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

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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, Vol. 100, No. 1, 07.2021, p. 14-28.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Brunet, T, Jech, R, Brugger, M, Kovacs, R, Alhaddad, B, Leszinski, G, Riedhammer, KM, Westphal, DS, Mahle, I, Mayerhanser, K, Skorvanek, M, Weber, S, Graf, E, Berutti, R, Necpál, J, Havránková, P, Pavelekova, P, Hempel, M, Kotzaeridou, U, Hoffmann, GF, Leiz, S, Makowski, C, Roser, T, Schroeder, SA, Steinfeld, R, Strobl-Wildemann, G, Hoefele, J, Borggraefe, I, Distelmaier, F, Strom, TM, Winkelmann, J, Meitinger, T, Zech, M & Wagner, M 2021, 'De novo variants in neurodevelopmental disorders-experiences from a tertiary care center', CLIN GENET, vol. 100, no. 1, pp. 14-28. https://doi.org/10.1111/cge.13946

APA

Brunet, T., Jech, R., Brugger, M., Kovacs, R., Alhaddad, B., Leszinski, G., Riedhammer, K. M., Westphal, D. S., Mahle, I., Mayerhanser, K., Skorvanek, M., Weber, S., Graf, E., Berutti, R., Necpál, J., Havránková, P., Pavelekova, P., Hempel, M., Kotzaeridou, U., ... Wagner, M. (2021). De novo variants in neurodevelopmental disorders-experiences from a tertiary care center. CLIN GENET, 100(1), 14-28. https://doi.org/10.1111/cge.13946

Vancouver

Brunet T, Jech R, Brugger M, Kovacs R, Alhaddad B, Leszinski G et al. De novo variants in neurodevelopmental disorders-experiences from a tertiary care center. CLIN GENET. 2021 Jul;100(1):14-28. https://doi.org/10.1111/cge.13946

Bibtex

@article{f7aa045d7fd249dd8de02b58c5d79e67,
title = "De novo variants in neurodevelopmental disorders-experiences from a tertiary care center",
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.",
keywords = "Adolescent, Adult, Child, Child, Preschool, Exome/genetics, Female, Genetic Predisposition to Disease/genetics, Genetic Variation/genetics, Humans, Infant, Infant, Newborn, Male, Middle Aged, Neurodevelopmental Disorders/genetics, Phenotype, Retrospective Studies, Tertiary Care Centers, Whole Exome Sequencing/methods, Young Adult",
author = "Theresa Brunet and Robert Jech and Melanie Brugger and Reka Kovacs and Bader Alhaddad and Gloria Leszinski and Riedhammer, {Korbinian M} and Westphal, {Dominik S} and Isabella Mahle and Katharina Mayerhanser and Matej Skorvanek and Sandrina Weber and Elisabeth Graf and Riccardo Berutti and J{\'a}n Necp{\'a}l and Petra Havr{\'a}nkov{\'a} and Petra Pavelekova and Maja Hempel and Urania Kotzaeridou and Hoffmann, {Georg F} and Steffen Leiz and Christine Makowski and Timo Roser and Schroeder, {Sebastian A} and Robert Steinfeld and Gertrud Strobl-Wildemann and Julia Hoefele and Ingo Borggraefe and Felix Distelmaier and Strom, {Tim M} and Juliane Winkelmann and Thomas Meitinger and Michael Zech and Matias Wagner",
note = "{\textcopyright} 2021 The Authors. Clinical Genetics published by John Wiley & Sons Ltd.",
year = "2021",
month = jul,
doi = "10.1111/cge.13946",
language = "English",
volume = "100",
pages = "14--28",
journal = "CLIN GENET",
issn = "0009-9163",
publisher = "Wiley-Blackwell",
number = "1",

}

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 -