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

Theresa Brunet, Robert Jech, Melanie Brugger, Reka Kovacs, Bader Alhaddad, Gloria Leszinski, Korbinian M. Riedhammer, Dominik S. Westphal, Isabella Mahle, Katharina Mayerhanser, Matej Skorvanek, Sandrina Weber, Elisabeth Graf, Riccardo Berutti, Ján Necpál, Petra Havránková, Petra Pavelekova, Maja Hempel, Urania Kotzaeridou, Georg F. HoffmannSteffen Leiz, Christine Makowski, Timo Roser, Sebastian A. Schroeder, Robert Steinfeld, Gertrud Strobl-Wildemann, Julia Hoefele, Ingo Borggraefe, Felix Distelmaier, Tim M. Strom, Juliane Winkelmann, Thomas Meitinger, Michael Zech, Matias Wagner

Research output: Contribution to journalArticlepeer-review

66 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)14-28
Number of pages15
JournalClinical Genetics
Volume100
Issue number1
DOIs
StatePublished - Jul 2021

Keywords

  • autism
  • candidate gene
  • de novo variant
  • exome sequencing
  • intellectual disability
  • neurodevelopmental disorder
  • reanalysis

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