, Belgium..
    Chitty, Lyn S.
    Great Ormond St Hosp & UCLH NHS Fdn Trusts, UCL Inst Child Hlth, Clin & Mol Genet Unit, London, England..
    Fellmann, Florence
    Univ Lausanne Hosp, Serv Med Genet, Lausanne, Switzerland..
    Forzano, Francesca
    Osped Galliera, Med Genet Unit, Genoa, Italy..
    Hall, Alison
    PHG Fdn, Cambridge, England..
    Henneman, Lidewij
    Vrije Univ Amsterdam Med Ctr, Sect Community Genet, Dept Clin Genet, Amsterdam, Netherlands.;Vrije Univ Amsterdam Med Ctr, EMGO Inst Hlth & Care Res, Amsterdam, Netherlands..
    Howard, Heidi C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Centre for Research Ethics and Bioethics.
    Lucassen, Anneke
    Univ Southampton, Dept Clin Eth & Law CELS, Southampton, Hants, England.;Wessex Clin Genet Serv, Southampton, Hants, England..
    Ormond, Kelly
    Stanford Univ, Sch Med, Dept Genet, Stanford, CA USA.;Stanford Univ, Sch Med, Stanford Ctr Biomed Eth, Stanford, CA USA..
    Peterlin, Borut
    Univ Ljubljana, Med Ctr, Clin Inst Med Genet, Ljubljana 61000, Slovenia..
    Radojkovic, Dragica
    Univ Belgrade, IMGGE, Lab Mol Biol, Belgrade, Serbia..
    Rogowski, Wolf
    Helmholtz Zentrum, Deutsch Forschungszentrum Gesundheit & Umwelt, Munich, Germany..
    Soller, Maria
    Lund Univ, Div Clin Genet, Lund, Sweden.;Univ Lund Hosp, Reg Labs Reg Skane, S-22185 Lund, Sweden..
    Tibben, Aad
    Leiden Univ, Med Ctr, Dept Clin Genet, Leiden, Netherlands..
    Tranebjaerg, Lisbeth
    Bispebjerg Hosp, Rigshosp, Dept Audiol, Copenhagen, Denmark.;Univ Copenhagen, Kennedy Ctr, Dept Clin Genet, Copenhagen, Denmark.;Univ Copenhagen, ICMM, Inst Cellular & Mol Med, Copenhagen, Denmark..
    van El, Carla G.
    Vrije Univ Amsterdam Med Ctr, Sect Community Genet, Dept Clin Genet, Amsterdam, Netherlands.;Vrije Univ Amsterdam Med Ctr, EMGO Inst Hlth & Care Res, Amsterdam, Netherlands..
    Cornel, Martina C.
    Vrije Univ Amsterdam Med Ctr, Sect Community Genet, Dept Clin Genet, Amsterdam, Netherlands.;Vrije Univ Amsterdam Med Ctr, EMGO Inst Hlth & Care Res, Amsterdam, Netherlands..
    Non-invasive prenatal testing for aneuploidy and beyond: challenges of responsible innovation in prenatal screening2015In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 23, no 11, p. 1438-1450Article in journal (Refereed)
    Abstract [en]

    This paper contains a joint ESHG/ASHG position document with recommendations regarding responsible innovation in prenatal screening with non-invasive prenatal testing (NIPT). By virtue of its greater accuracy and safety with respect to prenatal screening for common autosomal aneuploidies, NIPT has the potential of helping the practice better achieve its aim of facilitating autonomous reproductive choices, provided that balanced pretest information and non-directive counseling are available as part of the screening offer. Depending on the health-care setting, different scenarios for NIPT-based screening for common autosomal aneuploidies are possible. The trade-offs involved in these scenarios should be assessed in light of the aim of screening, the balance of benefits and burdens for pregnant women and their partners and considerations of cost-effectiveness and justice. With improving screening technologies and decreasing costs of sequencing and analysis, it will become possible in the near future to significantly expand the scope of prenatal screening beyond common autosomal aneuploidies. Commercial providers have already begun expanding their tests to include sex-chromosomal abnormalities and microdeletions. However, multiple false positives may undermine the main achievement of NIPT in the context of prenatal screening: the significant reduction of the invasive testing rate. This document argues for a cautious expansion of the scope of prenatal screening to serious congenital and childhood disorders, only following sound validation studies and a comprehensive evaluation of all relevant aspects. A further core message of this document is that in countries where prenatal screening is offered as a public health programme, governments and public health authorities should adopt an active role to ensure the responsible innovation of prenatal screening on the basis of ethical principles. Crucial elements are the quality of the screening process as a whole (including non-laboratory aspects such as information and counseling), education of professionals, systematic evaluation of all aspects of prenatal screening, development of better evaluation tools in the light of the aim of the practice, accountability to all stakeholders including children born from screened pregnancies and persons living with the conditions targeted in prenatal screening and promotion of equity of access.

  • 15. Eatough, Virginia
    et al.
    Santini, Helen
    Eiser, Christine
    Goller, Marie-Louise
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Krysa, Wioletta
    de Nicola, 'Annunziata'
    Paduanello, Matteo
    Petrollini, Martina
    Rakowicz, Maria
    Squitieri, Ferdinando
    Tibben, Aad
    Weille, Katie Lee
    Landwehrmeyer, Bernhard
    Quarrell, Oliver
    Smith, Jonathan A.
    The personal experience of parenting a child with Juvenile Huntington's Disease: perceptions across Europe2013In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 21, no 10, p. 1042-1048Article in journal (Refereed)
    Abstract [en]

    The study reported here presents a detailed description of what it is like to parent a child with juvenile Huntington's disease in families across four European countries. Its primary aim was to develop and extend findings from a previous UK study. The study recruited parents from four European countries: Holland, Italy, Poland and Sweden,. A secondary aim was to see the extent to which the findings from the UK study were repeated across Europe and the degree of commonality or divergence across the different countries. Fourteen parents who were the primary caregiver took part in a semistructured interview. These were analyzed using an established qualitative methodology, interpretative phenomenological analysis. Five analytic themes were derived from the analysis: the early signs of something wrong; parental understanding of juvenile Huntington's disease; living with the disease; other people's knowledge and understanding; and need for support. These are discussed in light of the considerable convergence between the experiences of families in the United Kingdom and elsewhere in Europe.

  • 16.
    Entesarian, Miriam
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Dahlqvist, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Shashi, Vandana
    Stanley, Christy S.
    Falahat, Babak
    Reardon, William
    Dahl, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    FGF10 missense mutations in aplasia of lacrimal and salivary glands (ALSG)2007In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 15, no 3, p. 379-382Article in journal (Refereed)
    Abstract [en]

    Aplasia of lacrimal and salivary glands (ALSG) is an autosomal dominant congenital anomaly characterized by aplasia, atresia or hypoplasia of the lacrimal and salivary systems. Affected individuals present with irritable eyes and dryness of the mouth with variable expressivity. Mutations in FGF10 were recently described in ALSG and in lacrimo-auriculo-dento-digital (LADD) syndrome which are overlapping clinical entities. We present here two families with ALSG associated with missense mutations (R80S and G138E, respectively) affecting highly conserved residues in FGF10. The clinical features of these patients further broaden the knowledge of FGF10-related phenotypes.

  • 17.
    Eriksson, Stefan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Centre for Research Ethics and Bioethics.
    Helgesson, Gert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Potential harms, anonymization, and the right to withdraw consent to biobank research2005In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 13, no 9, p. 1071-1076Article in journal (Refereed)
    Abstract [en]

    This paper discusses the potential harms involved in biobank research and how ethical review, informed consent, withdrawals, and anonymization of samples should be handled in the light of these harms. There is less risk involved in biobank research than in human subject research; it should therefore be treated differently. In our view, anonymization should not be an automatically permissible response to requests for withdrawal. Nor should a request for withdrawal necessarily stop research on identifiable samples. Apart from not being particularly appropriate for protecting the interests of individuals, anonymization of samples has a negative impact on research. We suggest that the current view on withdrawal from research, supported by the Declaration of Helsinki and subsequent ethical guidelines, be abandoned in the context of biobank research and be replaced by an approach inspired by the Nuremberg Code. This approach requires those wishing to withdraw their samples from research to present sufficient reason for doing so. Our interpretation of 'sufficient reason' includes all those involving genuine, deeply felt concerns that are not based on misconceptions. Still, this underlines the fact that we all share a responsibility for health research and that no one should take withdrawal from biobank research lightly.

