Am J Med Genet A. 2021 May;185(5):1468-1480. doi: 10.1002/ajmg.a.62138. Epub 2021 Feb 24.

Whole genome sequencing of 45 Japanese patients with intellectual disability.


Intellectual disability (ID) is characterized by significant limitations in both intellectual functioning and adaptive behaviors, originating before the age of 18 years. However, the genetic etiologies of ID are still incompletely elucidated due to the wide range of clinical and genetic heterogeneity. Whole genome sequencing (WGS) has been applied as a single-step clinical diagnostic tool for ID because it detects genetic variations with a wide range of resolution from single nucleotide variants (SNVs) to structural variants (SVs).
To explore the causative genes for ID, we employed WGS in 45 patients from 44 unrelated Japanese families and performed a stepwise screening approach focusing on the coding variants in the genes. Here, we report 12 pathogenic and likely pathogenic variants: seven heterozygous variants of ADNP, SATB2, ANKRD11, PTEN, TCF4, SPAST, and KCNA2, three hemizygous variants of SMS, SLC6A8, and IQSEC2, and one homozygous variant in AGTPBP1. Of these, four were considered novel.
Furthermore, a novel 76窶洩b deletion containing exons 1 and 2 in DYRK1A was identified. We confirmed the clinical and genetic heterogeneity and high frequency of de novo causative variants (8/12, 66.7%). This is the first report of WGS analysis in Japanese patients with ID. Our results would provide insight into the correlation between novel variants and expanded phenotypes of the disease.


理化学研究所との全ゲノム解析研究を行う共同研究で、未診断の知的障害患者44家系のうち計12家系(27%)において病因と考えられるバリアントを検出した。うち8例がde novoと高頻度であり、過去の報告と合致した。また、知的障害における高い遺伝的異質性を確認した。全ゲノム解析によって構造多型から1塩基置換まで包括的に検出可能であったことから、知的障害の遺伝学的解析における全ゲノム解析の診断的有用性が示唆された。

PMID:  33624935