Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study
Open accessAbstract
Background The genetic cause of intellectual disability in most patients is unclear because of the absence of morphological clues, information about the position of such genes, and suitable screening methods. Our aim was to identify de-novo variants in individuals with sporadic non-syndromic intellectual disability.Methods In this study, we enrolled children with intellectual disability and their parents from ten centres in Germany and Switzerland. We compared exome sequences between patients and their parents to identify de-novo variants. 20 children and their parents from the KORA Augsburg Diabetes Family Study were investigated as controls.Findings We enrolled 51 participants from the German Mental Retardation Network. 45 (88%) participants in the case group and 14 (70%) in the control group had de-novo variants. We identified 87 de-novo variants in the case group, with an exomic mutation rate of 1·71 per individual per generation. In the control group we identified 24 de-novo variants, which is 1·2 events per individual per generation. More participants in the case group had loss-of-function variants than in the control group (20/51 vs 2/20; p=0·022), suggesting their contribution to disease development. 16 patients carried de-novo variants in known intellectual disability genes with three recurrently mutated genes (STXBP1, SYNGAP1, and SCN2A). We deemed at least six loss-of-function mutations in six novel genes to be disease causing. We also identified several missense alterations with potential pathogenicity.Interpretation After exclusion of copy-number variants, de-novo point mutations and small indels are associated with severe, sporadic non-syndromic intellectual disability, accounting for 45-55% of patients with high locus heterogeneity. Autosomal recessive inheritance seems to contribute little in the outbred population investigated. The large number of de-novo variants in known intellectual disability genes is only partially attributable to known non-specific phenotypes. Several patients did not meet the expected syndromic manifestation, suggesting a strong bias in present clinical syndrome descriptions.Funding German Ministry of Education and Research, European Commission 7th Framework Program, and Swiss National Science Foundation.
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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 [13]
The ID/DD cohorts evaluated in the Satterstrom and Coe studies overlapped almost completely; each study used samples from five previously published studies, and four of the five were the same studies, accounting for 99% of the samples.
“In fact, the ID/DD cohorts evaluated in these two studies overlapped almost completely; each study used samples from five previously published studies, and four of the five were the same studies, accounting for 99% of the samples.11, 12, 13, 14, 15, 16”
From Insufficient Evidence for “Autism-Specific” Genes (2020) · cites this paper as [13]
CHD2, SYNGAP1, and SYNCRIP are also affected by LoF de novo SNVs in ID, and SYNGAP1 and DPYD are altered in schizophrenia.
“Three other genes affected by de novo CNVs (also picked by NETBAG)—CHD2, SYNGAP1, and SYNCRIP—are also affected by LoF de novo SNVs in ID,50,52 and two (SYNGAP1 and DPYD [MIM 612779]) are altered in schizophrenia.53”
From Convergence of genes and cellular pathways dysregulated in autism spectrum disorders (2014) · cites this paper as [50]
De novo SNVs in CHD2 have been reported in an ASD subject and in several individuals with a broad spectrum of neurodevelopmental disorders, including ID and epileptic encephalopathy.
“De novo SNVs in CHD2 have been reported in an ASD subject and in several individuals with a broad spectrum of neurodevelopmental disorders, including ID and epileptic encephalopathy8,49,50 (Figure S6).”
From Convergence of genes and cellular pathways dysregulated in autism spectrum disorders (2014) · cites this paper as [50]
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 [67]
Many strong neurobiological candidates have emerged from genes disrupted by de novo mutations, including previously identified ASD/ID genes.
“Many strong neurobiological candidates have emerged from the genes disrupted by de novo mutations in these studies, including mutations in previously identified ASD/ID genes.”
From A de novo convergence of autism genetics and molecular neuroscience (2014) · cites this paper as [29]
Exome sequencing of ASD/ID families has revealed a significant excess of de novo mutations in probands compared with unaffected siblings and has identified novel candidate genes.
“Exome sequencing of ASD/ID families has revealed a significant excess of de novo mutations in probands when compared to unaffected siblings and has identified novel candidate genes contributing to the neurological deficits.”
From A de novo convergence of autism genetics and molecular neuroscience (2014) · cites this paper as [29]
Sporadic cases of autism spectrum disorder and intellectual disability are enriched for disruptive de novo mutations.
“New exome sequencing technology has identified novel rare variants and has found that sporadic cases of ASD/ID are enriched for disruptive de novo mutations.”
From A de novo convergence of autism genetics and molecular neuroscience (2014) · cites this paper as [29]
Only three genes, CHD8, SCN2A, and SYNGAP1, had two independent truncating de novo mutations in any single study, and no gene had more than three mutations.
