Genetic and phenotypic analysis of 101 patients with developmental delay or intellectual disability using whole‐exome sequencing

Abstract

Whole‐exome sequencing (WES) enables identification of pathogenic variants, including copy number variants (CNVs). In this study, we performed WES in 101 Japanese patients with unexplained developmental delay (DD) or intellectual disability (ID) (63 males and 38 females), 98 of them with trio‐WES. Pathogenic variants were identified in 54 cases (53.5%), including four cases with pathogenic CNVs. In one case, a pathogenic variant was identified by reanalysis of exome data; and in two cases, two molecular diagnoses were identified. Among 58 pathogenic variants, 49 variants occurred de novo in 48 patients, including two somatic variants. The accompanying autism spectrum disorder and external ear anomalies were associated with detection of pathogenic variants with odds ratios of 11.88 (95% confidence interval [CI] 2.52–56.00) and 3.46 (95% CI 1.23–9.73), respectively. These findings revealed the importance of reanalysis of WES data and detection of CNVs and somatic variants in increasing the diagnostic yield for unexplained DD/ID. In addition, genetic testing is recommended when patients suffer from the autism spectrum disorder or external ear anomalies, which potentially suggests the involvement of genetic factors associated with gene expression regulation.

Genetic Analysis of Children With Unexplained Developmental Delay and/or Intellectual Disability by Whole-Exome Sequencing

“…In this study, WES was performed for 17 probands with DD/ID with an overall diagnostic yield of 58.8% (10/17), which is consistent with a recent study that WES identified pathogenic variants in 53.5% (54/101) of patients with DD/ID ( Hiraide et al, 2021 ). A total of eight de novo variants were detected, including five SNVs/Indels and three CNVs, corroborating the burden of de novo variants in DD/ID ( Brunet et al, 2021 ).…”

Expansion of the genotypic and phenotypic spectrum of CTCF‐related disorder guides clinical management: 43 new subjects and a comprehensive literature review

“…In 2021, a large‐scale exome sequencing study that aimed to identify genes implicated in neurodevelopmental disorders (Wang et al, 2020) reported clinical information for 13 additional cases of CRD. In addition, a few case reports have described the clinical features of subjects with CRD (Bastaki et al, 2017; Chen et al, 2019; Hiraide et al, 2021; Hori et al, 2017). Based on these publications, CRD is currently described as an autosomal dominant neurodevelopmental disorder associated with the ID, feeding difficulties/failure to thrive (FTT), microcephaly, and behavioral abnormalities.…”

The Polygenic Nature and Complex Genetic Architecture of Specific Learning Disorder

“…It is unclear how much of the missing heritability of SLD could be attributed to rare or de novo variants of moderate or high effect, even though this issue has been extensively studied with respect to ID, ASD and developmental delay [142][143][144]. With the emergence of NGS technology, the identification of rare variants could help fill in some of the missing pieces of the puzzle.…”