Genome sequencing identifies major causes of severe intellectual disability
Open accessAbstract
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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The prevalence of ASD in several ID/DD-ascertained cohorts is not quantified, and the prevalence of ID in ASD-ascertained cohorts is known only for a minority subset of participants.
“Because of this bias, the phenotypic overlap between the groups is unclear; the prevalence of ASD in several of the ID/DD-ascertained cohorts is not quantified,13, 14, 15,18,19 and the prevalence of ID in the ASD-ascertained cohorts is known only for a minority subset of participants.11,12”
From Insufficient Evidence for “Autism-Specific” Genes (2020) · cites this paper as [18]
Genetic approaches have identified causes for more than 1,000 Mendelian and fewer non-Mendelian forms of neurodevelopmental disorders, including intellectual disability, ASD, epilepsy, and schizophrenia.
“Various genetic approaches have been successful in identifying the causes of more than 1,000 Mendelian, and fewer non-Mendelian, forms of neurodevelopmental disorders: prototypical examples are intellectual disability62–68, autism spectrum disorder (ASD)69–77, epilepsy78,79 and schizophrenia80–82.”
From Systems biology and gene networks in neurodevelopmental and neurodegenerative disorders (2015) · cites this paper as [68]
Whole-exome sequencing studies have found enrichment of FMRP targets among rare mutations in schizophrenia, intellectual disability, and epilepsy.
“Additionally, whole-exome sequencing studies of other neurodevelopmental disorders have found enrichment for FMRP targets in rare mutations in schizophrenia81, intellectual disability68 and epilepsy78.”
From Systems biology and gene networks in neurodevelopmental and neurodegenerative disorders (2015) · cites this paper as [68]
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Self-citation
- 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
- Venue
- Nature
- Published
- 2014-06-04
- Volume
- 511
- Issue
- 7509
- Pages
- 344-347
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- 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 · 2013: 1
- FWCI
- 88.22
- Type
- journal article
- Language
- en
- Open access
- 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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