“In summary, only three genes [CHD8, SCN2A, and synaptic Ras GTPase activating protein 1 (SYNGAP1)] had two independent truncating de novo mutations in any single study, and no gene had more than three mutations.”
From A de novo convergence of autism genetics and molecular neuroscience (2014) · cites this paper as [29]
The strongest effects are observed for de novo loss-of-function or truncating mutations.
“We note that the strongest effects are observed for de novo loss-of-function (or truncating) mutations”
From A de novo convergence of autism genetics and molecular neuroscience (2014) · cites this paper as [29]
A de novo frame-shift in CHD2 was found in an ID case.
“a de novo frame-shift in CHD2 was found by Rauch et al. in an ID case [29]”
From A de novo convergence of autism genetics and molecular neuroscience (2014) · cites this paper as [29]
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“Unsurprisingly, many ASD 14 genes are also associated with NDD (22-26).”
Background
- Authors
- Rauch, A., Wieczorek, D., Graf, E., Wieland, T., Endele, S., Schwarzmayr, T., Albrecht, B., Bartholdi, D., Beygo, J., Di Donato, N., Dufke, A., Cremer, K., Hempel, M., Horn, D., Hoyer, J., Joset, P., Röpke, A., Moog, U., Riess, A., Thiel, C. T., Tzschach, A., Wiesener, A., Wohlleber, E., Zweier, C., Ekici, A. B., Zink, A. M., Rump, A., Meisinger, C., Grallert, H., Sticht, H., Schenck, A., Engels, H., Rappold, G., Schröck, E., Wieacker, P., Riess, O., Meitinger, T., Reis, A., & Strom, T. M.
- Affiliations
- Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
- Essen University Hospital (DE)
- Helmholtz Munich (DE)
- University of Zurich (CH)
- University of Tübingen (DE)
- Institut für Humangenetik (DE)
- Charité – Universitätsmedizin Berlin (DE)
- University of Münster (DE)
- Heidelberg University (DE)
- University of Bonn (DE)
- Technische Universität Dresden (DE)
- Radboud University Medical Center (NL)
- Corresponding author
- Strom, Tim M
- ORCID
- Rauch, Anita
- Wieczorek, Dagmar
- Graf, Elisabeth
- Wieland, Thomas
- Beygo, Jasmin
- Dufke, Andreas
- Hempel, Maja
- Horn, Denise
- Hoyer, Juliane
- Joset, Pascal
- Röpke, Albrecht
- Moog, Ute
- Thiel, Christian T
- Tzschach, Andreas
- Wiesener, Antje
- Wohlleber, Eva
- Zweier, Christiane
- Ekici, Arif B
- Rump, Andreas
- Meisinger, Christa
- Grallert, Harald
- Sticht, Heinrich
- Schenck, Annette
- Engels, Hartmut
- Rappold, Gudrun
- Schröck, Evelin
- Riess, Olaf
- Meitinger, Thomas
- Reis, André
- Venue
- The Lancet
- Publisher
- Elsevier BV
- Published
- 2012-11
- Volume
- 380
- Issue
- 9854
- Pages
- 1674-1682
- ISSN
- 0099-5355 (ISSN-L)
- 0140-6736
- OpenAlex
- W2138033133
- Cited by
- 1,041
- References
- 39
- Citations by year
- 2026: 16 · 2025: 25 · 2024: 41 · 2023: 48 · 2022: 49 · 2021: 75 · 2020: 61 · 2019: 103 · 2018: 103 · 2017: 106 · 2016: 115 · 2015: 104 · 2014: 122 · 2013: 67 · 2012: 2
- FWCI
- 56.68
- Type
- journal article
- Language
- en
- Open access
- green
- zenodo.org
- Licence
- Locations
- The Lancet (publishedVersion)
- PubMed (publishedVersion)
- Zurich Open Repository and Archive (University of Zurich) (acceptedVersion)
- mediaTUM (Technical University of Munich) (submittedVersion)
- Site cant be reached (submittedVersion)
- Radboud Repository (Radboud University) (submittedVersion)
- OPUS (Augsburg University) (submittedVersion)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion)
- Zenodo (CERN European Organization for Nuclear Research) (submittedVersion, other-oa)
- Zurich Open Repository and Archive (University of Zurich)
- Funders
- European Commission
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Keywords
- non-syndromic intellectual disability, de novo mutations, loss-of-function mutations, STXBP1, SYNGAP1, SCN2A, missense mutations, locus heterogeneity, exome sequencing, mutation rate, autosomal recessive inheritance
- MeSH terms
- Child, Female, Humans, Male, Intellectual Disability, Mutation, Case-Control Studies, Exome
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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