De novo variants in neurodevelopmental disorders-experiences from a tertiary care center
Standard
De novo variants in neurodevelopmental disorders-experiences from a tertiary care center. / 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; Strobl-Wildemann, Gertrud; Hoefele, Julia; Borggraefe, Ingo; Distelmaier, Felix; Strom, Tim M; Winkelmann, Juliane; Meitinger, Thomas; Zech, Michael; Wagner, Matias.
in: CLIN GENET, Jahrgang 100, Nr. 1, 07.2021, S. 14-28.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
Harvard
APA
Vancouver
Bibtex
}
RIS
TY - JOUR
T1 - De novo variants in neurodevelopmental disorders-experiences from a tertiary care center
AU - Brunet, Theresa
AU - Jech, Robert
AU - Brugger, Melanie
AU - Kovacs, Reka
AU - Alhaddad, Bader
AU - Leszinski, Gloria
AU - Riedhammer, Korbinian M
AU - Westphal, Dominik S
AU - Mahle, Isabella
AU - Mayerhanser, Katharina
AU - Skorvanek, Matej
AU - Weber, Sandrina
AU - Graf, Elisabeth
AU - Berutti, Riccardo
AU - Necpál, Ján
AU - Havránková, Petra
AU - Pavelekova, Petra
AU - Hempel, Maja
AU - Kotzaeridou, Urania
AU - Hoffmann, Georg F
AU - Leiz, Steffen
AU - Makowski, Christine
AU - Roser, Timo
AU - Schroeder, Sebastian A
AU - Steinfeld, Robert
AU - Strobl-Wildemann, Gertrud
AU - Hoefele, Julia
AU - Borggraefe, Ingo
AU - Distelmaier, Felix
AU - Strom, Tim M
AU - Winkelmann, Juliane
AU - Meitinger, Thomas
AU - Zech, Michael
AU - Wagner, Matias
N1 - © 2021 The Authors. Clinical Genetics published by John Wiley & Sons Ltd.
PY - 2021/7
Y1 - 2021/7
N2 - 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.
AB - 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.
KW - Adolescent
KW - Adult
KW - Child
KW - Child, Preschool
KW - Exome/genetics
KW - Female
KW - Genetic Predisposition to Disease/genetics
KW - Genetic Variation/genetics
KW - Humans
KW - Infant
KW - Infant, Newborn
KW - Male
KW - Middle Aged
KW - Neurodevelopmental Disorders/genetics
KW - Phenotype
KW - Retrospective Studies
KW - Tertiary Care Centers
KW - Whole Exome Sequencing/methods
KW - Young Adult
U2 - 10.1111/cge.13946
DO - 10.1111/cge.13946
M3 - SCORING: Journal article
C2 - 33619735
VL - 100
SP - 14
EP - 28
JO - CLIN GENET
JF - CLIN GENET
SN - 0009-9163
IS - 1
ER -