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  • 1.
    Angius, Andrea
    et al.
    CNR, Ist Ric Genet & Biomed, Cagliari, Italy.
    Uva, Paolo
    Ctr Adv Studies Res & Dev Sardinia CRS4, Sci & Technol Pk Polaris, Pula, Italy.
    Oppo, Manuela
    CNR, Ist Ric Genet & Biomed, Cagliari, Italy;Univ Sassari, Dipartimento Sci Biomed, Sassari, Italy.
    Buers, Insa
    Munster Univ, Cells Mot Cluster Excellence, Munster, Germany;Munster Univ, Childrens Hosp, Dept Gen Pediat, Munster, Germany.
    Persico, Ivana
    CNR, Ist Ric Genet & Biomed, Cagliari, Italy.
    Onano, Stefano
    CNR, Ist Ric Genet & Biomed, Cagliari, Italy;Univ Sassari, Dipartimento Sci Biomed, Sassari, Italy.
    Cuccuru, Gianmauro
    Ctr Adv Studies Res & Dev Sardinia CRS4, Sci & Technol Pk Polaris, Pula, Italy.
    Van Allen, Margot I.
    Univ British Columbia, Dept Med Genet, Vancouver, BC, Canada;BC Childrens & Womens Hlth Ctr, Prov Hlth Serv Author, Vancouver, BC, Canada;Victoria Isl Hlth Author, Dept Med Genet, Victoria, BC, Canada.
    Hulait, Gurdip
    BC Childrens & Womens Hlth Ctr, Prov Hlth Serv Author, Vancouver, BC, Canada.
    Aubertin, Gudrun
    Victoria Isl Hlth Author, Dept Med Genet, Victoria, BC, Canada.
    Muntoni, Francesco
    UCL Great Ormond St Hosp, Dubowitz Neuromuscular Ctr, London, England;Univ Hosp Wales, Inst Med Genet, Cardiff, S Glam, Wales.
    Fry, Andrew E.
    Annerén, Göran
    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.
    Stattin, Evalena
    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.
    Palomares-Bralo, Maria
    Santos-Simarro, Fernando
    Cucca, Francesco
    CNR, Ist Ric Genet & Biomed, Cagliari, Italy;Univ Sassari, Dipartimento Sci Biomed, Sassari, Italy.
    Crisponi, Giangiorgio
    Clin St Anna, Cagliari, Italy.
    Rutsch, Frank
    Munster Univ, Cells Mot Cluster Excellence, Munster, Germany;Munster Univ, Childrens Hosp, Dept Gen Pediat, Munster, Germany.
    Crisponi, Laura
    CNR, Ist Ric Genet & Biomed, Cagliari, Italy;Univ Sassari, Dipartimento Sci Biomed, Sassari, Italy.
    Exome sequencing in Crisponi/cold-induced sweating syndrome-like individuals reveals unpredicted alternative diagnoses2019In: Clinical Genetics, ISSN 0009-9163, E-ISSN 1399-0004, Vol. 95, no 5, p. 607-614Article in journal (Refereed)
    Abstract [en]

    Crisponi/cold-induced sweating syndrome (CS/CISS) is a rare autosomal recessive disorder characterized by a complex phenotype (hyperthermia and feeding difficulties in the neonatal period, followed by scoliosis and paradoxical sweating induced by cold since early childhood) and a high neonatal lethality. CS/CISS is a genetically heterogeneous disorder caused by mutations in CRLF1 (CS/CISS1), CLCF1 (CS/CISS2) and KLHL7 (CS/CISS-like). Here, a whole exome sequencing approach in individuals with CS/CISS-like phenotype with unknown molecular defect revealed unpredicted alternative diagnoses. This approach identified putative pathogenic variations in NALCN, MAGEL2 and SCN2A. They were already found implicated in the pathogenesis of other syndromes, respectively the congenital contractures of the limbs and face, hypotonia, and developmental delay syndrome, the Schaaf-Yang syndrome, and the early infantile epileptic encephalopathy-11 syndrome. These results suggest a high neonatal phenotypic overlap among these disorders and will be very helpful for clinicians. Genetic analysis of these genes should be considered for those cases with a suspected CS/CISS during neonatal period who were tested as mutation negative in the known CS/CISS genes, because an expedited and corrected diagnosis can improve patient management and can provide a specific clinical follow-up.

  • 2.
    Annerén, Göran
    et al.
    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.
    Uddenfeldt, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Janols, Lars-Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Asperger syndrome in a boy with a balanced de novo translocation: t(17;19)(p13.3;p11)1995In: American Journal of Medical Genetics, ISSN 0148-7299, E-ISSN 1096-8628, Vol. 56, no 3, p. 330p. 330-1Article in journal (Other academic)
  • 3.
    Annerén, Göran
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Hedov, Gerth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Wester, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Downs syndrom: ny kunskap ställer höga krav på medicinsk vård och habilitering1999In: Socialmedicinsk Tidskrift, ISSN 0037-833X, Vol. 76, no 1, p. 71-79Article in journal (Other academic)
  • 4.
    Arnell, Henrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Hjalmas, Kelm
    Jagervall, Martin
    Läckgren, Göran
    Stenberg, Arne
    Bengtsson, Bengt
    Wassen, Christer
    Emahazion, Tesfai
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Annerén, Göran
    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.
    Sundvall, Mats
    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.
    The genetics of primary nocturnal enuresis: inheritance and suggestion of a second major gene on chromosome 12q1997In: Journal of Medical Genetics, ISSN 0022-2593, E-ISSN 1468-6244, Vol. 34, no 5, p. 360-5Article in journal (Refereed)
    Abstract [en]

    Primary nocturnal enuresis (PNE), or bedwetting at night, affects approximately 10% of 6 year old children. Genetic components contribute to the pathogenesis and recently one locus was assigned to chromosome 13q. We evaluated the genetic factors and the pattern of inheritance for PNE in 392 families. Dominant transmission was observed in 43% and an apparent recessive mode of inheritance was observed in 9% of the families. Among the 392 probands the ratio of males to females was 3:1 indicating sex linked or sex influenced factors. Linkage to candidate regions was tested in 16 larger families segregating for autosomal dominant PNE. A gene for PNE was excluded from chromosome 13q in 11 families, whereas linkage to the interval D13S263-D13S291 was suggested (Zmax = 2.1) in three families. Further linkage analyses excluded about 1/3 of the genome at a 10 cM resolution except the region around D12S80 on chromosome 12q that showed a positive two point lod score in six of the families (Zmax = 4.2). This locus remains suggestive because the material was not sufficiently large to give evidence for heterogeneity. Our pedigree analysis indicates that major genes are involved in a large proportion of PNE families and the linkage results suggest that such a gene is located on chromosome 12q.

  • 5.
    Arnell, Henrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Nemeth, Antal
    Annerén, Göran
    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.
    Progressive familial intrahepatic cholestasis (PFIC): evidence for genetic heterogeneity by exclusion of linkage to chromosome 18q21-q221997In: Human Genetics, ISSN 0340-6717, E-ISSN 1432-1203, Vol. 100, no 3-4, p. 378-381Article in journal (Refereed)
    Abstract [en]

    Progressive familial intrahepatic cholestasis (PFIC) is the second most common form of familial intrahepatic cholestasis. The genes for PFIC and for a milder form of the disease, benign recurrent intrahepatic cholestasis (BRIC), were recently mapped to a 19-cM region on chromosome 18q21-q22. The results suggest that PFIC and BRIC are allelic diseases. We have studied 11 Swedish patients from eight families with clinical and biochemical features consistent with PFIC. The families were genotyped for markers D18S69, D18S64, D18S55 and D18S68, spanning the PFIC candidate region. Unexpectedly, the segregation of haplotypes excluded the entire region in three families, and no indications for shared haplotypes were found in the patients of the six remaining families. A four-point linkage analysis of all families excluded linkage from D18S69 to D18S55 (Zmax < -5). Thus, our data strongly suggest the presence of a second, yet unknown, locus for PFIC. The results indicate that great care should be taken when using 18q markers for prenatal diagnosis and genetic counseling for the disease.

  • 6. Becker, Kerstin
    et al.
    Di Donato, Nataliya
    Holder-Espinasse, Muriel
    Andrieux, Joris
    Cuisset, Jean-Marie
    Vallée, Louis
    Plessis, Ghislaine
    Jean, Nolwenn
    Delobel, Bruno
    Thuresson, Ann-Charlotte
    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.
    Annerén, Göran
    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.
    Ravn, Kirstine
    Tümer, Zeynep
    Tinschert, Sigrid
    Schrock, Evelin
    Jønch, Aia Elise
    Hackmann, Karl
    De novo microdeletions of chromosome 6q14.1-q14.3 and 6q12.1-q14.1 in two patients with intellectual disability: further delineation of the 6q14 microdeletion syndrome and review of the literature2012In: European Journal of Medical Genetics, ISSN 1769-7212, E-ISSN 1878-0849, Vol. 55, no 8-9, p. 490-497Article in journal (Refereed)
    Abstract [en]

    Interstitial 6q deletions can cause a variable phenotype depending on the size and location of the deletion. 6q14 deletions have been associated with intellectual disability and a distinct pattern of minor anomalies, including upslanted palpebral fissures with epicanthal folds, a short nose with broad nasal tip, anteverted nares, long philtrum, and thin upper lip. In this study we describe two patients with overlapping 6q14 deletions presenting with developmental delay and characteristic dysmorphism. Molecular karyotyping using array CGH analysis revealed a de novo 8.9 Mb deletion at 6q14.1-q14.3 and a de novo 11.3 Mb deletion at 6q12.1-6q14.1, respectively. We provide a review of the clinical features of twelve other patients with 6q14 deletions detected by array CGH analysis. By assessing all reported data we could not identify a single common region of deletion. Possible candidate genes in 6q14 for intellectual disability might be FILIP1, MYO6, HTR1B, and SNX14.

  • 7. Boudry-Labis, Elise
    et al.
    Demeer, Benedicte
    Le Caignec, Cedric
    Isidor, Bertrand
    Mathieu-Dramard, Michele
    Plessis, Ghislaine
    George, Alice M.
    Taylor, Juliet
    Aftimos, Salim
    Wiemer-Kruel, Adelheid
    Kohlhase, Juergen
    Annerén, Göran
    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.
    Firth, Helen
    Simonic, Ingrid
    Vermeesch, Joris
    Thuresson, Ann-Charlotte
    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.
    Copin, Henri
    Love, Donald R.
    Andrieux, Joris
    A novel microdeletion syndrome at 9q21.13 characterised by mental retardation, speech delay, epilepsy and characteristic facial features2013In: European Journal of Medical Genetics, ISSN 1769-7212, E-ISSN 1878-0849, Vol. 56, no 3, p. 163-170Article in journal (Refereed)
    Abstract [en]

    The increased use of array-CGH and SNP-arrays for genetic diagnosis has led to the identification of new microdeletion/microduplication syndromes and enabled genotype-phenotype correlations to be made. In this study, nine patients with 9q21 deletions were investigated and compared with four previously Decipher reported patients. Genotype-phenotype comparisons of 13 patients revealed several common major characteristics including significant developmental delay, epilepsy, neuro-behavioural disorders and recognizable facial features including hypertelorism, feature-less philtrum, and a thin upper lip. The molecular investigation identified deletions with different breakpoints and of variable lengths, but the 750 kb smallest overlapping deleted region includes four genes. Among these genes, RORB is a strong candidate for a neurological phenotype. To our knowledge, this is the first published report of 9q21 microdeletions and our observations strongly suggest that these deletions are responsible for a new genetic syndrome characterised by mental retardation with speech delay, epilepsy, autistic behaviour and moderate facial dysmorphy. 

