De Novo Mutations in Moderate or Severe Intellectual Disability

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.

GABRB3 mutations: a new and emerging cause of early infantile epileptic encephalopathy

“…To date, five other cases of GABRB3 early infantile epileptic encephalopathy have been reported,10, 13 to our knowledge (Table 1). We postulate that there are several features common in all these cases, including: (1) seizure onset in infancy, <10months of age, (2) multiple seizure types including infantile spasms, (3) variable EEG abnormalities, and (4) associated comorbidities such as neurodevelopmental delay, attention‐deficit–hyperactivity disorder, autistic features, and intellectual disability.…”

Effectiveness of whole-exome sequencing and costs of the traditional diagnostic trajectory in children with intellectual disability

“…The value of 1.88 validated de novo variants per patient in our study is consistent with the 1.71-1.98 validated de novo variants per patient previously reported in larger intellectual-disability cohorts, thereby validating our sequencing and analysis pipeline. 19,20 Autosomal recessive, X-linked recessive, and compound heterozygous inheritance models were also investigated, but no variants that could explain the patients' phenotype were detected. The lack of homozygous autosomal recessive causal variants was in accordance with our initial selection of only patients whose parents were nonconsanguineous.…”

De novo loss-of-function mutations in WAC cause a recognizable intellectual disability syndrome and learning deficits in Drosophila

“…8,9 Previously, we and others separately reported on an individual with a de novo mutation in the 'WW domain-containing adapter with coiled-coil' (WAC) gene using trio-based exome sequencing. 1, 10 The mutations were reported as potential cause of disease, based on mutation severity, protein function, its expression in fetal stages and high expression in adult brain. 1,10,11 WAC encodes a protein-regulating transcription-coupled histone H2B ubiquitination and contains two evolutionary conserved domains, including an N-terminal WW domain interacting with RNA polymerase II and a C-terminal coiled-coil domain promoting the RNF20/RNF40's E3 ligase activity for ubiquitination at active transcription sites.…”