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De novo variants in neurodevelopmental disorders—experiences from a tertiary care center
Author(s) -
Brunet Theresa,
Jech Robert,
Brugger Melanie,
Kovacs Reka,
Alhaddad Bader,
Leszinski Gloria,
Riedhammer Korbinian M.,
Westphal Dominik S.,
Mahle Isabella,
Mayerhanser Katharina,
Skorvanek Matej,
Weber Sandrina,
Graf Elisabeth,
Berutti Riccardo,
Necpál Ján,
Havránková Petra,
Pavelekova Petra,
Hempel Maja,
Kotzaeridou Urania,
Hoffmann Georg F.,
Leiz Steffen,
Makowski Christine,
Roser Timo,
Schroeder Sebastian A.,
Steinfeld Robert,
StroblWildemann Gertrud,
Hoefele Julia,
Borggraefe Ingo,
Distelmaier Felix,
Strom Tim M.,
Winkelmann Juliane,
Meitinger Thomas,
Zech Michael,
Wagner Matias
Publication year - 2021
Publication title -
clinical genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.543
H-Index - 102
eISSN - 1399-0004
pISSN - 0009-9163
DOI - 10.1111/cge.13946
Subject(s) - exome sequencing , phenotype , intellectual disability , biology , genetics , exome , gene , autism spectrum disorder , genetic heterogeneity , autism , computational biology , medicine , psychiatry
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.