  • 8. Dianzani, Irma
    et al.
    Garelli, E.
    Gustavsson, P.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Carando, A.
    Gustafsson, B.
    Dahl, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Annerén, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Rapp-Hodgkin and AEC syndromes due to a new frameshift mutation in the TP63 gene2003In: Journal of Medical Genetics, ISSN 0022-2593, E-ISSN 1468-6244, Vol. 40, no 12, p. e133-Article in journal (Refereed)
  • 9.
    Edman Ahlbom, Bodil
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Goetz, P
    Korenberg, JR
    Pettersson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Medical Genetics.
    Seemenova, E
    Wadelius, Claes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Zech, Lore
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Annerén, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Molecular analysis of chromosome 21 in a patient with a phenotype of down syndrome and apparently normal karyotype1996In: American Journal of Medical Genetics. Part A, ISSN 1552-4825, E-ISSN 1552-4833, Vol. 63, no 4, p. 566-572Article in journal (Refereed)
    Abstract [en]

    Down syndrome (DS) is caused in most cases by the presence of an extra chromosome 21. It has been shown that the DS phenotype is produced by duplication of only a small part of the long arm of chromosome 21, the 21q22 region, including and distal to locus D21S55. We present molecular investigations on a woman with clinically typical DS but apparently normal chromosomes. Her parents were consanguineous and she had a sister with a DS phenotype, who died at the age of 15 days. Repeated cytogenetic investigations (G-banding and high resolution banding) on the patient and her parents showed apparently normal chromosomes. Autoradiographs of quantitative Southern blots of DNAs from the patient, her parents, trisomy 21 patients, and normal controls were analyzed after hybridization with unique DNA sequences regionally mapped on chromosome 21. Sequences D21S59, D21S1, D21S11, D21S8, D21S17, D21S55, ERG, D21S15, D21S112, and COL6A1 were all found in two copies. Fluorescent in situ hybridization with a chromosome 21-specific genomic library showed no abnormalities and only two copies of chromosome 21 were detected. Nineteen markers from the critical region studied with polymerase chain reaction amplification of di- and tetranucleotide repeats did not indicate any partial trisomy 21. From this study we conclude that the patient does not have any partial submicroscopic trisomy for any segment of chromosome 21. It seems reasonable to assume that she suffers from an autosomal recessive disorder which is phenotypically indistinguishable from DS.

  • 10.
    Ekvall, Sara
    et al.
    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.
    Sjörs, Kerstin
    Cent Hosp Vasteras, Dept Pediat, Vasteras, Sweden.
    Jonzon, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Vihinen, Mauno
    Lund Univ, Dept Expt Med Sci, Lund, Sweden.
    Annerén, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Bondeson, Marie-Louise
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Novel association of neurofibromatosis type 1-causing mutations in families with neurofibromatosis-Noonan syndrome2014In: American Journal of Medical Genetics. Part A, ISSN 1552-4825, E-ISSN 1552-4833, Vol. 164, no 3, p. 579-587Article in journal (Refereed)
    Abstract [en]

    Neurofibromatosis-Noonan syndrome (NFNS) is a rare condition with clinical features of both neurofibromatosis type 1 (NF1) and Noonan syndrome (NS). All three syndromes belong to the RASopathies, which are caused by dysregulation of the RAS-MAPK pathway. The major gene involved in NFNS is NF1, but co-occurring NF1 and PTPN11 mutations in NFNS have been reported. Knowledge about possible involvement of additional RASopathy-associated genes in NFNS is, however, very limited. We present a comprehensive clinical and molecular analysis of eight affected individuals from three unrelated families displaying features of NF1 and NFNS. The genetic etiology of the clinical phenotypes was investigated by mutation analysis, including NF1, PTPN11, SOS1, KRAS, NRAS, BRAF, RAF1, SHOC2, SPRED1, MAP2K1, MAP2K2, and CBL. All three families harbored a heterozygous NF1 variant, where the first family had a missense variant, c.5425C>T;p.R1809C, the second family a recurrent 4bp-deletion, c.6789_6792delTTAC;p.Y2264Tfs*6, and the third family a splice-site variant, c.2991-1G>A, resulting in skipping of exon 18 and an in-frame deletion of 41 amino acids. These NF1 variants have all previously been reported in NF1 patients. Surprisingly, both c.6789_6792delTTAC and c.2991-1G>A are frequently associated with NF1, but association to NFNS has, to our knowledge, not previously been reported. Our results support the notion that NFNS represents a variant of NF1, genetically distinct from NS, and is caused by mutations in NF1, some of which also cause classical NF1. Due to phenotypic overlap between NFNS and NS, we propose screening for NF1 mutations in NS patients, preferentially when café-au-lait spots are present.

  • 11.
    Ekvall, Sara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Wilbe, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Dahlgren, Jovanna
    Gothenburg Univ, Sahlgrenska Acad, Dept Paediat, Gothenburg, Sweden..
    Legius, Eric
    Katholieke Univ Leuven, Dept Human Genet, Leuven, Belgium..
    van Haeringen, Arie
    Leiden Univ, Med Ctr, Dept Clin Genet, Leiden, Netherlands..
    Westphal, Otto
    Gothenburg Univ, Sahlgrenska Acad, Dept Paediat, Gothenburg, Sweden..
    Annerén, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Bondeson, Marie-Louise
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Mutation in NRAS in familial Noonan syndrome: case report and review of the literature2015In: BMC Medical Genetics, ISSN 1471-2350, E-ISSN 1471-2350, Vol. 16, article id 95Article in journal (Refereed)
    Abstract [en]

    Background: Noonan syndrome (NS), a heterogeneous developmental disorder associated with variable clinical expression including short stature, congenital heart defect, unusual pectus deformity and typical facial features, is caused by activating mutations in genes involved in the RAS-MAPK signaling pathway. Case presentation: Here, we present a clinical and molecular characterization of a small family with Noonan syndrome. Comprehensive mutation analysis of NF1, PTPN11, SOS1, CBL, BRAF, RAF1, SHOC2, MAP2K2, MAP2K1, SPRED1, NRAS, HRAS and KRAS was performed using targeted next-generation sequencing. The result revealed a recurrent mutation in NRAS, c.179G > A (p.G60E), in the index patient. This mutation was inherited from the index patient's father, who also showed signs of NS. Conclusions: We describe clinical features in this family and review the literature for genotype-phenotype correlations for NS patients with mutations in NRAS. Neither of affected individuals in this family presented with juvenile myelomonocytic leukemia (JMML), which together with previously published results suggest that the risk for NS individuals with a germline NRAS mutation developing JMML is not different from the proportion seen in other NS cases. Interestingly, 50 % of NS individuals with an NRAS mutation (including our family) present with lentigines and/or Cafe-au-lait spots. This demonstrates a predisposition to hyperpigmented lesions in NRAS-positive NS individuals. In addition, the affected father in our family presented with a hearing deficit since birth, which together with lentigines are two characteristics of NS with multiple lentigines (previously LEOPARD syndrome), supporting the difficulties in diagnosing individuals with RASopathies correctly. The clinical and genetic heterogeneity observed in RASopathies is a challenge for genetic testing. However, next-generation sequencing technology, which allows screening of a large number of genes simultaneously, will facilitate an early and accurate diagnosis of patients with RASopathies.

  • 12.
    Englund, Annika
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Jonsson, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Zander, Cecilia Soussi
    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.
    Gustafsson, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Annerén, Göran
    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.
    Changes in mortality and causes of death in the Swedish Down syndrome population2013In: American Journal of Medical Genetics. Part A, ISSN 1552-4825, E-ISSN 1552-4833, Vol. 161A, no 4, p. 642-649Article in journal (Refereed)
    Abstract [en]

    During the past few decades age at death for individuals with Down syndrome (DS) has increased dramatically. The birth frequency of infants with DS has long been constant in Sweden. Thus, the prevalence of DS in the population is increasing. The aim of the present study was to analyze mortality and causes of death in individuals with DS during the period 19692003. All individuals with DS that died between 1969 and 2003 in Sweden, and all individuals born with DS in Sweden between 1974 and 2003 were included. Data were obtained from the Swedish Medical Birth Register, the Swedish Birth Defects Register, and the National Cause of Death Register. Median age at death has increased by 1.8 years per year. The main cause of death was pneumonia. Death from congenital heart defects decreased. Death from atherosclerosis was rare but more frequent than reported previously. Dementia was not reported in any subjects with DS before 40 years of age, but was a main or contributing cause of death in 30% of the older subjects. Except for childhood leukemia, cancer as a cause of death was rare in all age groups. Mortality in DS, particularly infant mortality, has decreased markedly during the past decades. Median age at death is increasing and is now almost 60 years. Death from cancer is rare in DS, but death from dementia is common.

  • 13.
    Englund, Hillevi
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Annerén, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Gustafsson, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Wester, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Wiltfang, Jens
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Blennow, Kaj
    Höglund, Kina
    Increase in beta-Amyloid Levels in Cerebrospinal Fluid of Children with Down Syndrome2007In: Dementia and Geriatric Cognitive Disorders, ISSN 1420-8008, E-ISSN 1421-9824, Vol. 24, no 5, p. 369-374Article in journal (Refereed)
    Abstract [en]

    Background: Individuals with Down syndrome (DS) invariably develop Alzheimer's disease (AD) during their life span. It is therefore of importance to study young DS patients when trying to elucidate early events in AD pathogenesis. Aim: To investigate how levels of different amyloid- (A) peptides, as well as tau and phosphorylated tau, in cerebrospinal fluid (CSF) from children with DS change over time. The first CSF sample was taken at 8 months and the following two samples at 20-40 and 54 months of age. Results: Individual levels of the A peptides, as well as total A levels in CSF increased over time when measured with Western blot. Tau in CSF decreased whereas there was no change in levels of phosphorylated tau over time. Conclusion: The increasing levels of A in CSF during early childhood of DS patients observed in this study are probably due to the trisomy of the A precursor APP, which leads to an overproduction of A. Despite the increased CSF concentrations of A, there were no signs of an AD-indicating tau pattern in CSF, since the levels of total tau decreased and phosphorylated tau remained unchanged. This observation further strengthens the theory of A pathology preceding tau pathology in AD.

