De Novo Mutations in Moderate or Severe Intellectual Disability

TLDR

Genetic factors, particularly de novo mutations, are increasingly implicated in intellectual disability, yet their precise contribution and the genes involved remain largely undefined. This study aimed to screen for de novo mutations in individuals with moderate or severe intellectual disability. Exome sequencing of 41 probands and their parents identified 81 de novo coding or splice‑site variants, averaging 1.98 per proband. The cohort showed a significant excess of de novo single‑nucleotide and loss‑of‑function mutations, with 12 likely pathogenic variants in known ID genes (yielding ~29 % diagnostic rate) and 12 potentially pathogenic variants in novel genes, no inherited mutations, and protein‑network evidence supporting their role, underscoring DNMs as a major cause of moderate or severe ID.

Abstract

Genetics is believed to have an important role in intellectual disability (ID). Recent studies have emphasized the involvement of de novo mutations (DNMs) in ID but the extent to which they contribute to its pathogenesis and the identity of the corresponding genes remain largely unknown. Here, we report a screen for DNMs in subjects with moderate or severe ID. We sequenced the exomes of 41 probands and their parents, and confirmed 81 DNMs affecting the coding sequence or consensus splice sites (1.98 DNMs/proband). We observed a significant excess of de novo single nucleotide substitutions and loss-of-function mutations in these cases compared to control subjects, suggesting that at least a subset of these variations are pathogenic. A total of 12 likely pathogenic DNMs were identified in genes previously associated with ID (ARID1B, CHD2, FOXG1, GABRB3, GATAD2B, GRIN2B, MBD5, MED13L, SETBP1, TBR1, TCF4, WDR45), resulting in a diagnostic yield of ∼29%. We also identified 12 possibly pathogenic DNMs in genes (HNRNPU, WAC, RYR2, SET, EGR1, MYH10, EIF2C1, COL4A3BP, CHMP2A, PPP1CB, VPS4A, PPP2R2B) that have not previously been causally linked to ID. Interestingly, no case was explained by inherited mutations. Protein network analysis indicated that the products of many of these known and candidate genes interact with each other or with products of other ID-associated genes further supporting their involvement in ID. We conclude that DNMs represent a major cause of moderate or severe ID.