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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)
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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
Language english
Publication Year 2021
HGF-reported in Year 2021
ISSN (print) / ISBN 0009-9163
e-ISSN 1399-0004
Journal Clinical Genetics
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
Institute(s) Institute of Neurogenomics (ING)
Institute of Human Genetics (IHG)
POF-Topic(s) 30205 - Bioengineering and Digital Health
30501 - Systemic Analysis of Genetic and Environmental Factors that Impact Health
Research field(s) Genetics and Epidemiology
PSP Element(s) G-503200-001
G-500700-001
Grants Slovak Grant and Development Agency under contract
Operational Programme Integrated Infrastructure
Czech Ministry of Education under grant
Charles University, Prague, Czech Republic
DOI 10.1111/cge.13946
WOS ID WOS:000623501000001
Scopus ID 85101839280
PubMed ID 33619735
Erfassungsdatum 2021-05-10
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