  • 14.
    Frisk, Sofia
    et al.
    Karolinska Inst, Ctr Mol Med, Dept Mol Med & Surg, Stockholm, Sweden;Karolinska Univ Hosp, Karolinska Univ Lab, Dept Clin Genet, Stockholm, Sweden.
    Taylan, Fulya
    Karolinska Inst, Ctr Mol Med, Dept Mol Med & Surg, Stockholm, Sweden.
    Blaszczyk, Izabela
    Umea Univ Hosp, Dept Surg & Perioperat Sci, Hand & Plast Surg, Umea, Sweden.
    Nennesmo, Inger
    Karolinska Univ Hosp, Dept Pathol, Stockholm, Sweden.
    Annerén, Göran
    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.
    Herm, Bettina
    Ostersunds Hosp, Child & Adolescent Habilitat Ctr, Ostersund, Sweden.
    Stattin, Evalena
    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.
    Zachariadis, Vasilios
    Karolinska Inst, Ctr Mol Med, Dept Mol Med & Surg, Stockholm, Sweden.
    Lindstrand, Anna
    Karolinska Inst, Ctr Mol Med, Dept Mol Med & Surg, Stockholm, Sweden;Karolinska Univ Hosp, Karolinska Univ Lab, Dept Clin Genet, Stockholm, Sweden.
    Tesi, Bianca
    Karolinska Inst, Ctr Mol Med, Dept Mol Med & Surg, Stockholm, Sweden;Karolinska Univ Hosp, Karolinska Univ Lab, Dept Clin Genet, Stockholm, Sweden.
    Laurell, Tobias
    Karolinska Inst, Ctr Mol Med, Dept Mol Med & Surg, Stockholm, Sweden.
    Nordgren, Ann
    Karolinska Inst, Ctr Mol Med, Dept Mol Med & Surg, Stockholm, Sweden;Karolinska Univ Hosp, Karolinska Univ Lab, Dept Clin Genet, Stockholm, Sweden.
    Early activating somatic PIK3CA mutations promote ectopic muscle development and upper limb overgrowth2019In: Clinical Genetics, ISSN 0009-9163, E-ISSN 1399-0004, Vol. 96, no 2, p. 118-125Article in journal (Refereed)
    Abstract [en]

    PIK3CA-related overgrowth spectrum is a group of rare genetic disorders with asymmetric overgrowth caused by somatic mosaic PIK3CA mutations. Here, we report clinical data and molecular findings from two patients with congenital muscular upper limb overgrowth and aberrant anatomy. During debulking surgery, numerous ectopic muscles were found in the upper limbs of the patients. DNA sequencing, followed by digital polymerase chain reaction, was performed on DNA extracted from biopsies from hypertrophic ectopic muscles and identified the somatic mosaic PIK3CA hotspot mutations c.3140A > G, p.(His1047Arg) and c.1624G > A, p.(Glu542Lys) in a male (patient 1) and a female (patient 2) patient, respectively. Patient 1 had four ectopic muscles and unilateral isolated muscular overgrowth while patient 2 had 13 ectopic muscles and bilateral isolated muscular overgrowth of both upper limbs, indicating that her mutation occurred at early pre-somitic mesoderm state. The finding of PIK3CA mutations in ectopic muscles highlights the importance of PIK3CA in cell fate in early human embryonic development. Moreover, our findings provide evidence that the disease phenotype depends on the timing of PIK3CA mutagenesis during embryogenesis and confirm the diagnostic entity PIK3CA-related muscular overgrowth with ectopic accessory muscles.

  • 15. George, Lena
    et al.
    Granath, Fredrik
    Johansson, Anna L. V.
    Annerén, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Cnattingius, Sven
    Environmental tobacco smoke and risk of spontaneous abortion2006In: Epidemiology, ISSN 1044-3983, E-ISSN 1531-5487, Vol. 17, no 5, p. 500-505Article in journal (Refereed)
    Abstract [en]

    Background: Studies of exposure to environmental tobacco smoke (ETS) and risk of spontaneous abortion are limited to a few studies of self-reported exposure, and the results have been inconsistent. The aim of this study was to investigate risk of early spontaneous abortion related to ETS and active smoking as defined by plasma cotinine levels.

    Methods: We conducted a population-based case-control study in Uppsala County, Sweden, between January 1996 and December 1998. Cases were 463 women with spontaneous abortion at 6 to 12 completed weeks of gestation, and controls were 864 pregnant women matched to cases according to the week of gestation. Exposure status was defined by plasma cotinine concentrations: nonexposed, < 0.1 ng/mL; ETS-exposed, 0.1-15 ng/mL; and exposed to active smoking, > 15 ng/mL. Multivariable analysis was used to estimate the relative risk of spontaneous abortion associated with exposure to ETS and active smoking.

    Results: Nineteen percent of controls and 24% of cases were classified as having been exposed to ETS. Compared with nonexposed women, risk of spontaneous abortion was increased among both ETS-exposed women (adjusted odds ratio = 1.67; 95% confidence interval = 1.17-2.38) and active smokers (2.11; 1.36-3.27). We could not show a differential effect of exposure to ETS or active smoking between normal and abnormal fetal karyotype abortions.

    Conclusions: Nonsmoking pregnant women exposed to ETS may be at increased risk of spontaneous abortion. Given the high prevalence of ETS exposure, the public health consequences of passive smoking regarding early fetal loss may be substantial.

  • 16.
    Gudmundsson, Sanna
    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.
    Annerén, Göran
    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.
    Marcos-Alcalde, Íñigo
    Centro de Biología Molecular "Severo Ochoa" (CSIC-UAM), 28049, Madrid, Spain;Faculty of Experimental Sciences, Francisco de Vitoria University, Pozuelo de Alarcón, 28223, Madrid, Spain.
    Wilbe, Maria
    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.
    Melin, Malin
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Gómez-Puertas, Paulino
    Centro de Biología Molecular "Severo Ochoa" (CSIC-UAM), 28049, Madrid, Spain.
    Bondeson, Marie-Louise
    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.
    A novel RAD21 p.(Gln592del) variant expands the clinical description of Cornelia de Lange syndrome type 4: Review of the literature2019In: European Journal of Medical Genetics, ISSN 1769-7212, E-ISSN 1878-0849, Vol. 62, no 6, article id 103526Article in journal (Refereed)
    Abstract [en]

    Cornelia de Lange syndrome (CdLS) is a heterogeneous developmental disorder where 70% of clinically diagnosed patients harbor a variant in one of five CdLS associated cohesin proteins. Around 500 variants have been identified to cause CdLS, however only eight different alterations have been identified in the RAD21 gene, encoding the RAD21 cohesin complex component protein that constitute the link between SMC1A and SMC3 within the cohesin ring. We report a 15-month-old boy presenting with developmental delay, distinct CdLS-like facial features, gastrointestinal reflux in early infancy, testis retention, prominent digit pads and diaphragmatic hernia. Exome sequencing revealed a novel RAD21 variant, c.1774_1776del, p.(Gln592del), suggestive of CdLS type 4. Segregation analysis of the two healthy parents confirmed the variant as de novo and bioinformatic analysis predicted the variant as disease-causing. Assessment by in silico structural model predicted that the p.Gln592del variant results in a discontinued contact between RAD21-Lys591 and the SMC1A residues Glu1191 and Glu1192, causing changes in the RAD21-SMC1A interface. In conclusion, we report a patient that expands the clinical description of CdLS type 4 and presents with a novel RAD21 p.(Glu592del) variant that causes a disturbed RAD21-SMC1A interface according to in silco structural modeling.

  • 17.
    Gudmundsson, Sanna
    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. Uppsala University.
    Wilbe, Maria
    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.
    Gorniok, Beata Filipek
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Molin, Anna-Maja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ekvall, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Johansson, Josefin
    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.
    Allalou, Amin
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computerized Image Analysis and Human-Computer Interaction. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Division of Visual Information and Interaction.
    Gylje, Hans
    Department of Paediatrics, Central Hospital, Västerås, 721 89, Sweden..
    Kalscheuer, Vera M.
    Research Group Development and Disease, Max Planck Institute for Molecular Genetics, Berlin, 141 95, Germany..
    Ledin, Johan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Annerén, Göran
    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.
    Bondeson, Marie-Louise
    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.
    TAF1, associated with intellectual disability in humans, is essential for embryogenesis and regulates neurodevelopmental processes in zebrafish2019In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 10730Article in journal (Refereed)
    Abstract [en]

    The TATA-box binding protein associated factor 1 (TAF1) protein is a key unit of the transcription factor II D complex that serves a vital function during transcription initiation. Variants of TAF1 have been associated with neurodevelopmental disorders, but TAF1's molecular functions remain elusive. In this study, we present a five-generation family affected with X-linked intellectual disability that co-segregated with a TAF1 c. 3568C>T, p.(Arg1190Cys) variant. All affected males presented with intellectual disability and dysmorphic features, while heterozygous females were asymptomatic and had completely skewed X-chromosome inactivation. We investigated the role of TAF1 and its association to neurodevelopment by creating the first complete knockout model of the TAF1 orthologue in zebrafish. A crucial function of human TAF1 during embryogenesis can be inferred from the model, demonstrating that intact taf1 is essential for embryonic development. Transcriptome analysis of taf1 zebrafish knockout revealed enrichment for genes associated with neurodevelopmental processes. In conclusion, we propose that functional TAF1 is essential for embryonic development and specifically neurodevelopmental processes.

