Genetic studies in intellectual disability and related disorders

Abstract

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.

The Use of Next-Generation Sequencing for Research and Diagnostics for Intellectual Disability

“…The investigators discuss the possible overlap in genetic architecture and biological pathways, despite the apparent distinct pathogenesis for these disorders. In another review article, LoF mutations shared across different neurodevelopmental or neuropsychiatric disorders are discussed (Vissers et al 2015). In addition to LoF mutations in many genes shared between ASD and ID, the review lists LoF mutations in AUTS2 in both ID and SCZ, and in POGZ, SCN2A, and SYNGAP1 in ID, SCZ, and ASD.…”

Biallelic variants in LINGO1 are associated with autosomal recessive intellectual disability, microcephaly, speech and motor delay

“…1 It is an extremely heterogeneous group of disorders, as to date, over 700 genes have been implicated in syndromic and nonsyndromic ID. 2 Despite the considerable progress in disease gene identification, especially after the introduction of nextgeneration sequencing, at least 50% of the estimated genetic causes of ID remain unknown. 3 All Mendelian inheritance patterns have been reported with ID, and approximately half of them follow an autosomal recessive inheritance pattern (autosomal recessive intellectual disability).…”

A clinical approach to developmental delay and intellectual disability

“…A reduction in the cost of next-generation sequencing will likely lead to widespread use of family-based trio evaluation (proband and parents) by WES/ WGS as the second-tier test for GDD/ID in the near future, leading to a higher diagnostic yield. 10 However, many challenges (including ethical, clinical utility and cost-benefit analysis) need to be addressed before the routine implementation of WES/WGS in clinical practice. ■ …”