  • 18. Everett, Kate V.
    et al.
    Chioza, Barry
    Aicardi, Jean
    Aschauer, Harald
    Brouwer, Oebele
    Callenbach, Petra
    Covanis, Athanasios
    Dulac, Olivier
    Eeg-Olofsson, Orvar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Feucht, Martha
    Friis, Mogens
    Goutieres, Françoise
    Guerrini, Renzo
    Heils, Armin
    Kjeldsen, Marianne
    Lehesjoki, Anna-Elina
    Makoff, Andrew
    Nabbout, Rima
    Olsson, Ingrid
    Sander, Thomas
    Sirén, Auli
    McKeigue, Paul
    Robinson, Robert
    Taske, Nichole
    Rees, Michele
    Gardiner, Mark
    Linkage and association analysis of CACNG3 in childhood absence epilepsy2007In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 15, no 4, p. 463-472Article in journal (Refereed)
    Abstract [en]

    Childhood absence epilepsy (CAE) is an idiopathic generalised epilepsy characterised by absence seizures manifested by transitory loss of awareness with 2.5-4 Hz spike-wave complexes on ictal EEG. A genetic component to aetiology is established but the mechanism of inheritance and the genes involved are not fully defined. Available evidence suggests that genes encoding brain expressed voltage-gated calcium channels, including CACNG3 on chromosome 16p12-p13.1, may represent susceptibility loci for CAE. The aim of this work was to further evaluate CACNG3 as a susceptibility locus by linkage and association analysis. Assuming locus heterogeneity, a significant HLOD score (HLOD = 3.54, alpha = 0.62) was obtained for markers encompassing CACNG3 in 65 nuclear families with a proband with CAE. The maximum non-parametric linkage score was 2.87 (P < 0.002). Re-sequencing of the coding exons in 59 patients did not identify any putative causal variants. A linkage disequilibrium (LD) map of CACNG3 was constructed using 23 single nucleotide polymorphisms (SNPs). Transmission disequilibrium was sought using individual SNPs and SNP-based haplotypes with the pedigree disequilibrium test in 217 CAE trios and the 65 nuclear pedigrees. Evidence for transmission disequilibrium (P < or = 0.01) was found for SNPs within a approximately 35 kb region of high LD encompassing the 5'UTR, exon 1 and part of intron 1 of CACNG3. Re-sequencing of this interval was undertaken in 24 affected individuals. Seventy-two variants were identified: 45 upstream; two 5'UTR; and 25 intronic SNPs. No coding sequence variants were identified, although four variants are predicted to affect exonic splicing. This evidence supports CACNG3 as a susceptibility locus in a subset of CAE patients.

  • 19. Fadista, João
    et al.
    Lund, Marie
    Skotte, Line
    Geller, Frank
    Nandakumar, Priyanka
    Chatterjee, Sumantra
    Matsson, Hans
    Granström, Anna Löf
    Wester, Tomas
    Salo, Perttu
    Virtanen, Valtter
    Carstensen, Lisbeth
    Bybjerg-Grauholm, Jonas
    Hougaard, David Michael
    Pakarinen, Mikko
    Perola, Markus
    Nordenskjöld, Agneta
    Chakravarti, Aravinda
    Melbye, Mads
    Feenstra, Bjarke
    Genome-wide association study of Hirschsprung disease detects a novel low-frequency variant at the RET locus.2018In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 26, no 4, p. 561-569Article in journal (Refereed)
    Abstract [en]

    ; 322 cases and 4893 controls). The conditional signal was, however, not replicated in two HSCR cohorts from USA and Finland, leading to the hypothesis that rs144432435 tags a rare haplotype present in Denmark and Sweden. Using the genome-wide complex trait analysis method, we estimated the SNP heritability of HSCR to be 88%, close to estimates based on classical family studies. Moreover, by using Lasso (least absolute shrinkage and selection operator) regression we were able to construct a genetic HSCR predictor with a area under the receiver operator characteristics curve of 76% in an independent validation set. In conclusion, we combined the largest collection of sporadic Hirschsprung cases to date (586 cases) to further elucidate HSCR's genetic architecture.

  • 20.
    Farias, Fabiana H. G.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, 63110, USA.
    Dahlqvist, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Kozyrev, Sergey V.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Leonard, Dag
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Wilbe, Maria
    Department of Animal Breeding and Genetics, Swedish University of Agricultural Sciences (SLU), Box 7023, SE-750 07, Uppsala, Sweden.
    Abramov, Sergei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, 420008, Russia.
    Alexsson, Andrei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Pielberg, Gerli
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hansson-Hamlin, Helene
    Department of Clinical Sciences, Swedish University of Agricultural Sciences (SLU), Box 7054, SE-750 07, Uppsala, Sweden.
    Andersson, Göran
    Department of Animal Breeding and Genetics, Swedish University of Agricultural Sciences (SLU), Box 7023, SE-750 07, Uppsala, Sweden.
    Tandre, Karolina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Bengtsson, Anders A
    Department of Clinical Sciences Lund, Lund University, Skane University Hospital, SE-221 00, Lund, Sweden.
    Sjöwall, Christopher
    Department of Clinical and Experimental Medicine, Rheumatology/Division of Neuro and Inflammation Sciences, Linköping University, SE-581 85, Linköping, Sweden.
    Svenungsson, Elisabet
    Rheumatology Unit, Department of Medicine, Solna, Karolinska Institutet, Karolinska University Hospital, SE-171 76, Stockholm, Sweden.
    Gunnarsson, Iva
    Rheumatology Unit, Department of Medicine, Solna, Karolinska Institutet, Karolinska University Hospital, SE-171 76, Stockholm, Sweden.
    Rantapää-Dahlqvist, Solbritt
    Department of Public Health and Clinical Medicine/Rheumatology, Umeå University, SE-901 85, Umeå, Sweden.
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Sandling, Johanna K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Eloranta, Maija-Leena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Broad Institute, Cambridge, 7 Cambridge Center, Cambridge, MA, 02142, USA.
    A rare regulatory variant in the MEF2D gene affects gene regulation and splicing and is associated with a SLE sub-phenotype in Swedish cohorts2019In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 27, p. 432-441Article in journal (Refereed)
    Abstract [en]

    Systemic lupus erythematosus (SLE) is an autoimmune disorder with heterogeneous clinical presentation and complex etiology involving the interplay between genetic, epigenetic, environmental and hormonal factors. Many common SNPs identified by genome wide-association studies (GWAS) explain only a small part of the disease heritability suggesting the contribution from rare genetic variants, undetectable in GWAS, and complex epistatic interactions. Using targeted re-sequencing of coding and conserved regulatory regions within and around 215 candidate genes selected on the basis of their known role in autoimmunity and genes associated with canine immune-mediated diseases, we identified a rare regulatory variant rs200395694:G > T located in intron 4 of the MEF2D gene encoding the myocyte-specific enhancer factor 2D transcription factor and associated with SLE in Swedish cohorts (504 SLE patients and 839 healthy controls, p = 0.014, CI = 1.1-10). Fisher's exact test revealed an association between the genetic variant and a triad of disease manifestations including Raynaud, anti-U1-ribonucleoprotein (anti-RNP), and anti-Smith (anti-Sm) antibodies (p = 0.00037) among the patients. The DNA-binding activity of the allele was further studied by EMSA, reporter assays, and minigenes. The region has properties of an active cell-specific enhancer, differentially affected by the alleles of rs200395694:G > T. In addition, the risk allele exerts an inhibitory effect on the splicing of the alternative tissue-specific isoform, and thus may modify the target gene set regulated by this isoform. These findings emphasize the potential of dissecting traits of complex diseases and correlating them with rare risk alleles with strong biological effects.

