Next-Generation Sequencing in Intellectual Disability

Abstract

Next-generation sequencing technologies have revolutionized gene discovery in patients with intellectual disability (ID) and led to an unprecedented expansion in the number of genes implicated in this disorder. We discuss the strategies that have been used to identify these novel genes for both syndromic and nonsyndromic ID and highlight the phenotypic and genetic heterogeneity that underpin this condition. Finally, we discuss the future of defining the genetic etiology of ID, including the role of whole-genome sequencing, mosaicism, and the importance of diagnostic testing in ID.

Keywords: copy number variations; de novo mutations; intellectual disability; next generation sequencing.

Fig. 1

Next-generation sequencing approaches to gene discovery. (A) Autosomal dominant or sporadic “phenotype-first approaches” rely on the identification of mutations (red star) in a common gene in patients with the same syndrome (green) that are absent in controls (blue) and unaffected family members (purple). (B) Similarly, autosomal recessive syndromic forms of ID are caused by either homozygous or compound heterozygous mutations in the same gene in affected individuals. Parents are heterozygous for these mutations and the mutation may be present in control populations at a very low frequency (MAF, minor allele frequency). (C) Genotype-first or unbiased approaches employ WES in trios to identify de novo mutations in an affected individual. Novel ID genes are identified by recurrence, either by targeted or WES studies in individuals with ID (green) or other neurodevelopmental disorders (red) or overlap with known copy number variations (CNVs). ID, intellectual disability; WES, whole-genome sequencing.