  • 18.
    Hansson, Tony
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Women's and Children's Health.
    Dahlbom, Ingrid
    Rogberg, Siv
    Nyberg, Britt-Inger
    Dahlström, Jörgen
    Anneren, Göran
    Department of Genetics and Pathology.
    Klareskog, Lars
    Dannaeus, Anders
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Women's and Children's Health.
    Antitissue transglutaminase and antithyroid autoantibodies in children with Down syndrome and celiac disease.2005In: J Pediatr Gastroenterol Nutr, ISSN 0277-2116, Vol. 40, no 2, p. 170-4; discussion 125Article in journal (Refereed)
  • 19. Hedov, Gerth
    et al.
    Annerén, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Bättre stöd åt nyblivna föräldrar till barn med livslångt funktionshinder: Förslag till nya riktlinjer2010In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 107, no 22, p. 1477-1479Article in journal (Other academic)
  • 20.
    Hu, H.
    et al.
    Max Planck Inst Mol Genet, Dept Human Mol Genet, D-14195 Berlin, Germany..
    Haas, S. A.
    Max Planck Inst Mol Genet, Dept Computat Mol Biol, D-14195 Berlin, Germany..
    Chelly, J.
    Univ Paris 05, Paris, France.;CNRS, UMR 8104, Inst Cochin, Inst Natl Sante & Rech Med,Unit 1016, Paris, France..
    Van Esch, H.
    Univ Hosp Leuven, Ctr Human Genet, Leuven, Belgium..
    Raynaud, M.
    INSERM, Imaging & Brain U930, Tours, France.;Univ Tours, Tours, France.;Ctr Hosp Reg Univ, Serv Genet, Tours, France..
    de Brouwer, A. P. M.
    Radboud Univ Nijmegen, Med Ctr, Donders Inst Brain Cognit & Behav, Dept Human Genet, NL-6525 ED Nijmegen, Netherlands..
    Weinert, S.
    Max Delbruck Centrum Mol Med, Berlin, Germany.;Leibniz Inst Mol Pharmacol, Berlin, Germany..
    Froyen, G.
    VIB Ctr Biol Dis, Human Genome Lab, Leuven, Belgium.;Katholieke Univ Leuven, Dept Human Genet, Human Genome Lab, Leuven, Belgium..
    Frints, S. G. M.
    Maastricht Univ, Med Ctr, AzM, Dept Clin Genet, NL-6200 MD Maastricht, Netherlands.;Maastricht Univ, GROW, Sch Oncol & Dev Biol, NL-6200 MD Maastricht, Netherlands..
    Laumonnier, F.
    INSERM, Imaging & Brain U930, Tours, France.;Univ Tours, Tours, France..
    Zemojtel, T.
    Max Planck Inst Mol Genet, Dept Computat Mol Biol, D-14195 Berlin, Germany..
    Love, M. I.
    Max Planck Inst Mol Genet, Dept Computat Mol Biol, D-14195 Berlin, Germany..
    Richard, H.
    Max Planck Inst Mol Genet, Dept Computat Mol Biol, D-14195 Berlin, Germany..
    Emde, A-K
    Max Planck Inst Mol Genet, Dept Computat Mol Biol, D-14195 Berlin, Germany..
    Bienek, M.
    Max Planck Inst Mol Genet, Dept Human Mol Genet, D-14195 Berlin, Germany..
    Jensen, C.
    Max Planck Inst Mol Genet, Dept Human Mol Genet, D-14195 Berlin, Germany..
    Hambrock, M.
    Max Planck Inst Mol Genet, Dept Human Mol Genet, D-14195 Berlin, Germany..
    Fischer, U.
    Max Planck Inst Mol Genet, Dept Human Mol Genet, D-14195 Berlin, Germany..
    Langnick, C.
    Max Delbruck Centrum Mol Med, Berlin, Germany..
    Feldkamp, M.
    Max Delbruck Centrum Mol Med, Berlin, Germany..
    Wissink-Lindhout, W.
    Radboud Univ Nijmegen, Med Ctr, Donders Inst Brain Cognit & Behav, Dept Human Genet, NL-6525 ED Nijmegen, Netherlands..
    Lebrun, N.
    Univ Paris 05, Paris, France.;CNRS, UMR 8104, Inst Cochin, Inst Natl Sante & Rech Med,Unit 1016, Paris, France..
    Castelnau, L.
    Univ Paris 05, Paris, France.;CNRS, UMR 8104, Inst Cochin, Inst Natl Sante & Rech Med,Unit 1016, Paris, France..
    Rucci, J.
    Univ Paris 05, Paris, France.;CNRS, UMR 8104, Inst Cochin, Inst Natl Sante & Rech Med,Unit 1016, Paris, France..
    Montjean, R.
    Univ Paris 05, Paris, France.;CNRS, UMR 8104, Inst Cochin, Inst Natl Sante & Rech Med,Unit 1016, Paris, France..
    Dorseuil, O.
    Univ Paris 05, Paris, France.;CNRS, UMR 8104, Inst Cochin, Inst Natl Sante & Rech Med,Unit 1016, Paris, France..
    Billuart, P.
    Univ Paris 05, Paris, France.;CNRS, UMR 8104, Inst Cochin, Inst Natl Sante & Rech Med,Unit 1016, Paris, France..
    Stuhlmann, T.
    Max Delbruck Centrum Mol Med, Berlin, Germany.;Leibniz Inst Mol Pharmacol, Berlin, Germany..
    Shaw, M.
    Univ Adelaide, Sch Paediat & Reprod Hlth, Adelaide, SA, Australia.;Univ Adelaide, Robinson Res Inst, Adelaide, SA, Australia..
    Corbett, M. A.
    Univ Adelaide, Sch Paediat & Reprod Hlth, Adelaide, SA, Australia.;Univ Adelaide, Robinson Res Inst, Adelaide, SA, Australia..
    Gardner, A.
    Univ Adelaide, Sch Paediat & Reprod Hlth, Adelaide, SA, Australia.;Univ Adelaide, Robinson Res Inst, Adelaide, SA, Australia..
    Willis-Owen, S.
    Univ Adelaide, Sch Paediat & Reprod Hlth, Adelaide, SA, Australia.;Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, London, England..
    Tan, C.
    Univ Adelaide, Sch Paediat & Reprod Hlth, Adelaide, SA, Australia..
    Friend, K. L.
    Womens & Childrens Hosp, SA Pathol, Adelaide, SA, Australia..
    Belet, S.
    VIB Ctr Biol Dis, Human Genome Lab, Leuven, Belgium.;Katholieke Univ Leuven, Dept Human Genet, Human Genome Lab, Leuven, Belgium..
    van Roozendaal, K. E. P.
    Maastricht Univ, Med Ctr, AzM, Dept Clin Genet, NL-6200 MD Maastricht, Netherlands.;Maastricht Univ, GROW, Sch Oncol & Dev Biol, NL-6200 MD Maastricht, Netherlands..
    Jimenez-Pocquet, M.
    Ctr Hosp Reg Univ, Serv Genet, Tours, France..
    Moizard, M-P
    INSERM, Imaging & Brain U930, Tours, France.;Univ Tours, Tours, France.;Ctr Hosp Reg Univ, Serv Genet, Tours, France..
    Ronce, N.
    INSERM, Imaging & Brain U930, Tours, France.;Univ Tours, Tours, France.;Ctr Hosp Reg Univ, Serv Genet, Tours, France..
    Sun, R.
    Max Planck Inst Mol Genet, Dept Computat Mol Biol, D-14195 Berlin, Germany..
    O'Keeffe, S.
    Max Planck Inst Mol Genet, Dept Computat Mol Biol, D-14195 Berlin, Germany..
    Chenna, R.
    Max Planck Inst Mol Genet, Dept Computat Mol Biol, D-14195 Berlin, Germany..
    Van Boemmel, A.
    Max Planck Inst Mol Genet, Dept Computat Mol Biol, D-14195 Berlin, Germany..
    Goeke, J.
    Max Planck Inst Mol Genet, Dept Computat Mol Biol, D-14195 Berlin, Germany..
    Hackett, A.
    Genet Learning & Disabil Serv, Hunter Genet, Waratah, NSW, Australia..
    Field, M.
    Genet Learning & Disabil Serv, Hunter Genet, Waratah, NSW, Australia..
    Christie, L.
    Genet Learning & Disabil Serv, Hunter Genet, Waratah, NSW, Australia..
    Boyle, J.
    Genet Learning & Disabil Serv, Hunter Genet, Waratah, NSW, Australia..
    Haan, E.
    Womens & Childrens Hosp, SA Pathol, Adelaide, SA, Australia..
    Nelson, J.
    King Edward Mem Hosp, Genet Serv Western Australia, Perth, WA, Australia..
    Turner, G.
    Genet Learning & Disabil Serv, Hunter Genet, Waratah, NSW, Australia..
    Baynam, G.
    King Edward Mem Hosp, Genet Serv Western Australia, Perth, WA, Australia.;Univ Western Australia, Sch Paediat & Child Hlth, Perth, WA 6009, Australia.;Murdoch Univ, Inst Immunol & Infect Dis, Perth, WA, Australia.;Telethon Kids Inst, Perth, WA, Australia..
    Gillessen-Kaesbach, G.
    Univ Lubeck, Inst Humangenet, Lubeck, Germany..
    Mueller, U.
    Univ Giessen, Inst Humangenet, D-35390 Giessen, Germany.;Biol Ctr Human Genet, Frankfurt, Germany..
    Steinberger, D.
    Univ Giessen, Inst Humangenet, D-35390 Giessen, Germany.;Biol Ctr Human Genet, Frankfurt, Germany..
    Budny, B.
    Ponzan Univ Med Sci, Chair Dept Endocrinol Metab & Internal Dis, Poznan, Poland..
    Badura-Stronka, M.
    Ponzan Univ Med Sci, Chair Dept Med Genet, Poznan, Poland..
    Latos-Bielenska, A.
    Ponzan Univ Med Sci, Chair Dept Med Genet, Poznan, Poland..
    Ousager, L. B.
    Odense Univ Hosp, Dept Clin Genet, DK-5000 Odense, Denmark..
    Wieacker, P.
    Univ Klinikum Munster, Inst Humangenet, Munster, Germany..
    Criado, G. Rodriguez
    Hosp Virgen Rocio, Unidad Genet Clin, Seville, Spain..
    Bondeson, Marie-Louise
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Annerén, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Dufke, A.
    Inst Med Genet & Angew Genom, Tubingen, Germany..
    Cohen, M.
    Kinderzentrum Munchen, Munich, Germany..
    Van Maldergem, L.
    Univ Franche Comte, Ctr Genet Humaine, F-25030 Besancon, France..
    Vincent-Delorme, C.
    CHRU Lilles, Hop Jeanne Flandre, Serv Genet, Lille, France..
    Echenne, B.
    CHU Montpellier, Serve Neuropediat, Montpellier, France..
    Simon-Bouy, B.
    Ctr Hosp Versailles, Lab SESEP, Le Chesnay, France..
    Kleefstra, T.
    Radboud Univ Nijmegen, Med Ctr, Donders Inst Brain Cognit & Behav, Dept Human Genet, NL-6525 ED Nijmegen, Netherlands..
    Willemsen, M.
    Radboud Univ Nijmegen, Med Ctr, Donders Inst Brain Cognit & Behav, Dept Human Genet, NL-6525 ED Nijmegen, Netherlands..
    Fryns, J-P
    Univ Hosp Leuven, Ctr Human Genet, Leuven, Belgium..
    Devriendt, K.
    Univ Hosp Leuven, Ctr Human Genet, Leuven, Belgium..
    Ullmann, R.
    Max Planck Inst Mol Genet, Dept Human Mol Genet, D-14195 Berlin, Germany..
    Vingron, M.
    Max Planck Inst Mol Genet, Dept Computat Mol Biol, D-14195 Berlin, Germany..
    Wrogemann, K.
    Univ Manitoba, Dept Biochem & Med Genet, Winnipeg, MB, Canada..
    Wienker, T. F.
    Max Planck Inst Mol Genet, Dept Human Mol Genet, D-14195 Berlin, Germany..
    Tzschach, A.
    Max Planck Inst Mol Genet, Dept Human Mol Genet, D-14195 Berlin, Germany..
    van Bokhoven, H.
    Radboud Univ Nijmegen, Med Ctr, Donders Inst Brain Cognit & Behav, Dept Human Genet, NL-6525 ED Nijmegen, Netherlands..
    Gecz, J.
    Univ Adelaide, Sch Paediat & Reprod Hlth, Adelaide, SA, Australia..
    Jentsch, T. J.
    Max Delbruck Centrum Mol Med, Berlin, Germany.;Leibniz Inst Mol Pharmacol, Berlin, Germany..
    Chen, W.
    Max Delbruck Centrum Mol Med, Berlin, Germany..
    Ropers, H-H
    Max Planck Inst Mol Genet, Dept Human Mol Genet, D-14195 Berlin, Germany..
    Kalscheuer, V. M.
    Max Planck Inst Mol Genet, Dept Human Mol Genet, D-14195 Berlin, Germany..
    X-exome sequencing of 405 unresolved families identifies seven novel intellectual disability genes2016In: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 21, no 1, p. 133-148Article in journal (Refereed)
    Abstract [en]

    X-linked intellectual disability (XLID) is a clinically and genetically heterogeneous disorder. During the past two decades in excess of 100 X-chromosome ID genes have been identified. Yet, a large number of families mapping to the X-chromosome remained unresolved suggesting that more XLID genes or loci are yet to be identified. Here, we have investigated 405 unresolved families with XLID. We employed massively parallel sequencing of all X-chromosome exons in the index males. The majority of these males were previously tested negative for copy number variations and for mutations in a subset of known XLID genes by Sanger sequencing. In total, 745 X-chromosomal genes were screened. After stringent filtering, a total of 1297 non-recurrent exonic variants remained for prioritization. Co-segregation analysis of potential clinically relevant changes revealed that 80 families (20%) carried pathogenic variants in established XLID genes. In 19 families, we detected likely causative protein truncating and missense variants in 7 novel and validated XLID genes (CLCN4, CNKSR2, FRMPD4, KLHL15, LAS1L, RLIM and USP27X) and potentially deleterious variants in 2 novel candidate XLID genes (CDK16 and TAF1). We show that the CLCN4 and CNKSR2 variants impair protein functions as indicated by electrophysiological studies and altered differentiation of cultured primary neurons from Clcn4(-/-) mice or after mRNA knock-down. The newly identified and candidate XLID proteins belong to pathways and networks with established roles in cognitive function and intellectual disability in particular. We suggest that systematic sequencing of all X-chromosomal genes in a cohort of patients with genetic evidence for X-chromosome locus involvement may resolve up to 58% of Fragile X-negative cases.