  • 21.
    Fellmann, Florence
    et al.
    Univ Lausanne, ColLab, Lausanne, Switzerland.
    van El, Carla G.
    Vrije Univ Amsterdam, Amsterdam UMC, Dept Clin Genet, Sect Community Genet, Amsterdam, Netherlands;Vrije Univ Amsterdam, Amsterdam UMC, Amsterdam Publ Hlth Res Inst, Amsterdam, Netherlands.
    Charron, Philippe
    Sorbonne Univ, Hop Pitie Salpetriere, AP HP, Referral Ctr Inherited Cardiac Dis,ICAN,INSERM,UM, Paris, France;European Reference Network Rare & Low Prevalence, Amsterdam, Netherlands.
    Michaud, Katarzyna
    Lausanne Univ Hosp, Univ Ctr Legal Med Lausanne Geneva, Lausanne, Switzerland;Univ Lausanne, Lausanne, Switzerland.
    Howard, Heidi C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Centre for Research Ethics and Bioethics.
    Boers, Sarah N.
    Univ Med Ctr Utrecht, Dept Med Humanities, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands.
    Clarke, Angus J.
    Cardiff Univ, Inst Med Genet, Sch Med, Div Canc & Genet, Cardiff, S Glam, Wales.
    Duguet, Anne-Marie
    Univ Paul Sabatier Toulouse III, INSERM, UMR 1027, Toulouse, France.
    Forzano, Francesca
    Guys & St Thomas NHS Fdn Trust, Dept Clin Genet, London, England.
    Kauferstein, Silke
    Goethe Univ Frankfurt, Inst Legal Med, Frankfurt, Germany.
    Kayserili, Hulya
    Koc Univ, Sch Med KUSoM, Dept Med Genet, Istanbul, Turkey.
    Lucassen, Anneke
    Univ Southampton, Fac Med, Clin Eth & Law, Southampton, Hants, England;Univ Hosp Southampton NHS Fdn Trust, Clin Genet Serv, Southampton, Hants, England.
    Mendes, Alvaro
    Univ Porto, I3S, IBMC Inst Mol & Cell Biol, UnIGENe, Porto, Portugal;Univ Porto, I3S, IBMC Inst Mol & Cell Biol, CGPP Ctr Predict & Prevent Genet, Porto, Portugal.
    Patch, Christine
    Kings Coll London, Florence Nightingale Fac, Nursing & Midwifery Palliat Care, London, England;Queen Mary Univ London, Genom England, London, England.
    Radojkovic, Dragica
    Univ Belgrade, IMGGE, Belgrade, Serbia.
    Rial-Sebbag, Emmanuelle
    Univ Paul Sabatier Toulouse III, INSERM, UMR 1027, Toulouse, France.
    Sheppard, Mary N.
    European Reference Network Rare & Low Prevalence, Amsterdam, Netherlands;St Georges Med Sch, Cardiovasc Pathol Mol & Clin Sci Res Inst, London, England.
    Tasse, Anne-Marie
    McGill Univ, Publ Populat Project Genom & Soc P3G, Montreal, PQ, Canada;Genome Quebec Innovat Ctr, Montreal, PQ, Canada.
    Temel, Sehime G.
    Bursa Uludag Univ, Dept Med Genet, Fac Med, Bursa, Turkey;Bursa Uludag Univ, Dept Histol & Embryol, Fac Med, Bursa, Turkey.
    Sajantila, Antti
    Univ Helsinki, Dept Forens Med, Helsinki, Finland.
    Basso, Cristina
    European Reference Network Rare & Low Prevalence, Amsterdam, Netherlands;Univ Padua, Dept Cardiac Thorac & Vasc Sci, Cardiovasc Pathol Unit, Padua, Italy.
    Wilde, Arthur A. M.
    European Reference Network Rare & Low Prevalence, Amsterdam, Netherlands;Univ Amsterdam, Amsterdam UMC, Heart Ctr, Amsterdam, Netherlands;Univ Amsterdam, Dept Clin & Expt Cardiol, Amsterdam Cardiovasc Sci, Amsterdam, Netherlands.
    Cornel, Martina C.
    Vrije Univ Amsterdam, Amsterdam UMC, Dept Clin Genet, Sect Community Genet, Amsterdam, Netherlands;Vrije Univ Amsterdam, Amsterdam UMC, Amsterdam Publ Hlth Res Inst, Amsterdam, Netherlands.
    Benjamin, Caroline
    Borry, Pascal
    Clarke, Angus
    Cordier, Christophe
    Cornel, Martina
    van El, Carla
    Howard, Heidi
    Melegh, Bela
    Perola, Markus
    Peterlin, Borut
    Rogowski, Wolf
    Soller, Maria
    Stefansdottir, Vigdis
    de Wert, Guido
    European recommendations integrating genetic testing into multidisciplinary management of sudden cardiac death2019In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 27, no 12, p. 1763-1773Article in journal (Refereed)
    Abstract [en]

    Sudden cardiac death (SCD) accounts for 10-20% of total mortality, i.e., one in five individuals will eventually die suddenly. Given the substantial genetic component of SCD in younger cases, postmortem genetic testing may be particularly useful in elucidating etiological factors in the cause of death in this subset. The identification of genes responsible for inherited cardiac diseases have led to the organization of cardiogenetic consultations in many countries worldwide. Expert recommendations are available, emphasizing the importance of genetic testing and appropriate information provision of affected individuals, as well as their relatives. However, the context of postmortem genetic testing raises some particular ethical, legal, and practical (including economic or financial) challenges. The Public and Professional Policy Committee of the European Society of Human Genetics (ESHG), together with international experts, developed recommendations on management of SCD after a workshop sponsored by the Brocher Foundation and ESHG in November 2016. These recommendations have been endorsed by the ESHG Board, the European Council of Legal Medicine, the European Society of Cardiology working group on myocardial and pericardial diseases, the ERN GUARD-HEART, and the Association for European Cardiovascular Pathology. They emphasize the importance of increasing the proportion of both medical and medicolegal autopsies and educating the professionals. Multidisciplinary collaboration is of utmost importance. Public funding should be allocated to reach these goals and allow public health evaluation.

  • 22. Figueiredo, Joana
    et al.
    Söderberg, Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Simoes-Correia, Joana
    Grannas, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Suriano, Gianpaolo
    Seruca, Raquel
    The importance of E-cadherin binding partners to evaluate the pathogenicity of E-cadherin missense mutations associated to HDGC2013In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 21, no 3, p. 301-309Article in journal (Refereed)
    Abstract [en]

    In hereditary diffuse gastric cancer (HDGC), CDH1 germline gene alterations are causative events in 30% of the cases. In 20% of HDGC families, CDH1 germline mutations are of the missense type and the mutation carriers constitute a problem in terms of genetic counseling and surveillance. To access the pathogenic relevance of missense mutations, we have previously developed an in vitro method to functionally characterize them. Pathogenic E-cadherin missense mutants fail to aggregate and become more invasive, in comparison with cells expressing the wild-type (WT) protein. Herein, our aim was to develop a complementary method to unravel the pathogenic significance of E-cadherin missense mutations. We used cells stably expressing WT E-cadherin and seven HDGC-associated mutations (five intracellular and two extracellular) and studied by proximity ligation assays (PLA) how these mutants bind to fundamental regulators of E-cadherin function and trafficking. We focused our attention on the interaction with: p120, beta-catenin, PIPKI gamma and Hakai. We showed that cytoplasmic E-cadherin mutations affect the interaction of one or more binding partners, compromising the E-cadherin stability at the plasma membrane and likely affecting the adhesion complex competence. In the present work, we demonstrated that the study of the interplay between E-cadherin and its binding partners, using PLA, is an easy, rapid, quantitative and highly reproducible technique that can be applied in routine labs to verify the pathogenicity of E-cadherin missense mutants for HDGC diagnosis, especially those located in the intracellular domain of the protein.

  • 23.
    Forsberg, Lars A.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Back to the drawing board: loss of chromosome Y (LOY) inleukocytes is associated with age-related macular degeneration2019In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 27, p. 17-19Article in journal (Other academic)
  • 24.
    Frykholm, Carina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Klar, Joakim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Tomanovic, Tatjana
    Karolinska Hosp, Dept Hearing & Balance Disorders, Solna, Sweden.
    Ameur, Adam
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Dahl, Niklas
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Stereocilin gene variants associated with episodic vertigo: expansion of the DFNB16 phenotype2018In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 26, no 12, p. 1871-1874Article in journal (Refereed)
    Abstract [en]

    Vestibular disorders comprise a heterogeneous group of diseases with transient or permanent loss of vestibular function. Vestibulopathy is in most cases associated with migraine, Meniere disease, hereditary ataxias, or sensorineural hearing loss. We identified two brothers and their first cousin affected by hearing loss and episodic vertigo. The brothers were homozygous STRC nonsense variant [c.4027 C> T, p.(Q1343*)], whereas their first cousin was compound heterozygous for the STRC nonsense variant and a 97 kb deletion spanning the entire STRC gene. Clinical investigations confirmed pathological vestibular responses in addition to a characteristic DFNB16 hearing loss. The STRC gene encodes Stereocilin in the cochlea and in the vestibular organ where it ensheathes the kinocilium of the otolithic membranes. Stereocilin is associated with the gel overlaying the vestibular kinocilia, suggesting a role for the protein in sensing balance and spatial orientation. Our findings support such a function for Stereocilin in the vestibular organ and expand the phenotype associated with DFNB16.

