Department of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan.
Department of Pediatrics, Nagoya University Graduate School of Medicine, Aichi, Japan.
Am J Med Genet A. 2021 May;185(5):1468-1480. doi: 10.1002/ajmg.a.62138. Epub 2021 Feb 24.
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 kb 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.
智力残疾（ID）的特征是智力功能和适应行为方面存在显著限制，其发病起源于 18 岁之前。然而，由于临床和遗传异质性广泛，ID 的遗传病因仍不完全清楚。全基因组测序（WGS）已被用作 ID 的单一临床诊断工具，因为它可以检测具有广泛分辨率的遗传变异，从单核苷酸变异（SNV）到结构变异（SV）。为了探索 ID 的致病基因，我们对来自 44 个无关日本家庭的 45 名患者进行了 WGS，并采用了一种逐步筛选方法，重点关注基因中的编码变异。在这里，我们报告了 12 个致病性和可能致病性的变异：ADNP、SATB2、ANKRD11、PTEN、TCF4、SPAST 和 KCNA2 中的七个杂合变异、SMS、SLC6A8 和 IQSEC2 中的三个半合子变异以及 AGTPBP1 中的一个纯合子变异。其中，有四个被认为是新的。此外，还鉴定出 DYRK1A 中包含外显子 1 和 2 的 76kb 缺失的新型变异。我们证实了临床和遗传异质性以及新生致病变异的高频率（8/12，66.7%）。这是日本 ID 患者 WGS 分析的首次报告。我们的结果将为新型变异与疾病扩展表型之间的相关性提供深入了解。