  • 21.
    Klar, Joakim
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Åsling, Bengt
    Carlsson, Birgit
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Ulvsbäck, Magnus
    Dellsén, Anita
    Ström, Carina
    Rhedin, Margaretha
    Forslund, Anders
    Annerén, Göran
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Ludvigsson, Jonas
    Dahl, Niklas
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    RAR-related orphan receptor A isoform 1 (RORa1) is disrupted by a balanced translocation t(4;15)(q22.3;q21.3) associated with severe obesity.2005In: Eur J Hum Genet, ISSN 1018-4813Article in journal (Refereed)
    Abstract [en]

    We have identified a family comprising a mother and two children with idiopathic and profound obesity body mass index (BMI) 41-49 kg/m(2). The three family members carry a balanced reciprocal chromosome translocation t(4;15). We present here the clinical features of the affected individuals as well as the physical mapping and cloning of the chromosomal breakpoints. A detailed characterisation of the chromosomal breakpoints at chromosomes 4 and 15 revealed that the translocation is almost perfectly balanced with a very short insertion/deletion.

    The chromosome 15 breakpoint is positioned in intron 1 of the RAR-related orphan receptor A isoform 1 (RORa1) and the chromosome 4 breakpoint is positioned 133 kb telomeric to the transcriptional start of the unc-5 homolog B (UNC5C) and 154 kb centromeric of the transcriptional start of the pyruvate dehydrogenase (lipoamide) alpha 2 (PDHA2). The rearrangement creates a fusion gene, which includes the RORa1 exon 1 and UNC5C that is expressed in frame in adipocytes from the affected patients. We also show that this transcript is translated into a protein. From previous reports, it is shown that RORa1 is implicated in the regulation of adipogenesis and lipoprotein metabolism. We hypothesise that the obesity in this family is caused by (i) haploinsufficiency for RORa1 or, (ii) a gain of function mechanism mediated by the RORa1-UNC5C fusion gene.

  • 22. Le Blanc, Katarina
    et al.
    Götherström, Cecilia
    Ringdeén, Olle
    Hassan, Moustapha
    Horwitz, Edwin
    Annerén, Göran
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology. Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Axelsson, Ove
    Department of Women's and Children's Health.
    Nunn, Janice
    Ewald, Uwe
    Department of Women's and Children's Health.
    Nordén-Lindeberg, Solveig
    Department of Women's and Children's Health.
    Jansson, Monika
    Dalton, Ann
    Åström, Eva
    Westergren, Magnus
    Fetal Mesenchymal Stem-Cell Engraftment in Bone after In Utero Transplantation in a Patient with Severe Osteogenesis Imperfecta2005In: Transplantation, Vol. 79, no 11, p. 1607-14Article in journal (Refereed)
  • 23. Leoncini, Emanuele
    et al.
    Baranello, Giovanni
    Orioli, Iêda M
    Annerén, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Bakker, Marian
    Bianchi, Fabrizio
    Bower, Carol
    Canfield, Mark A
    Castilla, Eduardo E
    Cocchi, Guido
    Correa, Adolfo
    De Vigan, Catherine
    Doray, Berenice
    Feldkamp, Marcia L
    Gatt, Miriam
    Irgens, Lorentz M
    Lowry, R Brian
    Maraschini, Alice
    Mc Donnell, Robert
    Morgan, Margery
    Mutchinick, Osvaldo
    Poetzsch, Simone
    Riley, Merilyn
    Ritvanen, Annukka
    Gnansia, Elisabeth Robert
    Scarano, Gioacchino
    Sipek, Antonin
    Tenconi, Romano
    Mastroiacovo, Pierpaolo
    Frequency of holoprosencephaly in the International Clearinghouse Birth Defects Surveillance Systems: Searching for population variations.2008In: Birth defects research. Clinical and molecular teratology, ISSN 1542-0752, E-ISSN 1542-0760, Vol. 82, no 8, p. 585-591Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Holoprosencephaly (HPE) is a developmental field defect of the brain that results in incomplete separation of the cerebral hemispheres that includes less severe phenotypes, such as arhinencephaly and single median rnaxillary central incisor. Information on the epidemiology of HPE is limited, both because few population-based studies have been reported, and because small Studies must observe a greater number of years in order to accumulate sufficient numbers of births for a reliable estimate. METHODS: We collected data from 2000 through 2004 from 24 of the 46 Birth Defects Registry Members of the International Clearinghouse for Birth Defects Surveillance and Research. This Study is based on more than 7 million births in various areas from North and South America, Europe, and Australia. RESULTS: A total of 963 HPE cases were registered, yielding an overall prevalence of 1.31 per 10,000 births. Because the estimate was heterogeneous, possible causes of variations among populations were analyzed: random variation, Under-reporting and over-reporting bias, variation in proportion of termination of pregnancies among all registered cases and real differences among populations. CONCLUSIONS: The data do not suggest large differences in total prevalence of HPE among the studied Populations that would be useful to generate etiological hypotheses.

  • 24.
    Ljunger, Elisabeth
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Women's and Children's Health.
    Cnattingius, Sven
    Lundin, Catarina
    Anneren, Göran
    Chromosomal anomalies in first-trimester miscarriages.2005In: Acta Obstet Gynecol Scand, ISSN 0001-6349, Vol. 84, no 11, p. 1103-7Article in journal (Refereed)
  • 25.
    Ljunger, Elisabeth
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Stavreus-Evers, Anneli
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Cnattingius, Sven
    Clinical Epidemiology Unit, Dept of Medicine, Karolinska Institutet, Stockholm, Sweden.
    Ekbom, Anders
    Lundin, Catarina
    Annerén, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Sundström-Poromaa, Inger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Ultrasonographic findings in spontaneous miscarriage: relation to euploidy and aneuploidy2011In: Fertility and Sterility, ISSN 0015-0282, E-ISSN 1556-5653, Vol. 95, no 1, p. 221-224Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To evaluate a possible correlation between transvaginal ultrasound findings in miscarriages and cytogenetic analyses from chorionic villi obtained by dilatation and curettage. DESIGN: Prospective, population-based study. SETTING: University-based hospital. PATIENT(S): Five hundred seventy-six women with spontaneous miscarriage diagnosed between 6 and 12 completed pregnancy weeks. INTERVENTION(S): Transvaginal ultrasonography and dilatation and curettage. MAIN OUTCOME MEASURE(S): Cytogenetic analyses and ultrasound measurement of embryonic pole. RESULT(S): The mean gestational age was 9.5 weeks. Chromosomal analyses were successful in 259 cases, 159 with cytogenetic abnormalities and 100 euploidy. Empty gestational sacs were equally often found in euploidy and aneuploidy, whereas small embryonic or fetal poles were significantly more often associated with aneuploidy. CONCLUSION(S): A smaller than expected fetal size when a miscarriage is diagnosed during the first trimester is significantly associated with a chromosomal aberration.

  • 26. 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.

  • 27.
    Mansouri, Mahmoud Reza
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Carlsson, Birgit
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Davey, Edward
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Nordenskjöld, Agneta
    Dept of molecular medicine and surgery, Karolinska University hospital, Stockholm.
    Wester, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Annerén, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Läckgren, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Dahl, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Molecular genetic analysis of a de novo balanced translocation t(6;17) (p21.31;q11.2) associated with hypospadias and anorectal malformation2006In: Human Genetics, ISSN 0340-6717, E-ISSN 1432-1203, Vol. 119, no 1-2, p. 162-168Article in journal (Refereed)
  • 28.
    Molin, Anna-Maja
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Andrieux, J.
    Koolen, D. A.
    Malan, V.
    Carella, M.
    Colleaux, L.
    Cormier-Daire, V.
    David, A.
    de Leeuw, N.
    Delobel, B.
    Duban-Bedu, B.
    Fischetto, R.
    Flinter, F.
    Kjaergaard, S.
    Kok, F.
    Krepischi, A. C.
    Le Caignec, C.
    Ogilvie, C. Mackie
    Maia, S.
    Mathieu-Dramard, M.
    Munnich, A.
    Palumbo, O.
    Papadia, F.
    Pfundt, R.
    Reardon, W.
    Receveur, A.
    Rio, M.
    Darling, L. Ronsbro
    Rosenberg, C.
    Sa, J.
    Vallee, L.
    Vincent-Delorme, C.
    Zelante, L.
    Bondeson, Marie-Louise
    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.
    Annerén, Göran
    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.
    A novel microdeletion syndrome at 3q13.31 characterised by developmental delay, postnatal overgrowth, hypoplastic male genitals, and characteristic facial features2012In: Journal of Medical Genetics, ISSN 0022-2593, E-ISSN 1468-6244, Vol. 49, no 2, p. 104-109Article in journal (Refereed)
    Abstract [en]

    Background Congenital deletions affecting 3q11q23 have rarely been reported and only five cases have been molecularly characterised. Genotype. phenotype correlation has been hampered by the variable sizes and breakpoints of the deletions. In this study, 14 novel patients with deletions in 3q11q23 were investigated and compared with 13 previously reported patients. Methods Clinical data were collected from 14 novel patients that had been investigated by high resolution microarray techniques. Molecular investigation and updated clinical information of one cytogenetically previously reported patient were also included. Results The molecular investigation identified deletions in the region 3q12.3q21.3 with different boundaries and variable sizes. The smallest studied deletion was 580 kb, located in 3q13.31. Genotype. phenotype comparison in 24 patients sharing this shortest region of overlapping deletion revealed several common major characteristics including significant developmental delay, muscular hypotonia, a high arched palate, and recognisable facial features including a short philtrum and protruding lips. Abnormal genitalia were found in the majority of males, several having micropenis. Finally, a postnatal growth pattern above the mean was apparent. The 580 kb deleted region includes five RefSeq genes and two of them are strong candidate genes for the developmental delay: DRD3 and ZBTB20. Conclusion A newly recognised 3q13.31 microdeletion syndrome is delineated which is of diagnostic and prognostic value. Furthermore, two genes are suggested to be responsible for the main phenotype.

  • 29.
    Nyström, A-M
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Bondeson, M-L
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Skanke, N
    Mårtensson, J
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Strömberg, B
    Department of Women's and Children's Health.
    Gustafsson, J
    Department of Women's and Children's Health.
    Annerén, G
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    A novel nonsense mutation of the mineralocorticoid receptor gene in a Swedish family with pseudohypoaldosteronism type I (PHA1).2004In: J Clin Endocrinol Metab, ISSN 0021-972X, Vol. 89, no 1, p. 227-31Article in journal (Refereed)
    Abstract [en]

    Pseudohypoaldosteronism type I (PHA1) is a condition associated with salt wasting leading to dehydration, hypotension, hyperkalemia, and metabolic acidosis. Sporadic cases and two familial forms, one autosomal dominant and one autosomal recessive form, have been described. The autosomal dominant or sporadic form manifests milder salt wasting that remits with age. Mutations in the gene encoding the mineralocorticoid receptor (MR) have been identified in patients with the autosomal dominant inheritance. However, recent studies suggest that the autosomal dominant and sporadic forms are genetically heterogeneous and that additional genes might be involved. We report on the study of 15 members of a Swedish five-generation family with the autosomal dominant form of PHA1. Interestingly, neuropathy was found in two of five affected individuals. A novel heterozygous nonsense mutation C436X in exon 2 was identified in the index patient by linkage analysis, PCR, and direct sequencing of the MR gene. Analysis of the family demonstrated that the mutation segregated with PHA1 in the family. It is unclear whether the neuropathy is associated with the mutation found. Our results together with previously published data suggest that loss-of-function mutations of the MR gene located at 4q31.1, commonly are associated with the autosomal dominant form of PHA1.

