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Brunet, T.* ; Jech, R.* ; Brugger, M.* ; Kovacs, R.* ; Alhaddad, B.* ; Leszinski, G.* ; Riedhammer, K.M.* ; Westphal, D.S.* ; Mahle, I.* ; Mayerhanser, K.* ; Škorvánek, M.* ; Weber, S. ; Graf, E. ; Berutti, R.* ; Necpál, J.* ; Havránková, P.* ; Pavelekova, P.* ; Hempel, M.* ; Kotzaeridou, U.* ; Hoffmann, G.F.* ; Leiz, S.* ; Makowski, C.* ; Roser, T.* ; Schroeder, S.A.* ; Steinfeld, R.* ; Strobl-Wildemann, G.* ; Hoefele, J.* ; Borggraefe, I.* ; Distelmaier, F.* ; Strom, T.M.* ; Winkelmann, J. ; Meitinger, T.* ; Zech, M. ; Wagner, M.

De novo variants in neurodevelopmental disorders-experiences from a tertiary care center.

Clin. Genet. 100, 14-28 (2021)
Publ. Version/Full Text DOI
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
Up to 40% of neurodevelopmental disorders (NDDs) such as intellectual disability, developmental delay, autism spectrum disorder, and developmental motor abnormalities have a documented underlying monogenic defect, primarily due to de novo variants. Still, the overall burden of de novo variants as well as novel disease genes in NDDs await discovery. We performed parent-offspring trio exome sequencing in 231 individuals with NDDs. Phenotypes were compiled using human phenotype ontology terms. The overall diagnostic yield was 49.8% (n = 115/231) with de novo variants contributing to more than 80% (n = 93/115) of all solved cases. De novo variants affected 72 different-mostly constrained-genes. In addition, we identified putative pathogenic variants in 16 genes not linked to NDDs to date. Reanalysis performed in 80 initially unsolved cases revealed a definitive diagnosis in two additional cases. Our study consolidates the contribution and genetic heterogeneity of de novo variants in NDDs highlighting trio exome sequencing as effective diagnostic tool for NDDs. Besides, we illustrate the potential of a trio-approach for candidate gene discovery and the power of systematic reanalysis of unsolved cases.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Autism ; Candidate Gene ; De Novo Variant ; Exome Sequencing ; Intellectual Disability ; Neurodevelopmental Disorder ; Reanalysis
ISSN (print) / ISBN 0009-9163
e-ISSN 1399-0004
Quellenangaben Volume: 100, Issue: 1, Pages: 14-28 Article Number: , Supplement: ,
Publisher Wiley
Publishing Place 111 River St, Hoboken 07030-5774, Nj Usa
Reviewing status Peer reviewed
Grants Slovak Grant and Development Agency under contract
Operational Programme Integrated Infrastructure
Czech Ministry of Education under grant
Charles University, Prague, Czech Republic