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Gudmundsson, S., Annerén, G., Marcos-Alcalde, Í., Wilbe, M., Melin, M., Gómez-Puertas, P. & Bondeson, M.-L. (2019). A novel RAD21 p.(Gln592del) variant expands the clinical description of Cornelia de Lange syndrome type 4: Review of the literature. European Journal of Medical Genetics, 62(6), Article ID 103526.
Open this publication in new window or tab >>A novel RAD21 p.(Gln592del) variant expands the clinical description of Cornelia de Lange syndrome type 4: Review of the literature
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2019 (English)In: European Journal of Medical Genetics, ISSN 1769-7212, E-ISSN 1878-0849, Vol. 62, no 6, article id 103526Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
Elsevier, 2019
Keywords
Cohesin complex, Cohesin protein, Cohesinopathy, Cornelia de Lange syndrome type 4, RAD21 cohesin complex component
National Category
Genetics Health Sciences
Identifiers
urn:nbn:se:uu:diva-379362 (URN)10.1016/j.ejmg.2018.08.007 (DOI)000470115000001 ()30125677 (PubMedID)
Available from: 2019-03-15 Created: 2019-03-15 Last updated: 2019-06-26Bibliographically approved
Gudmundsson, S., Wilbe, M., Gorniok, B. F., Molin, A.-M., Ekvall, S., Johansson, J., . . . Bondeson, M.-L. (2019). TAF1, associated with intellectual disability in humans, is essential for embryogenesis and regulates neurodevelopmental processes in zebrafish. Scientific Reports, 9, Article ID 10730.
Open this publication in new window or tab >>TAF1, associated with intellectual disability in humans, is essential for embryogenesis and regulates neurodevelopmental processes in zebrafish
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2019 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 10730Article in journal (Refereed) Published
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.

Keywords
taf1, intellectual disability, zebrafish
National Category
Genetics
Research subject
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-379358 (URN)10.1038/s41598-019-46632-8 (DOI)000476874600028 ()31341187 (PubMedID)
Funder
EU, European Research Council, 241995
Note

Title in Thesis list of papers: TAF1, associated with intellectual disability in humans, is essential for life and regulates neurodevelopmental processes in zebrafish

Available from: 2019-03-15 Created: 2019-03-15 Last updated: 2019-09-23Bibliographically approved
Gudmundsson, S. (2019). Translational Research of Mendelian Disorders: Applications of Cutting-Edge Sequencing Techniques and Molecular Tools. (Doctoral dissertation). Uppsala: Acta Universitatis Upsaliensis
Open this publication in new window or tab >>Translational Research of Mendelian Disorders: Applications of Cutting-Edge Sequencing Techniques and Molecular Tools
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Up to 8% of all live-born children are affected with a congenital disorder. Some are Mendelian disorders of known etiology, but many are of undetermined genetic cause and mechanism, limiting diagnosis and treatment. This project aims to investigate the underlying causes of unresolved Mendelian disorders, and especially syndromes associated with intellectual disability, by using cutting-edge sequencing techniques and molecular tools in a translational setting that intends to directly benefit affected families.

In Paper I, we report the first keratitis-ichthyosis-deafness syndrome patient presenting with reversion of disease phenotype, a phenomenon known as revertant mosaicism. Third-generation sequencing and a cell assay were used to pin-point the mechanism of the somatic variants giving rise to healthy looking skin in the patient. In Paper II, we describe a novel approach to investigate parental origin, gonadal mosaicism, and estimate recurrence risk of disease in two families. Third-generation sequencing was used for haplotype phasing and detection of low-frequency variants in paternal sperm. The recurrence risk in future offspring in the families affected with Noonan syndrome and Treacher Collins syndrome was determined to be 40% and <0.1% respectively. In Paper III, we describe a novel variant in a patient affected with Cornelia de Lange Syndrome, primarily associated with intellectual disability. The affected gene is linked to an extremely rare form of the syndrome, with limited cases described in the literature, usually associated with mild symptoms. Investigation of rare intellectual disability syndromes was continued in Paper IV, by clinical and genetic characterization of six affected males with a likely pathogenic variant in the TAF1 gene. By creating the first TAF1 orthologue knockout we revealed that taf1 is essential for life and that lack of functional taf1 during embryonic development in zebrafish primarily impacts expression of genes in pathways associated with neurodevelopment. 