  • 25.
    Gainotti, Sabina
    et al.
    Ist Super Sanita, Natl Ctr Rare Dis, Vle Regina Elena 299, I-00162 Rome, Italy.
    Turner, Cathy
    Newcastle Univ, Inst Med Genet, Int Ctr Life, Newcastle Upon Tyne, Tyne & Wear, England.
    Woods, Simon
    Newcastle Univ, PEALS Policy Eth & Life Sci Res Ctr, Newcastle Upon Tyne, Tyne & Wear, England.
    Kole, Anna
    Rare Dis Europe, EURORDIS, Paris, France.
    McCormack, Pauline
    Newcastle Univ, PEALS Policy Eth & Life Sci Res Ctr, Newcastle Upon Tyne, Tyne & Wear, England.
    Lochmüller, Hanns
    Newcastle Univ, Inst Med Genet, Int Ctr Life, Newcastle Upon Tyne, Tyne & Wear, England.
    Riess, Olaf
    Univ Tubingen, Inst Human Genet & Appl Genom, Tubingen, Germany.
    Straub, Volker
    Newcastle Univ, Inst Med Genet, Int Ctr Life, Newcastle Upon Tyne, Tyne & Wear, England.
    Posada, Manuel
    SpainRDR, Inst Rare Dis Res, Madrid, Spain; ISCIII, CIBERER, Madrid, Spain.
    Taruscio, Domenica
    Ist Super Sanita, Natl Ctr Rare Dis, Vle Regina Elena 299, I-00162 Rome, Italy.
    Mascalzoni, Deborah
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Centre for Research Ethics and Bioethics. EURAC Res, Ctr Biomed, Bolzano, Italy.
    Improving the informed consent process in international collaborative rare disease research: effective consent for effective research2016In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 24, no 9, p. 1248-1254Article in journal (Refereed)
    Abstract [en]

    The increased international sharing of data in research consortia and the introduction of new technologies for sequencing challenge the informed consent (IC) process, adding complexities that require coordination between research centres worldwide. Rare disease consortia present special challenges since available data and samples may be very limited. Thus, it is especially relevant to ensure the best use of available resources but at the same time protect patients' right to integrity. To achieve this aim, there is an ethical duty to plan in advance the best possible consent procedure in order to address possible ethical and legal hurdles that could hamper research in the future. Therefore, it is especially important to identify key core elements (CEs) to be addressed in the IC documents for international collaborative research in two different situations: (1) new research collections (biobanks and registries) for which information documents can be created according to current guidelines and (2) established collections obtained without IC or with a previous consent that does not cover all CEs. We propose here a strategy to deal with consent in these situations. The principles have been applied and are in current practice within the RD-Connect consortia - a global research infrastructure funded by the European Commission Seventh Framework program but forward looking in terms of issues addressed. However, the principles established, the lessons learned and the implications for future research are of direct relevance to all internationally collaborative rare-disease projects.

  • 26.
    Hansson, Mats G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Centre for Research Ethics and Bioethics.
    Genomics for policy makers and for researchers. Review of: Genomics and society-Ethical, Legal, Cultural and Socioeconomic Implication. Edited by: Dhavendra Kumar and Ruth Chadwick. 2016In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 24, no 12, p. 1835-1835Article, book review (Other academic)
  • 27.
    Hansson, Mats G.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Centre for Research Ethics and Bioethics.
    Lochmuller, Hanns
    Newcastle Univ, Inst Med Genet, John Walton Muscular Dystrophy Res Ctr, Newcastle Upon Tyne, Tyne & Wear, England..
    Riess, Olaf
    Univ Tubingen, Rare Dis Ctr, Inst Med Genet & Appl Genom, Tubingen, Germany..
    Schaefer, Franz
    Heidelberg Univ, Ctr Pediat & Adolescent Med, Div Pediat Nephrol, Heidelberg, Germany..
    Orth, Michael
    Ulm Univ Hosp, Dept Neurol, Ulm, Germany..
    Rubinstein, Yaffa
    NIH, ORDR, Natl Ctr Adv Translat Sci, Bldg 10, Bethesda, MD 20892 USA..
    Molster, Caron
    Dept Hlth Govt Western Australia, Off Populat Hlth Genom, Publ Hlth & Clin Serv Div, Perth, WA, Australia..
    Dawkins, Hugh
    Dept Hlth Govt Western Australia, Off Populat Hlth Genom, Publ Hlth & Clin Serv Div, Perth, WA, Australia.;Murdoch Univ, Ctr Comparat Genom, Murdoch, WA, Australia.;Curtin Univ Technol, Ctr Populat Hlth Res, Bentley, WA, Australia.;Univ Western Australia, Sch Pathol & Lab Med, Nedlands, WA, Australia..
    Taruscio, Domenica
    Ist Super Sanita, Natl Ctr Rare Dis, Rome, Italy..
    Posada, Manuel
    SpainRDR, ISCIII, Inst rare Dis Res, Madrid, Spain.;CIBERER, Madrid, Spain..
    Woods, Simon
    Newcastle Univ, Policy Eth & Life Sci Res Ctr, Newcastle Upon Tyne, Tyne & Wear, England..
    The risk of re-identification versus the need to identify individuals in rare disease research2016In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 24, no 11, p. 1553-1558Article in journal (Refereed)
    Abstract [en]

    There is a growing concern in the ethics literature and among policy makers that de-identification or coding of personal data and biospecimens is not sufficient for protecting research subjects from privacy invasions and possible breaches of confidentiality due to the possibility of unauthorized re-identification. At the same time, there is a need in medical science to be able to identify individual patients. In particular for rare disease research there is a special and well-documented need for research collaboration so that data and biosamples from multiple independent studies can be shared across borders. In this article, we identify the needs and arguments related to de-identification and re-identification of patients and research subjects and suggest how the different needs may be balanced within a framework of using unique encrypted identifiers.

  • 28. Heath, Simon C.
    et al.
    Gut, Ivo G.
    Brennan, Paul
    McKay, James D.
    Bencko, Vladimir
    Fabianova, Eleonora
    Foretova, Lenka
    Georges, Michael
    Janout, Vladimir
    Kabesch, Michael
    Krokan, Hans E.
    Elvestad, Maiken B.
    Lissowska, Jolanta
    Mates, Dana
    Rudnai, Peter
    Skorpen, Frank
    Schreiber, Stefan
    Soria, José M.
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Meneton, Pierre
    Herçberg, Serge
    Galan, Pilar
    Szeszenia-Dabrowska, Neonilia
    Zaridze, David
    Génin, Emmanuel
    Cardon, Lon R.
    Lathrop, Mark
    Investigation of the fine structure of European populations with applications to disease association studies2008In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 16, no 12, p. 1413-1429Article in journal (Refereed)
    Abstract [en]

    An investigation into fine-scale European population structure was carried out using high-density genetic variation on nearly 6000 individuals originating from across Europe. The individuals were collected as control samples and were genotyped with more than 300 000 SNPs in genome-wide association studies using the Illumina Infinium platform. A major East-West gradient from Russian (Moscow) samples to Spanish samples was identified as the first principal component (PC) of the genetic diversity. The second PC identified a North-South gradient from Norway and Sweden to Romania and Spain. Variation of frequencies at markers in three separate genomic regions, surrounding LCT, HLA and HERC2, were strongly associated with this gradient. The next 18 PCs also accounted for a significant proportion of genetic diversity observed in the sample. We present a method to predict the ethnic origin of samples by comparing the sample genotypes with those from a reference set of samples of known origin. These predictions can be performed using just summary information on the known samples, and individual genotype data are not required. We discuss issues raised by these data and analyses for association studies including the matching of case-only cohorts to appropriate pre-collected control samples for genome-wide association studies.

  • 29. Hedberg, Carola
    et al.
    Melberg, Atle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Kuhl, Angelika
    Jenne, Dieter
    Oldfors, Anders
    Autosomal dominant myofibrillar myopathy with arrhythmogenic right ventricular cardiomyopathy 7 is caused by a DES mutation2012In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 20, no 9, p. 984-985Article in journal (Refereed)
    Abstract [en]

    Using exome sequencing we searched for the genetic cause of autosomal dominant myofibrillar myopathy with arrhythmogenic right ventricular cardiomyopathy (ARVC) in a Swedish family. A heterozygous C-to-T transition, c.1255C>T, p.Pro419Ser in the desmin gene on chromosome 2q35, was identified. Previous studies had demonstrated linkage to chromosome 10q22.3, but no causative mutation had been found in that region. Sanger sequencing of DNA from 17 family members confirmed the heterozygous c.1255C>T desmin mutation in seven out of ten family members that had been classified as affected in the previous study. Our new results demonstrate the usefulness of next-generation sequencing, and the diagnostic difficulties with some forms of dominantly inherited muscle diseases as they can display a wide clinical and morphological variability even within a given family.

