Whole genome sequencing of 45 Japanese patients with intellectual disability.
Whole genome sequencing of 45 Japanese patients with intellectual disability.
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DOI：
10.1002/ajmg.a.62138
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发表时间：
2021-05
期刊：
影响因子：
--
通讯作者：
Goto YI
中科院分区：
文献类型：
--
作者：
Abe-Hatano C;Iida A;Kosugi S;Momozawa Y;Terao C;Ishikawa K;Okubo M;Hachiya Y;Nishida H;Nakamura K;Miyata R;Murakami C;Takahashi K;Hoshino K;Sakamoto H;Ohta S;Kubota M;Takeshita E;Ishiyama A;Nakagawa E;Sasaki M;Kato M;Matsumoto N;Kamatani Y;Kubo M;Takahashi Y;Natsume J;Inoue K;Goto YI
智力残疾(ID)的特征是智力功能和适应行为方面的显著限制，起源于18 岁之前。然而，由于广泛的临床和遗传异质性，ID的遗传病因仍未完全阐明。全基因组测序技术(WGS)因能检测从单核苷酸变异(SNV)到结构变异(SVS)等多种分辨率的遗传变异，已成为ID的一种临床一步诊断工具。为了探索ID的致病基因，我们使用WGS对来自44个无关日本家庭的45名患者进行了逐步筛选，重点是基因中的编码变异。在这里，我们报告了12个致病和可能的致病变异：ADNP、SATB2、ANKRD11、PTEN、TCF4、SPAST和KCNA2的7个杂合变异，SMS、SLC6A8和IQSEC2的3个半合子变异，以及AGTPBP1的1个纯合子变异。在这些作品中，有四部被认为是小说。此外，在DYRK1a中还发现了一个含有外显子1和2的新的76 kb缺失。我们证实了临床和遗传的异质性和新的致病变异的高频率(8/12，66.7%)。这是对日本ID患者进行WGS分析的第一份报告。我们的结果将为深入了解新的变异和疾病扩展表型之间的相关性提供依据。
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.
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