By progressive translational research, using state-of-the-art methodology, this project has illuminated the implication of revertant and gonadal mosaicism in disease (Papers I-II), as well as two extremely rare intellectual disability syndromes (Papers III-IV). In total, five families affected with five different disorders have gained clinical and genetic diagnosis and/or further understanding of prognosis and recurrence risk. The study has led to improved understanding of disease etiology and basic developmental processes, enabling development of new therapies and improved care of future patients.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2019. p. 75
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1551
Keywords
translational research, Mendelian disorders, intellectual disability, sequencing technologies
National Category
Genetics
Identifiers
urn:nbn:se:uu:diva-379363 (URN)978-91-513-0595-0 (ISBN)
Public defence
2019-05-03, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjölds väg 20, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2019-04-10 Created: 2019-03-17 Last updated: 2019-05-07
Stattin, E.-L., Johansson, J., Gudmundsson, S., Ameur, A., Lundberg, S., Bondeson, M.-L. & Wilbe, M. (2018). A novel ECEL1 mutation expands the phenotype of distal arthrogryposis multiplex congenita type 5D to include pretibial vertical skin crease. American Journal of Medical Genetics. Part A, 176(6), 1405-1410
Open this publication in new window or tab >>A novel ECEL1 mutation expands the phenotype of distal arthrogryposis multiplex congenita type 5D to include pretibial vertical skin crease
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2018 (English)In: American Journal of Medical Genetics. Part A, ISSN 1552-4825, E-ISSN 1552-4833, Vol. 176, no 6, p. 1405-1410Article in journal (Refereed) Published
Abstract [en]

Arthrogryposis multiplex congenita (AMC) is a heterogeneous disorder characterized by multiple joint contractures often in association with other congenital abnormalities. Pretibial linear vertical creases are a rare finding associated with arthrogryposis, and the etiology of the specific condition is unknown. We aimed to genetically and clinically characterize a boy from a consanguineous family, presenting with AMC and pretibial vertical linear creases on the shins. Whole exome sequencing and variant analysis revealed homozygous novel missense variants of ECEL1 (c.1163T > C, p.Leu388Pro, NM_004826) and MUSK (c.2572C > T, p.Arg858Cys, NM_005592). Both variants are predicted to have deleterious effects on the protein function, with amino acid positions highly conserved among species. The variants segregated in the family, with healthy mother, father, and sister being heterozygous carriers and the index patient being homozygous for both mutations. We report on a unique patient with a novel ECEL1 homozygous mutation, expanding the phenotypic spectrum of Distal AMC Type 5D to include vertical linear skin creases. The homozygous mutation in MUSK is of unknown clinical significance. MUSK mutations have previously shown to cause congenital myasthenic syndrome, a neuromuscular disorder with defects in the neuromuscular junction.

Place, publisher, year, edition, pages
WILEY, 2018
Keywords
arthrogryposis multiplex congenital, congenital myasthenic syndrome, ECEL1, vertical linear skin creases, whole exome sequencing
National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-364512 (URN)10.1002/ajmg.a.38691 (DOI)000434040600017 ()29663639 (PubMedID)
Available from: 2018-11-05 Created: 2018-11-05 Last updated: 2018-11-05Bibliographically approved
Bondeson, M.-L., Ericson, K., Gudmundsson, S., Ameur, A., Ponten, F., Wesström, J., . . . Wilbe, M. (2017). A nonsense mutation in CEP55 defines a new locus for a Meckel-like syndrome, an autosomal recessive lethal fetal ciliopathy.. Clinical Genetics, 92(5), 510-516
Open this publication in new window or tab >>A nonsense mutation in CEP55 defines a new locus for a Meckel-like syndrome, an autosomal recessive lethal fetal ciliopathy.
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2017 (English)In: Clinical Genetics, ISSN 0009-9163, E-ISSN 1399-0004, Vol. 92, no 5, p. 510-516Article in journal (Refereed) Published
Abstract [en]

Mutations in genes involved in the cilium-centrosome complex are called ciliopathies. Meckel-Gruber syndrome (MKS) is a ciliopathic lethal autosomal recessive syndrome characterized by genetically and clinically heterogeneous manifestations, including renal cystic dysplasia, occipital encephalocele and polydactyly. Several genes have previously been associated with MKS and MKS-like phenotypes, but there are still genes remaining to be discovered. We have used whole exome sequencing (WES) to uncover the genetics of a suspected autosomal recessive Meckel syndrome phenotype in a family with two affected fetuses. RNA studies and histopathological analysis was performed for further delineation. WES lead to identification of a homozygous nonsense mutation c.256C>T (p.Arg86*) in CEP55 (centrosomal protein of 55 kDa) in the affected fetus. The variant has previously been identified in carriers in low frequencies, and segregated in the family. CEP55 is an important centrosomal protein required for the mid-body formation at cytokinesis. Our results expand the list of centrosomal proteins implicated in human ciliopathies and provide evidence for an essential role of CEP55 during embryogenesis and development of disease.