  • 30.
    Nyström, Anna-Maja
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Ekvall, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Berglund, Erna
    Inst. för Pediatrik, Skellefteå Central Lasarett.
    Björkqvist, Maria
    Inst. för Pediatrik, Örebro Universitetssjukhus.
    Braathen, Gunnar
    Inst. för Pediatrik, Sahlgrenska Universitetsjukhuset, Göteborg.
    Duchen, Karel
    Inst. för Pediatrik, Universitetsjukhuset i Linköping.
    Enell, Henrik
    Inst. för Pediatrik, Rikshospitalet i Halmstad.
    Holmberg, Eva
    Klinisk Genetik, Sahlgrenska Universitetsjukhuset, Göteborg.
    Holmlund, Ulrika
    Inst. för Pediatrik, Centrallasarettet, Västerås.
    Olsson-Engman, Mia
    Inst. för Pediatrik, Länssjukhuset, Karlskrona.
    Annerén, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Bondeson, Marie-Louise
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Noonan and cardio-facio-cutanenous syndromes: two clinically and genetically overlapping disorders2008In: Journal of Medical Genetics, ISSN 0022-2593, E-ISSN 1468-6244, Vol. 45, no 8, p. 500-506Article in journal (Refereed)
    Abstract [en]

    Background: Noonan syndrome (NS) and cardio-facio-cutaneous syndrome (CFC) are related disorders associated with disrupted RAS/RAF/MEK/ERK signalling. NS, characterised by facial dysmorphism, congenital heart defects and short stature, is caused by mutations in the genes PTPN11, SOS1, KRAS and RAF1. CFC is distinguished from NS by the presence of ectodermal abnormalities and more severe mental retardation in addition to the NS phenotype. The genetic aetiology of CFC was recently assigned to four genes: BRAF, KRAS, MEK1 and MEK2. Methods: A comprehensive mutation analysis of BRAF, KRAS, MEK1, MEK2 and SOS1 in 31 unrelated patients without mutations in PTPN11 is presented. Results: Mutations were identified in seven patients with CFC (two in BRAF, one in KRAS, one in MEK1, two in MEK2 and one in SOS1). Two mutations were novel: MEK1 E203Q and MEK2 F57L. The SOS1 E433K mutation, identified in a patient diagnosed with CFC, has previously been reported in patients with NS. In one patient with NS, we also identified a mutation, BRAF K499E, that has previously been reported in patients with CFC. We thus suggest involvement of BRAF in the pathogenesis of NS also. Conclusions: Taken together, our results indicate that the molecular and clinical overlap between CFC and NS is more complex than previously suggested and that the syndromes might even represent allelic disorders. Furthermore, we suggest that the diagnosis should be refined to, for example, NS–PTPN11-associated or CFC–BRAF-associated syndromes after the genetic defect has been established, as this may affect the prognosis and treatment of the patients.

  • 31.
    Nyström, Anna-Maja
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Ekvall, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Strömberg, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Holmström, Gerd
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Ophthalmology.
    Thuresson, Ann-Charlotte
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Annerén, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Bondeson, Marie-Louise
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    A severe form of Noonan syndrome and autosomal dominant café-au-lait spots: evidence for different genetic origins2009In: Acta Paediatrica, ISSN 0803-5253, E-ISSN 1651-2227, Vol. 98, no 4, p. 693-698Article in journal (Refereed)
    Abstract [en]

    Aim: The clinical overlap among Noonan syndrome (NS), cardio-facio-cutaneous (CFC), LEOPARD and Costello syndromes as well as Neurofibromatosis type 1 is extensive, which complicates the process of diagnosis. Further genotype–phenotype correlations are required to facilitate future diagnosis of these patients. Therefore, investigations of the genetic cause of a severe phenotype in a patient with NS and the presence of multiple café-au-lait spots (CAL) spots in the patient and four members of the family were performed. Methods: Mutation analyses of candidate genes, PTPN11, NF1, SPRED1 and SPRED2, associated with these syndromes, were conducted using DNA sequencing. Results: A previously identified de novo mutation, PTPN11 F285L and an inherited NF1 R1809C substitution in the index patient were found. However, neither PTPN11 F285L, NF1 R1809C, SPRED1 nor SPRED2 segregated with CAL spots in the family. The results indicate that the familial CAL spots trait in this family is caused by a mutation in another gene, distinct from previous genes associated with CAL spots in these syndromes. Conclusion: We suggest that the atypical severe symptoms in the index patient may be caused by an additive effect on the F285L mutation in PTPN11 by another mutation, for example the NF1 R1809C or alternatively, the not yet identified gene mutation associated with CAL spots in this family.

  • 32.
    Nyström, Anna-Maja
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Ekvall, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Thuresson, Ann-Charlotte
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Kamali-Moghaddam, Masood
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Westermark, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Annerén, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Bondeson, Marie-Louise
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Investigation of gene dosage imbalances in patients with Noonan syndrome using multiplex ligation-dependent probe amplification analysis2010In: European Journal of Medical Genetics, ISSN 1769-7212, E-ISSN 1878-0849, Vol. 53, no 3, p. 117-121Article in journal (Refereed)
    Abstract [en]

    The RAS-MAPK syndromes are a group of clinically and genetically related disorders caused by dysregulation of the RAS-MAPK pathway. A member of this group of disorders, Noonan syndrome (NS), is associated with several different genes within the RAS-MAPK pathway. To date, mutations in PTPN11, SOS1, KRAS, RAF1 and SHOC2 are known to cause NS and a small group of patients harbour mutations in BRAF, MEK1 or NRAS. The majority of the mutations are predicted to cause an up-regulation of the pathway; hence they are gain-of-function mutations. Despite recent advances in gene identification in NS, the genetic aetiology is still unknown in about of patients.To investigate the contribution of gene dosage imbalances of RAS-MAPK-related genes to the pathogenesis of NS, a multiplex ligation-dependent probe amplification (MLPA) assaywas developed. Two probe sets were designed for seven RAS-MAPK-syndrome-related candidate genes: PTPN11, SOS1, RAF1, KRAS, BRAF, MEK1 and MEK2. The probe sets were validated in 15 healthy control individuals and in glioma tumour cell lines. Subsequently, 44 NS patients negative for mutations in known NS-associated genes were screened using the two probe sets. The MLPA results for the patients revealed no gene dosage imbalances. In conclusion, the present results exclude copy number variation of PTPN11, SOS1, RAF1, KRAS, BRAF, MEK1 and MEK2 as a common pathogenic mechanism of NS. The validated and optimised RAS-MAPK probe sets presented here enable rapid high throughput screening of further patients with RAS-MAPK syndromes.

  • 33. Palomares, Maria
    et al.
    Delicado, Alicia
    Mansilla, Elena
    Luisa de Torres, Maria
    Vallespin, Elena
    Fernandez, Luis
    Martinez-Glez, Victor
    Garcia-Minaur, Sixto
    Nevado, Julian
    Santos Simarro, Fernando
    Ruiz-Perez, Victor L.
    Lynch, Sally Ann
    Sharkey, Freddie H.
    Thuresson, Ann-Charlotte
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Annerén, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Belligni, Elga F.
    Luisa Martinez-Fernandez, Maria
    Bermejo, Eva
    Nowakowska, Beata
    Kutkowska-Kazmierczak, Anna
    Bocian, Ewa
    Obersztyn, Ewa
    Luisa Martinez-Frias, Maria
    Hennekam, Raoul C. M.
    Lapunzina, Pablo
    Characterization of a 8q21.11 Microdeletion Syndrome Associated with Intellectual Disability and a Recognizable Phenotype2011In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 89, no 2, p. 295-301Article in journal (Refereed)
    Abstract [en]

    We report eight unrelated individuals with intellectual disability and overlapping submicroscopic deletions of 8q21.11 (0.66-13.55 Mb in size). The deletion was familial in one and simplex in seven individuals. The phenotype was remarkably similar and consisted of a round face with full cheeks, a high forehead, ptosis, cornea opacities, an underdeveloped alae, a short philtrum, a cupid's bow of the upper lip, down-turned corners of the mouth, micrognathia, low-set and prominent ears, and mild finger and toe anomalies (camptodactyly, syndactyly, and broadening of the first rays). Intellectual disability, hypotonia, decreased balance, sensorineural hearing loss, and unusual behavior were frequently observed. A high-resolution oligonucleotide array showed different proximal and distal breakpoints in all of the individuals. Sequencing studies in three of the individuals revealed that proximal and distal breakpoints were located in unique sequences with no apparent homology. The smallest region of overlap was a 539.7 kb interval encompassing three genes: a Zinc Finger Homeobox 4 (ZFHX4), one microRNA of unknown function, and one nonfunctional pseudogen. ZFHX4 encodes a transcription factor expressed in the adult human brain, skeletal muscle, and liver. It has been suggested as a candidate gene for congenital bilateral isolated ptosis. Our results suggest that the 8q21.11 submicroscopic deletion represents a clinically recognizable entity and that a haploinsufficient gene or genes within the minimal deletion region could underlie this syndrome.

  • 34. Schoumans, Jacqueline
    et al.
    Nordgren, Ann
    Ruivenkamp, Claudia
    Bröndum-Nielsen, Karen
    Teh, Bin Tean
    Annerén, Göran
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Holmberg, Eva
    Nordenskjöld, Magnus
    Anderlid, Britt-Marie
    Genome-wide screening using array-CGH does not reveal microdeletions/microduplications in children with Kabuki syndrome.2005In: Eur J Hum Genet, ISSN 1018-4813, Vol. 13, no 2, p. 260-3Article in journal (Refereed)
  • 35.
    Schuster, Jens
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Halvardson, Jonatan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Lorenzo, Laureanne Pilar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Ameur, Adam
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Sobol, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Raykova, Doroteya
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Annerén, Göran
    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, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Dahl, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Transcriptome Profiling Reveals Degree of Variability in Induced Pluripotent Stem Cell Lines: Impact for Human Disease Modeling2015In: Cellular Reprogramming, ISSN 2152-4971, E-ISSN 2152-4998, Vol. 17, no 5, p. 327-337Article in journal (Refereed)
    Abstract [en]

    Induced pluripotent stem cell (iPSC) technology has become an important tool for disease modeling. Insufficient data on the variability among iPSC lines derived from a single somatic parental cell line have in practice led to generation and analysis of several, usually three, iPSC sister lines from each parental cell line. We established iPSC lines from a human fibroblast line (HDF-K1) and used transcriptome sequencing to investigate the variation among three sister lines (iPSC-K1A, B, and C). For comparison, we analyzed the transcriptome of an iPSC line (iPSC-K5B) derived from a different fibroblast line (HDF-K5), a human embryonic stem cell (ESC) line (ESC-HS181), as well as the two parental fibroblast lines. All iPSC lines fulfilled stringent criteria for pluripotency. In an unbiased cluster analysis, all stem cell lines (four iPSCs and one ESC) clustered together as opposed to the parental fibroblasts. The transcriptome profiles of the three iPSC sister lines were indistinguishable from each other, and functional pathway analysis did not reveal any significant hits. In contrast, the expression profiles of the ESC line and the iPSC-K5B line were distinct from that of the sister lines iPSC-K1A, B, and C. Differentiation to embryoid bodies and subsequent analysis of germ layer markers in the five stem cell clones confirmed that the distribution of their expression profiles was retained. Taken together, our observations stress the importance of using iPSCs of different parental origin rather than several sister iPSC lines to distinguish disease-associated mechanisms from genetic background effects in disease modeling.