  • 30. Hedberg, Carola
    et al.
    Melberg, Atle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Kuhl, Angelika
    Jenne, Dieter
    Oldfors, Anders
    Functional characterization of desmin mutant p.P419S Reply2013In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 21, no 6, p. 590-590Article in journal (Refereed)
  • 31.
    Heldin, Carl-Henrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Lennartsson, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Hellberg, Carina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Feedback Control: The role of negative feedback in signal transduction control2008In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 16, no 7, p. 769-770Article in journal (Other academic)
    Abstract [en]

    -

  • 32.
    Henneman, Lidewij
    et al.
    Vrije Univ Amsterdam, Med Ctr, Dept Clin Genet, Sect Community Genet, Amsterdam, Netherlands.;Vrije Univ Amsterdam, Med Ctr, EMGO Inst Hlth & Care Res, Amsterdam, Netherlands..
    Borry, Pascal
    Univ Leuven, Ctr Biomed Eth & Law, Leuven, Belgium..
    Chokoshvili, Davit
    Univ Leuven, Ctr Biomed Eth & Law, Leuven, Belgium.;Univ Hosp Ghent, Ctr Med Genet Ghent, Ghent, Belgium..
    Cornel, Martina C.
    Vrije Univ Amsterdam, Med Ctr, Dept Clin Genet, Sect Community Genet, Amsterdam, Netherlands.;Vrije Univ Amsterdam, Med Ctr, EMGO Inst Hlth & Care Res, Amsterdam, Netherlands..
    van El, Carla G.
    Vrije Univ Amsterdam, Med Ctr, Dept Clin Genet, Sect Community Genet, Amsterdam, Netherlands.;Vrije Univ Amsterdam, Med Ctr, EMGO Inst Hlth & Care Res, Amsterdam, Netherlands..
    Forzano, Francesca
    Osped Galliera, Med Genet Unit, Genoa, Italy..
    Hall, Alison
    PHG Fdn, Cambridge, England..
    Howard, Heidi C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Centre for Research Ethics and Bioethics.
    Janssens, Sandra
    Univ Hosp Ghent, Ctr Med Genet Ghent, Ghent, Belgium..
    Kayserili, Hulya
    Koc Univ, Sch Med, Dept Med Genet, Istanbul, Turkey..
    Lakeman, Phillis
    Univ Amsterdam, Acad Med Ctr, Dept Clin Genet, Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands..
    Lucassen, Anneke
    Univ Southampton, Dept Clin Eth & Law CELS, Southampton, Hants, England.;Wessex Clin Genet Serv, Southampton, Hants, England..
    Metcalfe, Sylvia A.
    Univ Melbourne, Murdoch Childrens Res Inst, Parkville, Vic 3052, Australia.;Univ Melbourne, Dept Paediat, Parkville, Vic 3052, Australia..
    Vidmar, Lovro
    Univ Ljubljana, Med Ctr, Clin Inst Med Genet, Ljubljana 1000, Slovenia..
    de Wert, Guido
    Maastricht Univ, Res Sch CAPHRI, Dept Hlth Eth & Soc, NL-6200 MD Maastricht, Netherlands.;Maastricht Univ, Res Sch GROW, NL-6200 MD Maastricht, Netherlands..
    Dondorp, Wybo J.
    Maastricht Univ, Res Sch CAPHRI, Dept Hlth Eth & Soc, NL-6200 MD Maastricht, Netherlands.;Maastricht Univ, Res Sch GROW, NL-6200 MD Maastricht, Netherlands..
    Peterlin, Borut
    Univ Ljubljana, Med Ctr, Clin Inst Med Genet, Ljubljana 1000, Slovenia..
    Responsible implementation of expanded carrier screening2016In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 24, no 6, p. E1-E12Article in journal (Refereed)
    Abstract [en]

    This document of the European Society of Human Genetics contains recommendations regarding responsible implementation of expanded carrier screening. Carrier screening is defined here as the detection of carrier status of recessive diseases in couples or persons who do not have an a priori increased risk of being a carrier based on their or their partners' personal or family history. Expanded carrier screening offers carrier screening for multiple autosomal and X-linked recessive disorders, facilitated by new genetic testing technologies, and allows testing of individuals regardless of ancestry or geographic origin. Carrier screening aims to identify couples who have an increased risk of having an affected child in order to facilitate informed reproductive decision making. In previous decades, carrier screening was typically performed for one or few relatively common recessive disorders associated with significant morbidity, reduced life-expectancy and often because of a considerable higher carrier frequency in a specific population for certain diseases. New genetic testing technologies enable the expansion of screening to multiple conditions, genes or sequence variants. Expanded carrier screening panels that have been introduced to date have been advertised and offered to health care professionals and the public on a commercial basis. This document discusses the challenges that expanded carrier screening might pose in the context of the lessons learnt from decades of population-based carrier screening and in the context of existing screening criteria. It aims to contribute to the public and professional discussion and to arrive at better clinical and laboratory practice guidelines.

  • 33. Hietala, M
    et al.
    Grön, K
    Syvänen, Ann-Christine
    Peltonen, L
    Aula, P
    Prospects of carrier screening of aspartylglucosaminuria in Finland1993In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 1, no 4, p. 296-300Article in journal (Refereed)
    Abstract [en]

    The frequency of carriers of the AGUFin mutation, the predominant mutation causing aspartylglucosaminuria in Finland, was determined in a population sample comprising 553 newborns from a delivery hospital in southern Finland, and 607 from a hospital in northern Finland. The AGUFin point mutation was identified from cord blood samples using the PCR-based, solid-phase minisequencing method. Nineteen carriers of the AGUFin mutation were detected, 8 (1:69) in the sample from the southern and 11 (1:55) from the northern population, respectively. The solid-phase minisequencing method proved to be rapid and convenient for the detection of the AGUFin mutation, and can readily be applied in large-scale carrier screening at the population level.

  • 34. Hoefsloot, Lies H
    et al.
    Roux, Anne-Françoise
    Bitner-Glindzicz, Maria
    EMQN Best Practice guidelines for diagnostic testing of mutations causing non-syndromic hearing impairment at the DFNB1 locus.2013In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 21, no 11, p. 1325-1329Article in journal (Refereed)
  • 35.
    Howard, Heidi Carmen
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Centre for Research Ethics and Bioethics.
    Knoppers, Bartha Maria
    Cornel, Martina C
    Wright Clayton, Ellen
    Sénécal, Karine
    Borry, Pascal
    Whole-genome sequencing in newborn screening?: A statement on the continued importance of targeted approaches in newborn screening programmes2015In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 23, no 12, p. 1593-1600Article in journal (Refereed)
    Abstract [en]

    The advent and refinement of sequencing technologies has resulted in a decrease in both the cost and time needed to generate data on the entire sequence of the human genome. This has increased the accessibility of using whole-genome sequencing and whole-exome sequencing approaches for analysis in both the research and clinical contexts. The expectation is that more services based on these and other high-throughput technologies will become available to patients and the wider population. Some authors predict that sequencing will be performed once in a lifetime, namely, shortly after birth. The Public and Professional Policy Committee of the European Society of Human Genetics, the Human Genome Organisation Committee on Ethics, Law and Society, the PHG Foundation and the P3G International Paediatric Platform address herein the important issues and challenges surrounding the potential use of sequencing technologies in publicly funded newborn screening (NBS) programmes. This statement presents the relevant issues and culminates in a set of recommendations to help inform and guide scientists and clinicians, as well as policy makers regarding the necessary considerations for the use of genome sequencing technologies and approaches in NBS programmes. The primary objective of NBS should be the targeted analysis and identification of gene variants conferring a high risk of preventable or treatable conditions, for which treatment has to start in the newborn period or in early childhood.

