Elsevier

The Lancet

Volume 380, Issue 9854, 10–16 November 2012, Pages 1674-1682
The Lancet

Articles
Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study

https://doi.org/10.1016/S0140-6736(12)61480-9Get rights and content

Summary

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.

Introduction

Intellectual disability is defined as substantial impairment of cognitive and adaptive functions that has onset in childhood1 and has an estimated prevalence of 1·5–2·0%.2 Whereas frequency estimates of mild intellectual disability differ between studies, most researchers agree that severe intellectual disability (an intelligence quotient of <50) has a prevalence of 0·3–0·4%.2 Studies of genetic changes in children with intellectual disability have led to the identification of mutations in many genes on the X chromosome3 and some genes on autosomal chromosomes.4, 5 However, the genetic basis of the disorder is still unclear in most affected children, especially those with non-syndromic intellectual disability, in whom there are no physical signs.6 The difficulty of establishing the genetics of intellectual disability could be because of the high locus heterogeneity and—for autosomal dominant inheritance—the large reproductive disadvantage of the disease, which hampers use of linkage analysis and subsequent positional cloning. The introduction of array-based copy-number analysis led to the identification of de-novo microdeletions and duplications present in several genes in roughly 14% of patients with intellectual disability.7 Sequencing of candidate genes and use of next-generation sequencing techniques showed that a large proportion of sporadic cases might be caused by de-novo point mutations and small insertions or deletions.4, 8 Our aim was to identify de-novo variants by exome sequencing in patients with intellectual disability.

Section snippets

Study design and patients

Between February and November, 2011, we enrolled patients with severe non-syndromic intellectual disability and both healthy, non-consanguineous parents from ten centres of the German Mental Retardation Network. Inclusion criteria were severe intellectual disability with grossly preserved motor function, absence of malformations, absence of syndrome-specific minor anomalies, absence of specific neurological signs, absence of causative copy number variants by high resolution molecular

Results

We enrolled 51 patients from the German Mental Retardation Network, 32 girls and 19 boys. All but three had non-specific intellectual disability with an intelligence quotient of less than 60, and all but five had height, weight, or head circumference within 2·5 SDs of the mean. 17 patients had a history of seizures and 15 had autistic behaviour. 36 patients had cerebral MRI scans, of whom 17 had non-specific minor anomalies such as mild brain atrophy, delayed myelination, and cysts.

To identify

Discussion

The mutation rate for coding variants was high in cases compared with controls and with patients included in previous studies of autism spectrum disorders.13, 14, 21 Including variants both in genes known to cause intellectual disability and in new candidate genes, we estimate that—after exclusion of copy number variations—severe intellectual disability could be caused by de-novo variants in approximately 45–55% of patients. Because of the high locus heterogeneity, final conclusions about the

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