  • 36. Sharkey, Freddie H.
    et al.
    Foulds, N.
    Thuresson, Ann-Charlotte
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Collins, A. L.
    Annerén, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Hedberg, B. O.
    Delaney, C. A.
    Iremonger, J.
    Murray, C. M.
    Maher, E.
    Crolla, J. A.
    Costigan, C.
    Lam, W.
    FitzPatrick, D.
    Regan, R.
    Ennis, S.
    Lynch, S. A.
    The 12q14 microdeletion syndrome, 6 new cases confirming the role of HMGA2 in growth2010In: Journal of Medical Genetics, ISSN 0022-2593, E-ISSN 1468-6244, Vol. 47, no Suppl. 1, p. S90-S90Article in journal (Other academic)
  • 37. Skogberg, Gabriel
    et al.
    Lundberg, Vanja
    Lindgren, Susanne
    Gudmundsdottir, Judith
    Sandstrom, Kerstin
    Kämpe, Olle
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity.
    Annerén, Göran
    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.
    Gustafsson, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Sunnegardh, Jan
    van der Post, Sjoerd
    Telemo, Esbjorn
    Berglund, Martin
    Ekwall, Olov
    Altered Expression of Autoimmune Regulator in Infant Down Syndrome Thymus, a Possible Contributor to an Autoimmune Phenotype2014In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 193, no 5, p. 2187-2195Article in journal (Refereed)
    Abstract [en]

    Down syndrome (DS), caused by trisomy of chromosome 21, is associated with immunological dysfunctions such as increased frequency of infections and autoimmune diseases. Patients with DS share clinical features, such as autoimmune manifestations and specific autoantibodies, with patients affected by autoimmune polyendocrine syndrome type 1. Autoimmune polyendocrine syndrome type 1 is caused by mutations in the autoimmune regulator (AIRE) gene, located on chromosome 21, which regulates the expression of tissue-restricted Ags (TRAs) in thymic epithelial cells. We investigated the expression of AIRE and TRAs in DS and control thymic tissue using quantitative PCR. AIRE mRNA levels were elevated in thymic tissue from DS patients, and trends toward increased expression of the AIRE-controlled genes INSULIN and CHRNA1 were found. Immunohistochemical stainings showed altered cell composition and architecture of the thymic medulla in DS individuals with increased frequencies of AIRE-positive medullary epithelial cells and CD11c-positive dendritic cells as well as enlarged Hassall's corpuscles. In addition, we evaluated the proteomic profile of thymic exosomes in DS individuals and controls. DS exosomes carried a broader protein pool and also a larger pool of unique TRAs compared with control exosomes. In conclusion, the increased AIRE gene dose in DS could contribute to an autoimmune phenotype through multiple AIRE-mediated effects on homeostasis and function of thymic epithelial cells that affect thymic selection processes.

  • 38.
    Söderbergh, Annika
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Gustafsson, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Ekwall, Olov
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Hallgren, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Nilsson, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Kämpe, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Rorsman, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Annerén, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Autoantibodies linked to autoimmune polyendocrine syndrome type I are prevalent in Down syndrome2006In: Acta Paediatrica, ISSN 0803-5253, E-ISSN 1651-2227, Vol. 95, no 12, p. 1657-1660Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Patients with Down syndrome are prone to autoimmune diseases which also occur in the recessive disease autoimmune polyendocrine syndrome type I (APS I). Since this disease is caused by mutations in the gene AIRE on chromosome 21, one might speculate that altered expression of AIRE contributes to autoimmune disease in Down syndrome. AIM: To study the prevalence of 11 well-defined autoantibodies, five of which are specific for APS I, associated with various manifestations of APS I in patients with Down syndrome. METHODS: Sera from 48 patients with Down syndrome were analysed. Autoantibodies against 21-hydroxylase, 17alpha-hydroxylase, side-chain cleavage enzyme, aromatic L-amino acid decarboxylase, cytochrome P4501A2, tyrosine hydroxylase, tryptophan hydroxylase, glutamic acid decarboxylase 65, tyrosine phosphatase IA-2 and transglutaminase were analysed using an immunoprecipitation assay, and thyroid peroxidase autoantibodies were measured using a haemagglutination assay. RESULTS: Seven of 48 patients had elevated titres of autoantibodies: one against 21-hydroxylase, three against aromatic L-amino acid decarboxylase, one against cytochrome P4501A2, one against glutamic acid decarboxylase 65 and one against tyrosine phosphatase IA-2. None of the patients had clinical or laboratory signs of disease coupled to the respective autoantibody. CONCLUSION: Four patients with Down syndrome had autoantibodies hitherto regarded as unique for APS I, which may suggest a dysregulation of AIRE.

  • 39.
    Tentler, D.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Gustavsson, P.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Leisti, J.
    Schueler, M.
    Chelly, J.
    Timonen, E.
    Annerén, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Willard, H.F.
    Dahl, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Deletion including the oligophrenin-1 gene associated with enlarged cerebral ventricles, cerebellar hypoplasia, seizures and ataxia1999In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 7, no 5, p. 541-8Article in journal (Refereed)
    Abstract [en]

    Non-specific X-linked mental retardation is a heterogeneous group of disorders with an incidence of approximately 1 in 500 males. A recently identified gene in Xq12, encoding a Rho-GTPase-activating protein, was found to be mutated in individuals with mental retardation. We describe here two sisters with a 46,XY karyotype and a microdeletion of the oligophrenin-1 gene and 1.1 Mb of flanking DNA. We have characterised the molecular interval defining this microdeletion syndrome with the fibre-FISH technique. A visual physical map of 1.2 Mb was constructed which spans the oligophrenin-1 gene and the androgen receptor gene. The analysis of the patients revealed a deletion which extended from the 5' end of the AR gene to a region approximately 80 kb proximal to the EPLG2 gene. The clinical manifestations of the two sisters include psychomotor retardation, seizures, ataxia, hypotonia and complete androgen insensitivity. Cranial MRI scans show enlargement of the cerebral ventricles and cerebellar hypoplasia. Our findings give further support for the involvement of the oligophrenin-1 gene in specific morphological abnormalities of the brain which is of importance in the investigation of male patients presenting with mental retardation. In combination with our results from physical mapping we suggest that a region around the oligophrenin-1 locus is relatively bereft of vital genes.

  • 40.
    Tentler, Dmitry
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Brandberg, Göran
    Betancur, Catalina
    Gillberg, Christopher
    Annerén, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Orsmark, Christina
    Green, Eric D.
    Carlsson, Birgit
    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.
    A balanced reciprocal translocation t(5;7)(q14;q32) associated with autistic disorder: molecular analysis of the chromosome 7 breakpoint2001In: American Journal of Medical Genetics, ISSN 0148-7299, E-ISSN 1096-8628, Vol. 105, no 8, p. 729-36Article in journal (Refereed)
    Abstract [en]

    Autism is a neuropsychiatric disorder characterized by impairments in social interaction, restricted and stereotypic pattern of interest with onset by 3 years of age. The results of genetic linkage studied for autistic disorder (AD) have suggested a susceptibility locus for the disease on the long arm of chromosome 7. We report a girl with AD and a balanced reciprocal translocation t(5;7)(q14;q32). The mother carries the translocation but do not express the disease. Fluorescent in situ hybridization (FISH) analysis with chromosome 7-specific YAC clones showed that the breakpoint coincides with the candidate region for AD. We identified a PAC clone that spans the translocation breakpoint and the breakpoint was mapped to a 2 kb region. Mutation screening of the genes SSBP and T2R3 located just centromeric to the breakpoint was performed in a set of 29 unrelated autistic sibling pairs who shared at least one chromosome 7 haplotype. We found no sequence variations, which predict amino acid alterations. Two single nucleotide polymorphisms were identified in the T2R3 gene, and associations between allele variants and AD in our population were not found. The methylation pattern of different chromosome 7 regions in the patient's genomic DNA appears normal. Here we report the clinical presentation of the patient with AD and the characterization of the genomic organization across the breakpoint at 7q32. The precise localization of the breakpoint on 7q32 may be relevant for further linkage studies and molecular analysis of AD in this region.

  • 41. Terhal, Paulien A.
    et al.
    Nievelstein, Rutger Jan A. J.
    Verver, Eva J. J.
    Topsakal, Vedat
    van Dommelen, Paula
    Hoornaert, Kristien
    Le Merrer, Martine
    Zankl, Andreas
    Simon, Marleen E. H.
    Smithson, Sarah F.
    Marcelis, Carlo
    Kerr, Bronwyn
    Clayton-Smith, Jill
    Kinning, Esther
    Mansour, Sahar
    Elmslie, Frances
    Goodwin, Linda
    van der Hout, Annemarie H.
    Veenstra-Knol, Hermine E.
    Herkert, Johanna C.
    Lund, Allan M.
    Hennekam, Raoul C. M.
    Megarbane, Andre
    Lees, Melissa M.
    Wilson, Louise C.
    Male, Alison
    Hurst, Jane
    Alanay, Yasemin
    Annerén, Göran
    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.
    Betz, Regina C.
    Bongers, Ernie M. H. F.
    Cormier-Daire, Valerie
    Dieux, Anne
    David, Albert
    Elting, Mariet W.
    van den Ende, Jenneke
    Green, Andrew
    van Hagen, Johanna M.
    Hertel, Niels Thomas
    Holder-Espinasse, Muriel
    den Hollander, Nicolette
    Homfray, Tessa
    Hove, Hanne D.
    Price, Susan
    Raas-Rothschild, Annick
    Rohrbach, Marianne
    Schroeter, Barbara
    Suri, Mohnish
    Thompson, Elizabeth M.
    Tobias, Edward S.
    Toutain, Annick
    Vreeburg, Maaike
    Wakeling, Emma
    Knoers, Nine V.
    Coucke, Paul
    Mortier, Geert R.
    A Study of the Clinical and Radiological Features in a Cohort of 93 Patients with a COL2A1 Mutation Causing Spondyloepiphyseal Dysplasia Congenita or a Related Phenotype2015In: American Journal of Medical Genetics. Part A, ISSN 1552-4825, E-ISSN 1552-4833, Vol. 167A, no 3, p. 461-475Article in journal (Refereed)
    Abstract [en]

    Type 2 collagen disorders encompass a diverse group of skeletal dysplasias that are commonly associated with orthopedic, ocular, and hearing problems. However, the frequency of many clinical features has never been determined. We retrospectively investigated the clinical, radiological, and genotypic data in a group of 93 patients with molecularly confirmed SEDC or a related disorder. The majority of the patients (80/93) had short stature, with radiological features of SEDC (n=64), others having SEMD (n=5), Kniest dysplasia (n=7), spondyloperipheral dysplasia (n=2), or Torrance-like dysplasia (n=2). The remaining 13 patients had normal stature with mild SED, Stickler-like syndrome or multiple epiphyseal dysplasia. Over 50% of the patients had undergone orthopedic surgery, usually for scoliosis, femoral osteotomy or hip replacement. Odontoid hypoplasia was present in 56% (95% CI 38-74) and a correlation between odontoid hypoplasia and short stature was observed. Atlanto-axial instability, was observed in 5 of the 18 patients (28%, 95% CI 10-54) in whom flexion-extension films of the cervical spine were available; however, it was rarely accompanied by myelopathy. Myopia was found in 45% (95% CI 35-56), and retinal detachment had occurred in 12% (95% CI 6-21; median age 14 years; youngest age 3.5 years). Thirty-two patients complained of hearing loss (37%, 95% CI 27-48) of whom 17 required hearing aids. The ophthalmological features and possibly also hearing loss are often relatively frequent and severe in patients with splicing mutations. Based on clinical findings, age at onset and genotype-phenotype correlations in this cohort, we propose guidelines for the management and follow-up in this group of disorders.