  • 36.
    Howard, Heidi Carmen
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Centre for Research Ethics and Bioethics.
    van El, Carla G.
    Vrije Univ Amsterdam Med Ctr, Dept Clin Genet, Sect Community Genet, Amsterdam.; Vrije Univ Amsterdam Med Ctr, EMGO Inst Hlth & Care Res, Amsterdam.
    Forzano, Francesca
    Great Ormond St Hosp Sick Children, Dept Clin Genet, London.
    Radojkovic, D.
    Univ Belgrade, Inst Mol Genet & Genet Engn, Lab Mol Genet, Belgrade.
    Rial-Sebbag, E.
    Univ Toulouse 3 Paul Sabatier, UMR 1027, INSERM, Fac Med, Toulouse.
    de Wert, G.
    Maastricht Univ, Dept Hlth Eth & Soc, Res Sch CAPHRI, Maastricht.; Maastricht Univ, Res Sch GROW, Maastricht.
    Borry, P.
    Katholieke Univ Leuven, Leuven Inst Genom & Soc, Dept Publ Hlth & Primary Care, Ctr Biomed Eth & Law, Leuven.
    Cornel, M. C.
    Vrije Univ Amsterdam Med Ctr, Dept Clin Genet, Sect Community Genet, Amsterdam.; Vrije Univ Amsterdam Med Ctr, EMGO Inst Hlth & Care Res, Amsterdam.
    One small edit for humans, one giant edit for humankind? Points and questions to consider for a responsible way forward for gene editing in humans2018In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 26, no 1, p. 1-11Article in journal (Refereed)
    Abstract [en]

    Gene editing, which allows for specific location(s) in the genome to be targeted and altered by deleting, adding or substituting nucleotides, is currently the subject of important academic and policy discussions. With the advent of efficient tools, such as CRISPR-Cas9, the plausibility of using gene editing safely in humans for either somatic or germ line gene editing is being considered seriously. Beyond safety issues, somatic gene editing in humans does raise ethical, legal and social issues (ELSI), however, it is suggested to be less challenging to existing ethical and legal frameworks; indeed somatic gene editing is already applied in (pre-) clinical trials. In contrast, the notion of altering the germ line or embryo such that alterations could be heritable in humans raises a large number of ELSI; it is currently debated whether it should even be allowed in the context of basic research. Even greater ELSI debates address the potential use of germ line or embryo gene editing for clinical purposes, which, at the moment is not being conducted and is prohibited in several jurisdictions. In the context of these ongoing debates surrounding gene editing, we present herein guidance to further discussion and investigation by highlighting three crucial areas that merit the most attention, time and resources at this stage in the responsible development and use of gene editing technologies: (1) conducting careful scientific research and disseminating results to build a solid evidence base; (2) conducting ethical, legal and social issues research; and (3) conducting meaningful stakeholder engagement, education and dialogue.

  • 37.
    Ingman, Max
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Gyllensten, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    A recent genetic link between Sami and the Volga-Ural region of Russia2007In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 15, no 1, p. 115-120Article in journal (Refereed)
    Abstract [en]

    The genetic origin of the Sami is enigmatic and contributions from Continental Europe, Eastern Europe and Asia have been proposed. To address the evolutionary history of northern and southern Swedish Sami, we have studied their mtDNA haplogroup frequencies and complete mtDNA genome sequences. While the majority of mtDNA diversity in the northern Swedish, Norwegian and Finnish Sami is accounted for by haplogroups V and U5b1b1, the southern Swedish Sami have other haplogroups and a frequency distribution similar to that of the Continental European population. Stratification of the southern Sami on the basis of occupation indicates that this is the result of recent admixture with the Swedish population. The divergence time for the Sami haplogroup V sequences is 7600 YBP (years before present), and for U5b1b1, 5500 YBP amongst Sami and 6600 YBP amongst Sami and Finns. This suggests an arrival in the region soon after the retreat of the glacial ice, either by way of Continental Europe and/or the Volga-Ural region. Haplogroup Z is found at low frequency in the Sami and Northern Asian populations but is virtually absent in Europe. Several conserved substitutions group the Sami Z lineages strongly with those from Finland and the Volga-Ural region of Russia, but distinguish them from Northeast Asian representatives. This suggests that some Sami lineages shared a common ancestor with lineages from the Volga-Ural region as recently as 2700 years ago, indicative of a more recent contribution of people from the Volga-Ural region to the Sami population.

  • 38.
    Ingman, Max
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Gyllensten, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    SNP frequency estimation using massively parallel sequencing of pooled DNA2008In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 17, no 3, p. 383-386Article in journal (Refereed)
    Abstract [en]

    Resequencing of genomic regions that have been implicated by linkage and/or association studies to harbor genetic susceptibility loci represents a necessary step to identify causal variants. Massively parallel sequencing (MPS) offers the possibility of SNP discovery and frequency determination among pooled DNA samples. The strategies of pooling DNA samples and pooling PCR amplicons generated from individual DNA samples were evaluated, and both were found to return accurate estimates of SNP frequencies across varying levels of sequence coverage.European Journal of Human Genetics advance online publication, 15 October 2008; doi:10.1038/ejhg.2008.182.

  • 39.
    Johansson, Åsa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Curran, Joanne E.
    Johnson, Matthew P.
    Freed, Katy A.
    Fenstad, Mona H.
    Björge, Line
    Eide, Irina P.
    Carless, Melanie A.
    Rainwater, David L.
    Goring, Harald H. H.
    Austgulen, Rigmor
    Moses, Eric K.
    Blangero, John
    Identification of ACOX2 as a shared genetic risk factor for preeclampsia and cardiovascular disease2011In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 19, no 7, p. 796-800Article in journal (Refereed)
    Abstract [en]

    Preeclampsia (PE) is a serious complication of pregnancy, which is highly correlated with later life cardiovascular disease (CVD). Many risk factors are common for both diseases, but the contribution of shared genes remains to be determined. In this study, we used an integrative strategy to assess lipid traits as risk factors for PE and CVD by whole genome transcriptional profiling performed on Norwegian decidua basalis tissues (N=95) from preeclamptic and normal pregnancies and on blood lymphocytes (N=1240) from the San Antonio Family Heart Study (SAFHS). Among 222 genes that were differentially expressed (false discovery rate (FDR) P-value < 0.05) between the PE, cases and controls, we found one gene, ACOX2 (acyl-coenzyme A oxidase 2, branched chain), that was downregulated in PE whose transcription was also inversely correlated with triglyceride levels (P=5.6 x 10(-7); FDR P-value=0.0002) in SAFHS. We further report associations between SNPs in the ACOX2 gene and the transcription level (P-value=0.0045) of the gene, as well as with triglyceride levels (P-value=0.0051). ACOX2 is involved in bile acid production, a process that has been associated with both oxidative stress and regulation of triglyceride levels. Oxidative stress and increased triglyceride levels are known risk factors for CVD and both have also been associated with PE. Our results suggest that downregulation of ACOX2 is a shared risk factor for PE and CVD.

  • 40.
    Johansson, Åsa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Ingman, Max
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Mack, Steven J
    Erlich, Henry
    Gyllensten, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Genetic origin of the Swedish Sami inferred from HLA class I and class II allele frequencies2008In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 16, no 11, p. 1341-1349Article in journal (Refereed)
    Abstract [en]

    Sami of northern Scandinavia are genetic outliers among European populations and their origin has been difficult to determine. In order to study the genetic origin of the Swedish Sami, we have performed high-resolution typing of the class I HLA-A and -B loci and the class II DRB1, DQB1 and DQA1 loci in the northern and southern Swedish Sami. Several of the common class I alleles in Sami (B*0702, B*1501, B*4002 and A*0301) are found at high frequency in other European populations. However, a number of class I and class II alleles (B*4001, A*2402, DRB1*0901 and DRB1*1101) in the Swedish Sami are characteristic of Asian populations. Admixture analyses indicate that 87% of the Sami gene pool is of European origin and that the Asian contribution is 13%. Our HLA analyses indicate a higher proportion of Asian ancestry in the Sami than shown by previous genetic studies.

  • 41.
    Johnsson, Linus
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Centre for Research Ethics and Bioethics.
    Helgesson, Gert
    LIME, Karolinska Institutet, Stockholm.
    Rafnar, Thorunn
    UVS, Snorrabraut 60, Reykjavik, Iceland.
    Halldorsdottir, Ingibjörg
    UVS, Snorrabraut 60, Reykjavik, Iceland.
    Chia, Kee-Seng
    Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
    Eriksson, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Centre for Research Ethics and Bioethics.
    Hansson, Mats G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Centre for Research Ethics and Bioethics.
    Hypothetical and factual willingness to participate in biobank research2010In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 18, p. 1261-1264Article in journal (Refereed)
    Abstract [en]

    In the debate on biobank regulation, arguments often draw upon findings in surveys on public attitudes. However, surveys on willingness to participate in research may not always predict actual participation rates. We compared hypothetical willingness as estimated in 11 surveys conducted in Sweden, Iceland, United Kingdom, Ireland, United States and Singapore to factual participation rates in 12 biobank studies. Studies were matched by country and approximate time frame. Of 22 pairwise comparisons, 12 suggest that factual willingness to participate in biobank research is greater than hypothetical, six indicate the converse relationship, and four are inconclusive. Factual donors, in particular when recruited in health care or otherwise face-to-face with the researcher, are possibly motivated by factors that are less influential in a hypothetical context, such as altruism, trust, and sense of duty. The value of surveys in assessing factual willingness may thus be limited.