Keywords
CEP55, Meckel-like, ciliopathy, cytokinesis, whole exome sequencing
National Category
Clinical Medicine Clinical Laboratory Medicine
Research subject
Pathology
Identifiers
urn:nbn:se:uu:diva-318127 (URN)10.1111/cge.13012 (DOI)000412590300007 ()28295209 (PubMedID)
Funder
Magnus Bergvall FoundationLars Hierta Memorial FoundationSwedish Society for Medical Research (SSMF)
Available from: 2017-03-23 Created: 2017-03-23 Last updated: 2019-01-04Bibliographically approved
Wilbe, M., Gudmundsson, S., Johansson, J., Ameur, A., Stattin, E.-L., Annerén, G., . . . Bondeson, M.-L. (2017). A novel approach using long-read sequencing and ddPCR to investigate gonadal mosaicism and estimate recurrence risk in two families with developmental disorders. Prenatal Diagnosis, 37(11), 1146-1154
Open this publication in new window or tab >>A novel approach using long-read sequencing and ddPCR to investigate gonadal mosaicism and estimate recurrence risk in two families with developmental disorders
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2017 (English)In: Prenatal Diagnosis, ISSN 0197-3851, E-ISSN 1097-0223, Vol. 37, no 11, p. 1146-1154Article in journal (Refereed) Published
Abstract [en]

Objective

De novo mutations contribute significantly to severe early-onset genetic disorders. Even if the mutation is apparently de novo, there is a recurrence risk due to parental germ line mosaicism, depending on in which gonadal generation the mutation occurred.

Methods

We demonstrate the power of using SMRT sequencing and ddPCR to determine parental origin and allele frequencies of de novo mutations in germ cells in two families whom had undergone assisted reproduction.

Results

In the first family, a TCOF1 variant c.3156C>T was identified in the proband with Treacher Collins syndrome. The variant affects splicing and was determined to be of paternal origin. It was present in <1% of the paternal germ cells, suggesting a very low recurrence risk. In the second family, the couple had undergone several unsuccessful pregnancies where a de novo mutation PTPN11 c.923A>C causing Noonan syndrome was identified. The variant was present in 40% of the paternal germ cells suggesting a high recurrence risk.

Conclusions

Our findings highlight a successful strategy to identify the parental origin of mutations and to investigate the recurrence risk in couples that have undergone assisted reproduction with an unknown donor or in couples with gonadal mosaicism that will undergo preimplantation genetic diagnosis.

National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-342916 (URN)10.1002/pd.5156 (DOI)000415897200012 ()28921562 (PubMedID)
Funder
Swedish Society for Medical Research (SSMF)
Available from: 2018-02-26 Created: 2018-02-26 Last updated: 2019-03-17Bibliographically approved
Gudmundsson, S., Wilbe, M., Ekvall, S., Ameur, A., Cahill, N., Alexandrov, L. B., . . . Bondeson, M.-L. (2017). Revertant mosaicism repairs skin lesions in a patient with keratitis-ichthyosis-deafness syndrome by second-site mutations in connexin 26. Human Molecular Genetics, 26(6), 1070-1077
Open this publication in new window or tab >>Revertant mosaicism repairs skin lesions in a patient with keratitis-ichthyosis-deafness syndrome by second-site mutations in connexin 26
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2017 (English)In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 26, no 6, p. 1070-1077Article in journal (Refereed) Published
Abstract [en]

