Cited by 1,125Genomics and Rare DiseasesGenomic variations and chromosomal abnormalitiesGenetics and Neurodevelopmental Disorders

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Genome sequencing identifies major causes of severe intellectual disability

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Gilissen, Christian, Hehir-Kwa, Jayne Y., Thung, Djie Tjwan, van de Vorst, Maartje, van Bon, Bregje W. M., Willemsen, Marjolein H., Kwint, Michael, Janssen, Irene M., Hoischen, Alexander, Schenck, Annette, Leach, Richard, Klein, Robert, Tearle, Rick, Bo, Tan, Pfundt, Rolph, Yntema, Helger G., de Vries, Bert B. A., Kleefstra, Tjitske, Brunner, Han G., Vissers, Lisenka E. L. M., Veltman, Joris A.·2014·Nature

DOI 10.1038/nature13394

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Abstract

Severe intellectual disability (ID) occurs in 0.5% of newborns and is thought to be largely genetic in origin. The extensive genetic heterogeneity of this disorder requires a genome-wide detection of all types of genetic variation. Microarray studies and, more recently, exome sequencing have demonstrated the importance of de novo copy number variations (CNVs) and single-nucleotide variations (SNVs) in ID, but the majority of cases remain undiagnosed. Here we applied whole-genome sequencing to 50 patients with severe ID and their unaffected parents. All patients included had not received a molecular diagnosis after extensive genetic prescreening, including microarray-based CNV studies and exome sequencing. Notwithstanding this prescreening, 84 de novo SNVs affecting the coding region were identified, which showed a statistically significant enrichment of loss-of-function mutations as well as an enrichment for genes previously implicated in ID-related disorders. In addition, we identified eight de novo CNVs, including single-exon and intra-exonic deletions, as well as interchromosomal duplications. These CNVs affected known ID genes more frequently than expected. On the basis of diagnostic interpretation of all de novo variants, a conclusive genetic diagnosis was reached in 20 patients. Together with one compound heterozygous CNV causing disease in a recessive mode, this results in a diagnostic yield of 42% in this extensively studied cohort, and 62% as a cumulative estimate in an unselected cohort. These results suggest that de novo SNVs and CNVs affecting the coding region are a major cause of severe ID. Genome sequencing can be applied as a single genetic test to reliably identify and characterize the comprehensive spectrum of genetic variation, providing a genetic diagnosis in the majority of patients with severe ID.

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Authors: Gilissen, C., Hehir-Kwa, J. Y., Thung, D. T., van de Vorst, M., van Bon, B. W. M., Willemsen, M. H., Kwint, M., Janssen, I. M., Hoischen, A., Schenck, A., Leach, R., Klein, R., Tearle, R., Bo, T., Pfundt, R., Yntema, H. G., de Vries, B. B. A., Kleefstra, T., Brunner, H. G., Vissers, L. E. L. M., & Veltman, J. A.
Affiliations: Radboud University Nijmegen (NL)
Radboud University Medical Center (NL)
Complete Genomics (United States) (US)
Central South University (CN)
Corresponding author: Veltman, Joris A.
ORCID: Gilissen, Christian
Willemsen, Marjolein H.
Kwint, Michael
Hoischen, Alexander
Schenck, Annette
Tearle, Rick
Pfundt, Rolph
Yntema, Helger G.
Kleefstra, Tjitske
Brunner, Han G.
Vissers, Lisenka E. L. M.
Veltman, Joris A.
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2014-06-04
Volume: 511
Issue: 7509
Pages: 344-347
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/nature13394
OpenAlex: W2045392412
Cited by: 1,125
References: 29
Citations by year: 2026: 30 · 2025: 45 · 2024: 50 · 2023: 74 · 2022: 93 · 2021: 87 · 2020: 102 · 2019: 115 · 2018: 122 · 2017: 129 · 2016: 137 · 2015: 110 · 2014: 28
FWCI: 88.22
Type: journal article
Language: en
Open access: green
cris.maastrichtuniversity.nl
Licence: other-oa
www.springer.com/tdm (tdm)
Locations: Nature (publishedVersion)
PubMed (publishedVersion)
Research Publications (Maastricht University) (acceptedVersion, other-oa)
RePEc: Research Papers in Economics (submittedVersion)
Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion)
Radboud Repository (Radboud University) (submittedVersion)
Radboud Repository (Radboud University) (submittedVersion, other-oa)
Research Publications (Maastricht University) (submittedVersion)
Newcastle University ePrints (Newcastle Univesity)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
Keywords: severe intellectual disability, de novo copy number variation, loss-of-function mutations, whole genome sequencing, genetic diagnosis, diagnostic yield, recessive inheritance, undiagnosed genetic disorders
MeSH terms: Chromosomes, Human, Pair 4, Humans, Male, Intellectual Disability, Mutation, Cohort Studies, Genome, Human, Sequence Analysis, DNA, Gene Duplication, Polymorphism, Single Nucleotide, Guanine Nucleotide Exchange Factors, Chromosomes, Human, X, DNA Copy Number Variations

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Genome sequencing identifies major causes of severe intellectual disability

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