  • 42.
    Ternby, Ellen
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Annerén, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Ingvoldstad, Charlotta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Caring Sciences.
    Lindgren, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Axelsson, Ove
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    What do pregnant women know about Downs syndrome when they come for prenatal diagnosis?2012Conference paper (Other academic)
  • 43.
    Ternby, Ellen
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Axelsson, Ove
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning i Sörmland (CKFD).
    Annerén, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Lindgren, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology. Karolinska Inst, Dept Clin Sci Intervent & Technol CLINTEC Obstet, Stockholm, Sweden.
    Ingvoldstad, Charlotta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology. Karolinska Inst, Dept Clin Sci Intervent & Technol CLINTEC Obstet, Stockholm, Sweden.
    Why do pregnant women accept or decline prenatal diagnosis for Down syndrome?2016In: Journal of community genetics, ISSN 1868-310X, Vol. 7, no 3, p. 237-242Article in journal (Refereed)
    Abstract [en]

    To investigate if actual knowledge of Down syndrome (DS), influences the decision to accept or decline prenatal diagnosis (PND). Secondary aims were to elucidate reasons for accepting or declining PND and investigate differences between the accepting and declining group in perceived information, knowing someone with DS and thoughts about decision-making. A questionnaire was completed by 76 pregnant women who underwent invasive testing and 65 women who declined tests for chromosomal aberrations in Uppsala, Sweden. Apart from one question no significant differences were found in knowledge of DS between women declining or accepting PND for DS. Both groups had varying and in several respects low levels of knowledge about DS and its consequences. Most common reasons to accept PND were 'to ease my worries' and 'to do all possible tests to make sure the baby is healthy'. Corresponding statements declining PND were 'termination of pregnancy is not an option' and 'because invasive tests increase the risk of miscarriage'. More women declining PND knew someone with DS. Knowledge of DS at these levels is not a major factor when women decide to accept or decline PND for DS. Their choice is mostly based on opinions and moral values.

  • 44.
    Ternby, Ellen
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Ingvoldstad, Charlotta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology. Department of Clinical Science, Intervention and Technology (CLINTEC), Obstetrics and Gynecology, Karolinska Institutet, Stockholm, Sweden.
    Annerén, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Axelsson, Ove
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning i Sörmland (CKFD).
    Midwives and information on prenatal testing with focus on Down syndrome2015In: Prenatal Diagnosis, ISSN 0197-3851, E-ISSN 1097-0223, Vol. 35, no 12, p. 1202-1207Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To investigate midwives' knowledge of prenatal diagnosis especially Down syndrome, information given by midwives to parents, expectant parents' requests for information and how midwives perceive their own competence to give information.

    METHOD: A cross-sectional, prospective study with a questionnaire was completed by 64 out of 70 midwives working in the outpatient antenatal care in Uppsala County, Sweden.

    RESULTS: The midwives had varying and in some areas low levels of knowledge about Down syndrome. Information about Down syndrome was most often given only when asked for or when there was an increased probability of a Down syndrome pregnancy. The most common questions from expectant parents concerned test methods and risk assessments while questions regarding symptoms of Down syndrome and consequences of having a child with Down syndrome were uncommon. The majority (83-89%) had insufficient or no education regarding different prenatal tests. Only 2 midwives (3%) had received education about Down syndrome and 10% felt they had sufficient knowledge to inform about the syndrome. More education about prenatal tests and Down syndrome was desired by 94%.

    CONCLUSION: It is important to ensure that midwives in antenatal care have sufficient knowledge to inform expectant parents about the conditions screened for.

  • 45.
    Ternby, Ellen
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Ingvoldstad, Charlotta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology. 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.
    Annerén, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Lindgren, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Axelsson, Ove
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning i Sörmland (CKFD). Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Information and knowledge about Down syndrome among women and partners after first trimester combined testing2015In: Acta Obstetricia et Gynecologica Scandinavica, ISSN 0001-6349, E-ISSN 1600-0412, Vol. 94, no 3, p. 329-32Article in journal (Refereed)
    Abstract [en]

    We assessed reasons among women and partners for choosing combined ultrasound-biochemistry testing, information and knowledge about Down syndrome and decisions concerning invasive procedures and termination of pregnancy in a prospective cohort study in Uppsala County. In all 105 pregnant women and 104 partners coming for a combined ultrasound-biochemistry test answered a questionnaire. The most common reason for a combined ultrasound-biochemistry test was "to perform all tests possible to make sure the baby is healthy". Internet and midwives were the most common sources of information. Seventy-two percent had not received information on what it means to live with a child with Down syndrome. Many expectant parents perceived information as insufficient. Both women and partners had varying or low levels of knowledge about medical, cognitive and social consequences of Down syndrome. Twenty-five percent had not decided on an invasive test if indicated and only 42% would consider termination of pregnancy with a Down syndrome diagnosis.

  • 46.
    Thuresson, Ann-Charlotte
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Bondeson, Marie-Louise
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Edeby, Christina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Ellis, P.
    Langford, C.
    Dumanski, Jan P.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Annerén, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Whole-genome array-CGH for detection of submicroscopic chromosomal imbalances in children with mental retardation2007In: Cytogenetic and Genome Research, ISSN 1424-8581, E-ISSN 1424-859X, Vol. 118, no 1, p. 1-7Article in journal (Refereed)
    Abstract [en]

    Chromosomal imbalances are the major cause of mental retardation (MR). Many of these imbalances are caused by submicroscopic deletions or duplications not detected by conventional cytogenetic methods. Microarray-based comparative genomic hybridization (array-CGH) is considered to be superior for the investigation of chromosomal aberrations in children with MR, and has been demonstrated to improve the diagnostic detection rate of these small chromosomal abnormalities. In this study we used 1 Mb genome-wide array-CGH to screen 48 children with MR and congenital malformations for submicroscopic chromosomal imbalances, where the underlying cause was unknown. All children were clinically investigated and subtelomere FISH analysis had been performed in all cases. Suspected microdeletion syndromes such as deletion 22q11.2, Williams-Beuren and Angelman syndromes were excluded before array-CGH analysis was performed. We identified de novo interstitial chromosomal imbalances in two patients (4%), and an interstitial deletion inherited from an affected mother in one patient (2%). In another two of the children (4%), suspected imbalances were detected but were also found in one of the non-affected parents. The yield of identified de novo alterations detected in this study is somewhat less than previously described, and might reflect the importance of which selection criterion of patients to be used before array-CGH analysis is performed. However, array-CGH proved to be a high-quality and reliable tool for genome-wide screening of MR patients of unknown etiology.

  • 47. Wang, Peter
    et al.
    Carrion, Prescilla
    Qiao, Ying
    Tyson, Christine
    Hrynchak, Monica
    Calli, Kristina
    Lopez-Rangel, Elena
    Andrieux, Joris
    Delobel, Bruno
    Duban-Bedu, Benedicte
    Thuresson, Ann-Charlotte
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Annerén, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Liu, Xudong
    Rajcan-Separovic, Evica
    Lewis, M. E. Suzanne
    Genotype-phenotype analysis of 18q12.1-q12.2 copy number variation in autism2013In: European Journal of Medical Genetics, ISSN 1769-7212, E-ISSN 1878-0849, Vol. 56, no 8, p. 420-425Article in journal (Refereed)
    Abstract [en]

    Autism Spectrum Disorders (ASD) are complex neurodevelopmental conditions characterized by delays in social interactions and communication as well as displays of restrictive/repetitive interests. DNA copy number variants have been identified as a genomic susceptibility factor in ASDs and imply significant genetic heterogeneity. We report a 7-year-old female with ADOS-G and ADI-R confirmed autistic disorder harbouring a de novo 4 Mb duplication (18q12.1). Our subject displays severely deficient expressive language, stereotypic and repetitive behaviours, mild intellectual disability (ID), focal epilepsy, short stature and absence of significant dysmorphic features. Search of the PubMed literature and DECIPHER database identified 4 additional cases involving 18q12.1 associated with autism and/or ID that overlap our case: one duplication, two deletions and one balanced translocation. Notably, autism and ID are seen with genomic gain or loss at 18q12.1, plus epilepsy and short stature in duplication cases, and hypotonia and tall stature in deletion cases. No consistent dysmorphic features were noted amongst the reviewed cases. We review prospective ASD/ID candidate genes integral to 18q12.1, including those coding for the desmocollin/desmoglein cluster, ring finger proteins 125 and 138, trafficking protein particle complex 8 and dystrobrevin-alpha. The collective clinical and molecular features common to microduplication 18q12.1 suggest that dosage-sensitive, position or contiguous gene effects may be associated in the etiopathogenesis of this autism-ID-epilepsy syndrome. 

  • 48.
    Wentzel, Christian
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Annerén, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Thuresson, Ann-Charlotte
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    A maternal de novo non-reciprocal translocation results in a 6q13-q16 deletion in one offspring and a 6q13-q16 duplication in another2014In: European Journal of Medical Genetics, ISSN 1769-7212, E-ISSN 1878-0849, Vol. 57, no 6, p. 259-263Article in journal (Refereed)
    Abstract [en]

    Here we report a case of two siblings with reciprocal aberrations, one presenting with a deletion and the other carrying two novel duplications at 6q13q16.1. Interestingly, both alterations were inherited from a healthy mother carrying a non-reciprocal translocation of 6q13q16 to 15q11. Deletions at 6q13q16.1 have been previously described; however this is the first characterisation of a 6q13q16.1 duplication. In this report we provide a comprehensive molecular and phenotypical characterisation of the affected siblings and discuss the profiles of previously identified patients carrying 6q deletions. (C) 2014 Elsevier Masson SAS. All rights reserved.

  • 49.
    Wentzel, Christian
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Annerén, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Thuresson, Ann-Charlotte
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Unbalanced de novo translocation in mother resulting in one child with a 6q13-q16 deletion and one child with a 6q13-q16 duplicationManuscript (preprint) (Other academic)
    Abstract [en]

    Here we report on two sisters with reciprocal CNVs at 6q13-q16.1. Both the deletion and the duplication were inherited from the healthy mother carrying an insertion of 6q13-q16 to 15q11. The deleted region in one of the sisters has previously been described. However, to our knowledge this is the first report of a duplication at the region 6q13q16. In the report we submit a detailed phenotypical description of both patients as well as candidate genes for some of the various symptoms that the patients presented.

  • 50.
    Wentzel, Christian
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Fernström, Maria
    Öhrner, Ylva
    Annerén, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Thuresson, Ann-Charlotte
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Clinical variability of the 22q11.2 duplication syndrome2008In: European Journal of Medical Genetics, ISSN 1769-7212, E-ISSN 1878-0849, Vol. 51, no 6, p. 501-510Article in journal (Refereed)
    Abstract [en]

    The 22q11.2 duplication syndrome is an extremely variable disorder with a phenotype ranging from normal to learning disability and congenital defects. Both patients with a de novo 22q11.2 duplication and patients in whom the duplication has been inherited from a phenotypically normal parent have been reported. In this study we present two familial cases with a 3Mb 22q11.2 duplication detected by array-CGH. We also review the findings in 36 reported cases with the aim of delineating the phenotype of the 22q11.2 duplication syndrome. In a majority of the reported cases where parents have been tested, the duplication seems to have been inherited from a normal parent with minor abnormalities. With this in mind we recommend that family members of patients with a 22q11.2 duplication to be tested for this genetic defect.

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