  • 42. Khan, Tahir Naeem
    et al.
    Klar, Joakim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Tariq, Muhammad
    Baig, Shehla Anjum
    Malik, Naveed Altaf
    Yousaf, Raja
    Baig, Shahid Mahmood
    Dahl, Niklas
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Evidence for autosomal recessive inheritance in SPG3A caused by homozygosity for a novel ATL1 missense mutation2014In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 22, no 10, p. 1180-1184Article in journal (Refereed)
    Abstract [en]

    Hereditary spastic paraplegias (HSPs) comprise a heterogeneous group of disorders characterized by progressive spasticity and weakness of the lower limbs. Autosomal dominant and 'pure' forms of HSP account for similar to 80% of cases in Western societies of whom 10% carry atlastin-1 (ATL1) gene mutations. We report on a large consanguineous family segregating six members with early onset HSP. The pedigree was compatible with both autosomal dominant and autosomal recessive inheritance. Whole-exome sequencing and segregation analysis revealed a homozygous novel missense variant c.353G>A, p.(Arg118Gln) in ATL1 in all six affected family members. Seven heterozygous carriers, five females and two males, showed no clinical signs of HSP with the exception of sub-clinically reduced vibration sensation in one adult female. Our combined findings show that homozygosity for the ATL1 missense variant remains the only plausible cause of HSP, whereas heterozygous carriers are asymptomatic. This apparent autosomal recessive inheritance adds to the clinical complexity of spastic paraplegia 3A and calls for caution using directed genetic screening in HSP.

  • 43.
    Klar, Joakim
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Ali, Zafar
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. PIEAS, Natl Inst Biotechnol & Genet Engn, Human Mol Genet Lab, Faisalabad, Pakistan.
    Farooq, Muhammad
    PIEAS, Natl Inst Biotechnol & Genet Engn, Human Mol Genet Lab, Faisalabad, Pakistan.
    Khan, Kamal
    PIEAS, Natl Inst Biotechnol & Genet Engn, Human Mol Genet Lab, Faisalabad, Pakistan.
    Wikström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Iqbal, Maria
    PIEAS, Natl Inst Biotechnol & Genet Engn, Human Mol Genet Lab, Faisalabad, Pakistan.
    Zulfiqar, Shumaila
    PIEAS, Natl Inst Biotechnol & Genet Engn, Human Mol Genet Lab, Faisalabad, Pakistan.
    Faryal, Sanam
    PIEAS, Natl Inst Biotechnol & Genet Engn, Human Mol Genet Lab, Faisalabad, Pakistan.
    Baig, Shahid Mahmood
    PIEAS, Natl Inst Biotechnol & Genet Engn, Human Mol Genet Lab, Faisalabad, Pakistan.
    Dahl, Niklas
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    A missense variant in ITPR1 provides evidence for autosomal recessive SCA29 with asymptomatic cerebellar hypoplasia in carriers.2017In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 25, no 7, p. 848-853Article in journal (Refereed)
    Abstract [en]

    Spinocerebellar ataxias (SCA) comprise a heterogeneous group of inherited neurological disorders characterized by a range of symptoms from both cerebellar and extra cerebellar structures. We investigated the cause of autosomal recessive, congenital SCA in six affected family members from a large consanguineous family. Using whole-exome sequencing, we identified a homozygous ITPR1 missense variant [c.5360T>C; p.(L1787P)] segregating in all affected individuals. Heterozygous carriers were asymptomatic despite cerebellar hypoplasia. Variants in the ITPTR1 gene have previously been associated exclusively with autosomal dominant SCA15 and SCA29 with slow or no progression. The L1787 residue is highly conserved and the leucine to proline substitution has a predicted destabilizing effect on the protein structure. Additionally, the L1787P variant is located in a domain separated from previously described and dominant-acting missense variants consistent with a distinct effect on IP3R1 tetramer structure and function. Taken together, we show for the first time that a biallelic ITPR1 missense variant may cause an autosomal recessive and infantile onset SCA29, albeit with subclinical cerebellar hypoplasia in carriers. Our findings add to the genetic complexity of SCA29 and broaden the correlations between ITPR1 variants and their clinical expression.

  • 44.
    Klar, Joakim
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Raykova, Doroteya
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Gustafson, Elisabet
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Paediatric Surgery.
    Tóthová, Iveta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab. University of Presov.
    Ameur, Adam
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Wanders, Alkwin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Dahl, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Phenotypic expansion of visceral myopathy associated with ACTG2 tandem base substitution2015In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 23, no 12, p. 1679-1683Article in journal (Refereed)
    Abstract [en]

    Familial visceral myopathy (FVM) is a rare heritable and heterogeneous condition due to impaired smooth muscle function. We identified a family segregating 11 individuals with a spectrum of visceral symptoms involving the small intestine, colon, biliary tract, urinary tract and uterus. Whole-exome sequencing revealed a novel heterozygous tandem base substitution c.806_807delinsAA (p.(Gly269Glu)) in ACTG2, encoding smooth muscle actin γ-2, in affected family members. Variants in ACTG2 were recently identified in FVM with intestinal pseudo-obstruction as well as with the congenital megacystics-microcolon-intestinal hypoperistalsis syndrome. In our family, eight affected members presented with severe complications from the biliary and/or the urinary tracts in addition to gastrointestinal pseudo-obstructions. Furthermore, all affected mothers had a history of assisted deliveries owing to poor progress during labor and weak uterine contractions. The variable involvement of multiple smooth muscle-dependent organs in our family, including the biliary tract and the uterus, add to the phenotypic spectrum associated with ACTG2 missense variants.

  • 45. Konings, Annelies
    et al.
    Van Laer, Lut
    Michel, Sophie
    Pawelczyk, Malgorzata
    Carlsson, Per-Inge
    Bondeson, Marie-Louise
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Rajkowska, Elzbieta
    Dudarewicz, Adam
    Vandevelde, Ann
    Fransen, Erik
    Huyghe, Jeroen
    Borg, Erik
    Sliwinska-Kowalska, Mariola
    Van Camp, Guy
    Variations in HSP70 genes associated with noise-induced hearing loss in two independent populations2009In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 17, no 3, p. 329-35Article in journal (Refereed)
    Abstract [en]

    Noise-induced hearing loss (NIHL) is one of the most important occupational health hazards. Millions of people worldwide are exposed daily to harmful levels of noise. NIHL is a complex disease resulting from an interaction between genetic and environmental factors. Although the environmental risk factors have been studied extensively, little is known about the genetic factors. Heat-shock proteins (HSPs) are induced after exposure to severe noise. When first induced by exposure to moderate sound levels, they can protect the ear from damage from excessive noise exposure. This protection is highly variable between individuals. An association of HSP70 genes with NIHL has been described by Yang et al (2006) in a Chinese sample set of noise-exposed workers. In this study, three polymorphisms (rs1043618, rs1061581 and rs2227956) in HSP70-1, HSP70-2 and HSP70-hom, respectively, were genotyped in 206 Swedish and 238 Polish DNA samples of noise-exposed subjects and analyzed. One SNP, rs2227956 in HSP70-hom, resulted in a significant association with NIHL in both sample sets. In addition, rs1043618 and rs1061581 were significant in the Swedish sample set. Analysis of the haplotypes composed of the three SNPs revealed significant associations between NIHL and haplotype GAC in both sample sets and with haplotype CGT in the Swedish sample set. In conclusion, this study replicated the association of HSP70 genes with NIHL in a second and third independent noise-exposed sample set, hereby adding to the evidence that HSP70 genes may be NIHL susceptibility genes.