Revertant mosaicism(RM) is a naturally occurring phenomenon where the pathogenic effect of a germline mutation is corrected by a second somatic event. Development of healthy-looking skin due to RM has been observed in patients with various inherited skin disorders, but not in connexin-related disease. We aimed to clarify the underlying molecular mechanisms of suspected RM in the skin of a patient with keratitis-ichthyosis-deafness (KID) syndrome. The patient was diagnosed with KID syndrome due to characteristic skin lesions, hearing deficiency and keratitis. Investigation of GJB2 encoding connexin (Cx) 26 revealed heterozygosity for the recurrent de novo germline mutation, c. 148G>A, p. Asp50Asn. At age 20, the patient developed spots of healthy-looking skin that grew in size and number within widespread erythrokeratodermic lesions. Ultradeep sequencing of two healthy-looking skin biopsies identified five somatic nonsynonymous mutations, independently present in cis with the p. Asp50Asn mutation. Functional studies of Cx26 in HeLa cells revealed co-expression of Cx26-Asp50Asn and wild-type Cx26 in gap junction channel plaques. However, Cx26-Asp50Asn with the second-site mutations identified in the patient displayed no formation of gap junction channel plaques. We argue that the second-site mutations independently inhibit Cx26-Asp50Asn expression in gap junction channels, reverting the dominant negative effect of the p. Asp50Asn mutation. To our knowledge, this is the first time RM has been reported to result in the development of healthy-looking skin in a patient with KID syndrome.

Place, publisher, year, edition, pages
OXFORD UNIV PRESS, 2017
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-324349 (URN)10.1093/hmg/ddx017 (DOI)000400911000004 ()28158657 (PubMedID)
Funder
Swedish Research Council, K2013-57X-22309-3
Available from: 2017-06-15 Created: 2017-06-15 Last updated: 2019-03-17Bibliographically approved
Matsson, H., Söderhall, C., Einarsdottir, E., Lamontagne, M., Gudmundsson, S., Backman, H., . . . Klar, J. (2016). Targeted high-throughput sequencing of candidate genes for chronic obstructive pulmonary disease. BMC Pulmonary Medicine, 16, Article ID 146.
Open this publication in new window or tab >>Targeted high-throughput sequencing of candidate genes for chronic obstructive pulmonary disease
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2016 (English)In: BMC Pulmonary Medicine, ISSN 1471-2466, E-ISSN 1471-2466, Vol. 16, article id 146Article in journal (Refereed) Published
Abstract [en]

Background: Reduced lung function in patients with chronic obstructive pulmonary disease (COPD) is likely due to both environmental and genetic factors. We report here a targeted high-throughput DNA sequencing approach to identify new and previously known genetic variants in a set of candidate genes for COPD. Methods: Exons in 22 genes implicated in lung development as well as 61 genes and 10 genomic regions previously associated with COPD were sequenced using individual DNA samples from 68 cases with moderate or severe COPD and 66 controls matched for age, gender and smoking. Cases and controls were selected from the Obstructive Lung Disease in Northern Sweden (OLIN) studies. Results: In total, 37 genetic variants showed association with COPD (p < 0.05, uncorrected). Several variants previously discovered to be associated with COPD from genetic genome-wide analysis studies were replicated using our sample. Two high-risk variants were followed-up for functional characterization in a large eQTL mapping study of 1,111 human lung specimens. The C allele of a synonymous variant, rs8040868, predicting a p.(S45=) in the gene for cholinergic receptor nicotinic alpha 3 (CHRNA3) was associated with COPD (p = 8.8 x 10(-3)). This association remained (p = 0.003 and OR = 1.4, 95 % CI 1.1-1.7) when analysing all available cases and controls in OLIN (n = 1,534). The rs8040868 variant is in linkage disequilibrium with rs16969968 previously associated with COPD and altered expression of the CHRNA5 gene. A follow-up analysis for detection of expression quantitative trait loci revealed that rs8040868-C was found to be significantly associated with a decreased expression of the nearby gene cholinergic receptor, nicotinic, alpha 5 (CHRNA5) in lung tissue. Conclusion: Our data replicate previous result suggesting CHRNA5 as a candidate gene for COPD and rs8040868 as a risk variant for the development of COPD in the Swedish population.

Keywords
COPD, Sequencing, eQTL, Association, Lung development, CHRNA5
National Category
Respiratory Medicine and Allergy
Identifiers
urn:nbn:se:uu:diva-311194 (URN)10.1186/s12890-016-0309-y (DOI)000388035500004 ()27835950 (PubMedID)
Funder
Swedish Society for Medical Research (SSMF)Magnus Bergvall Foundation, 014-00163
Available from: 2016-12-22 Created: 2016-12-22 Last updated: 2017-11-29Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-2332-074x

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