Genetic factors play a major part in intellectual disability (ID), but genetic studies have been complicated for a long time by the extreme clinical and genetic heterogeneity. Recently, progress has been made using different next-generation sequencing approaches in combination with new functional readout systems. This approach has provided novel insights into the biological pathways underlying ID, improved the diagnostic process and offered new targets for therapy. In this Review, we highlight the insights obtained from recent studies on the role of genetics in ID and its impact on diagnosis, prognosis and therapy. We also discuss the future directions of genetics research for ID and related neurodevelopmental disorders.
At a glance
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The first study to apply patient–parent trio-based whole-genome sequencing in a cohort of 50 patients with unexplained ID. A conclusive diagnosis was made in 21 of 50 patients. Also, it was estimated that genome sequencing as a first-tier test would identify the genetic cause in 62% of severe ID cases.
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The first study to use exome sequencing of patient–parent trios to identify de novo mutations in a complex trait characterized by extreme genetic heterogeneity.
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First results of one of the largest sequencing projects to date, applying a statistical framework for the identification of new disease genes for developmental disorders.
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A first systematic study of the genetics underlying recessive intellectual disability using homozygosity mapping and targeted NGS to identify many new candidate ID genes.
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Important consortium statement on the use of genomic microarrays as first-tier diagnostic tests in individuals with intellectual disability and congenital abnormalities.
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One of the first studies investigating the role of de novo mutations of candidate ID genes.
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This study was one of the first of a series of large-scale trio-based sequencing projects identifying de novo mutations in neurodevelopmental disorders. The authors performed exome sequencing of more than 200 ASD patients and their parents.
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These authors proposed guidelines for summarizing confidence in variant pathogenicity in the era of NGS. The authors especially emphasize the use of statistical frameworks to assess genetic, informatic and functional evidence.
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- Refining analyses of copy number variation identifies specific genes associated with developmental delay. Nat. Genet. 46, 1063–1071 (2014).
The largest study to date for copy number analysis in individuals with developmental delay.
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- Mutations in SWI/SNF chromatin remodeling complex gene ARID1B cause Coffin–Siris syndrome. Nat. Genet. 44, 379–380 (2012).
The recent identification of a novel ID gene for which mutations explain a relatively large fraction of ID patients. This study shows that frequently mutated ID genes can still be identified.
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- Parental somatic mosaicism is underrecognized and influences recurrence risk of genomic disorders. Am. J. Hum. Genet. 95, 173–182 (2014). et al.
- De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes. Nat. Genet. 44, 934–940 (2012). et al.
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Important study for ID genetics in that it pioneers the detection of mosaic mutations in human neurons.
- Recurrent de novo mutations in PACS1 cause defective cranial-neural-crest migration and define a recognizable intellectual-disability syndrome. Am. J. Hum. Genet. 91, 1122–1127 (2012). et al.
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- Disruptions of topological chromatin domains cause pathogenic rewiring of gene–enhancer interactions. Cell 161, 1012–1025 (2015).
A nice demonstration of the identification of de novo non-coding CNVs causing a Mendelian disorder. The authors show the extensive amount of functional evidence that is required to prove pathogenicity for non-coding variants.
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Exciting study providing the first evidence that a deficiency in postnatal neurogenesis underlies the ID observed in Kabuki syndrome, and suggesting that this can be rescued by HDAC inhibitors.
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- Supplementary information S1 (table) (473 KB)
Genes linked to isolated ID and ID-associated disorders