  • 46. Kuhl, Angelika
    et al.
    Melberg, Atle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Meinl, Edgar
    Nürnberg, Gudrun
    Nürnberg, Peter
    Kehrer-Sawatzki, Hildegard
    Jenne, Dieter
    Myofibrillar myopathy with arrhythmogenic right ventricular cardiomyopathy 7: corroboration and narrowing of the critical region on 10q22.32008In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 16, no 3, p. 367-373Article in journal (Refereed)
    Abstract [en]

    Several years ago, autosomal dominant myofibrillar myopathy (MFM) in combination with arrhythmogenic right ventricular cardiomyopathy (ARVC7) was tentatively mapped to a 10.6-Mbp (million base pairs) region on chromosome 10q22.3 between D10S605 (78.9 Mbp) and D10S215 (89.5 Mbp) in a Swedish family assuming that ARVC7 was allelic with cardiomyopathy, dilated 1C (CMD1C). To date, neither the genetic defect in ARVC7 nor CMD1C has been reported. In a comprehensive follow-up study were-examined and confirmed the previous linkage data for ARVC7 using a high-density single nucleotide polymorphism marker panel from Affymetrix (Human Mapping 10K Array). No other regions with significant evidence for linkage were discovered. The critical interval was narrowed down to 4.27 Mbp between D10S1645 and D10S1786. This reduced the total number of candidate genes to 18 of which 17 (RAI17, PPIF, C100RF56, SFTPA1, SFTPA2, SFTPA1B, SFTPA2B, SFTPD, C100RF57, PLAC9, ANXA11, MAT1A, DYDC1, DYDC2, C100RF58, TSPAN14 and SH2D4B) are shared with the CMD1C region. No disease-causing mutation was found in their coding regions. Moreover, metavinculin (VCL) and ZASP/cypher (LDB3) proximal and distal to this linked region were excluded by sequence analysis. To search for submicroscopic and intragenic deletions by PCR, we generated hybrid cell lines carrying only the affected or normal chromosome 10 homolog. All sequence tagged sites and exons were present on both homologs. We speculate that regulatory mutations in 1 of the 18 genes from 10q22.3 are responsible for a heterogenous spectrum of clinically distinct myodegenerative disorders, affecting both skeletal and cardiac muscles to variable degrees.

  • 47.
    Lindahl, Katarina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Astrom, Eva
    Rubin, Carl-Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Grigelioniene, Giedre
    Malmgren, Barbro
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Kindmark, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Genetic epidemiology, prevalence, and genotype-phenotype correlations in the Swedish population with osteogenesis imperfecta2015In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 23, no 8, p. 1042-1050Article in journal (Refereed)
    Abstract [en]

    Osteogenesis imperfecta (OI) is a rare hereditary bone fragility disorder, caused by collagen I mutations in 90% of cases. There are no comprehensive genotype-phenotype studies on 4100 families outside North America, and no population-based studies determining the genetic epidemiology of OI. Here, detailed clinical phenotypes were recorded, and the COL1A1 and COL1A2 genes were analyzed in 164 Swedish OI families (223 individuals). Averages for bone mineral density (BMD), height and yearly fracture rate were calculated and related to OI and mutation type. N-terminal helical mutations in both the alpha 1-and alpha 2-chains were associated with the absence of dentinogenesis imperfecta (P<0.0001 vs 0.0049), while only those in the alpha 1-chain were associated with blue sclera (P = 0.0110). Comparing glycine with serine substitutions, alpha 1-alterations were associated with more severe phenotype (P = 0.0031). Individuals with type I OI caused by qualitative vs quantitative mutations were shorter (P < 0.0001), but did not differ considering fractures or BMD. The children in this cohort were estimated to represent >95% of the complete Swedish pediatric OI population. The prevalence of OI types I, III, and IV was 5.16, 0.89, and 1.35/100 000, respectively (7.40/100 000 overall), corresponding to what has been estimated but not unequivocally proven in any population. Collagen I mutation analysis was performed in the family of 97% of known cases, with causative mutations found in 87%. Qualitative mutations caused 32% of OI type I. The data reported here may be helpful to predict phenotype, and describes for the first time the genetic epidemiology in > 95% of an entire OI population.

  • 48.
    Lundmark, Per E
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Liljedahl, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Boomsma, Dorret I
    Mannila, Heikki
    Martin, Nicholas G
    Palotie, Aarno
    Peltonen, Leena
    Perola, Markus
    Spector, Tim D
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Evaluation of HapMap data in six populations of European descent2008In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 16, no 9, p. 1142-1150Article in journal (Refereed)
    Abstract [en]

    We studied how well the European CEU samples used in the Haplotype Mapping Project (HapMap) represent five European populations by analyzing nuclear family samples from the Swedish, Finnish, Dutch, British and Australian (European ancestry) populations. The number of samples from each population (about 30 parent-offspring trios) was similar to that in the HapMap sample sets. A panel of 186 single nucleotide polymorphisms (SNPs) distributed over the 1.5 Mb region of the GRID2 gene on chromosome 4 was genotyped. The genotype data were compared pair-wise between the HapMap sample and the other population samples. Principal component analysis (PCA) was used to cluster the data from different populations with respect to allele frequencies and to define the markers responsible for observed variance. The only sample with detectable differences in allele frequencies was that from Kuusamo, Finland. This sample also separated from the others, including the other Finnish sample, in the PCA analysis. A set of tagSNPs was defined based on the HapMap data and applied to the samples. The tagSNPs were found to capture the genetic variation in the analyzed region at r(2)>0.8 at levels ranging from 95% in the Kuusamo sample to 87% in the Australian sample. To capture the maximal genetic variation in the region, the Kuusamo, HapMap and Australian samples required 58, 63 and 73 native tagSNPs, respectively. The HapMap CEU sample represents the European samples well for tagSNP selection, with some caution regarding estimation of allele frequencies in the Finnish Kuusamo sample, and a slight reduction in tagging efficiency in the Australian sample.

  • 49. Lynch, Sally Ann
    et al.
    Foulds, Nicola
    Thuresson, Ann-Charlotte
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Collins, Amanda L.
    Annerén, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Hedberg, Bernt-Oves
    Delaney, Carol A.
    Iremonger, James
    Murray, Caroline M.
    Crolla, John A.
    Costigan, Colm
    Lam, Wayne
    Fitzpatrick, David R.
    Regan, Regina
    Ennis, Sean
    Sharkey, Freddie
    The 12q14 microdeletion syndrome: six new cases confirming the role of HMGA2 in growth2011In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 19, no 5, p. 534-539Article in journal (Refereed)
    Abstract [en]

    We report six patients with array deletions encompassing 12q14. Out of a total of 2538 array investigations carried out on children with developmental delay and dysmorphism in three diagnostic testing centres, six positive cases yielded a frequency of 1 in 423 for this deletion syndrome. The deleted region in each of the six cases overlaps significantly with previously reported cases with microdeletions of this region. The chromosomal range of the deletions extends from 12q13.3q15. In the current study, we report overlapping deletions of variable extent and size but primarily comprising chromosomal bands 12q13.3q14.1. Four of the six deletions were confirmed as de novo events. Two cases had deletions that included HMGA2, and both children had significant short stature. Neither case had osteopoikilosis despite both being deleted for LEMD3. Four cases had deletions that ended proximal to HMGA2 and all of these had much better growth. Five cases had congenital heart defects, including two with atrial septal defects, one each with pulmonary stenosis, sub-aortic stenosis and a patent ductus. Four cases had moderate delay, two had severe developmental delay and a further two had a diagnosis of autism. All six cases had significant speech delay with subtle facial dysmorphism.

  • 50. Madrigal, Irene
    et al.
    Alvarez-Mora, Maria Isabel
    Rosell, Jordi
    Rodríguez-Revenga, Laia
    Karlberg, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Sauer, Sascha
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Mila, Montserrat
    A novel splicing mutation in the IQSEC2 gene that modulates the phenotype severity in a family with intellectual disability.2016In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 24, no 8, p. 1117-1123Article in journal (Refereed)
    Abstract [en]

    The IQSEC2 gene is located on chromosome Xp11.22 and encodes a guanine nucleotide exchange factor for the ADP-ribosylation factor family of small GTPases. This gene is known to have a significant role in cytoskeletal organization, dendritic spine morphology and synaptic organization. Variants in IQSEC2 cause moderate to severe intellectual disability in males and a variable phenotype in females because this gene escapes from X-chromosome inactivation. Here we report on the first splicing variant in IQSEC2 (g.88032_88033del; NG_021296.1) that co-segregates in a family diagnosed with an X-linked form of ID. In a percentage of the cells, the variant activates an intraexonic splice acceptor site that abolishes 26 amino acids from the highly conserved PH domain of IQSEC2 and creates a premature stop codon 36 amino acids later in exon 13. Interestingly, the percentage of aberrant splicing seems to correlate with the severity of the disease in each patient. The impact of this variant in the target tissue is unknown, but we can hypothesize that these differences may be related to the amount of abnormal IQSEC2 transcript. To our knowledge, we are reporting a novel mechanism of IQSEC2 involvement in ID. Variants that affect splicing are related to many genetic diseases and the understanding of their role in disease expands potential opportunities for gene therapy. Modulation of aberrant splicing transcripts can become a potent therapeutic approach for many of these diseases.

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