Exome sequencing identifies de novo splicing variant in XRCC6 in sporadic case of autism.,Journal of Human Genetics

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Exome sequencing identifies de novo splicing variant in XRCC6 in sporadic case of autism.
Journal of Human Genetics ( IF 2.6 ) Pub Date : 2019-12-12 , DOI: 10.1038/s10038-019-0707-0
Calvin P Sjaarda _{1,

2} , Shalandra Wood _{1,

2} , Amy J M McNaughton _{1,

2} , Sarah Taylor _{1,

2} , Melissa L Hudson _{1,

2} , Xudong Liu _{1,

2} , Andrea Guerin ₃ , Muhammad Ayub ₂

Affiliation

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder with heterogeneity in presentation, genetic etiology, and clinical outcome. Although numerous ASD susceptibility genes have been described, they only account for a small fraction of the estimated heritability, supporting the need to identify more risk variants. This study reports the whole exome sequencing for 24 simplex families with sporadic cases of ASD. These families were selected following a rigorous family history study designed to exclude families with any history of neurodevelopmental or psychiatric disease. Fifteen rare, de novo variants, including fourteen missense variants and one splicing variant, in thirteen families were identified. We describe a splicing variant in XRCC6 which was predicted to destroy the 5' splice site in intron 9 and introduce a premature stop codon. We observed intron 9 retention in XRCC6 transcripts and reduced XRCC6 expression in the proband. Reduced XRCC6 activity and function may be relevant to ASD etiology due to XRCC6's role in nonhomologous DNA repair and interactions of the C-terminal SAP domain with DEAF1, a nuclear transcriptional regulator that is important during embryonic development.

中文翻译：

外显子组测序在散发性自闭症病例中鉴定出 XRCC6 中的从头剪接变体。

自闭症谱系障碍 (ASD) 是一种复杂的神经发育障碍，在表现、遗传病因和临床结果方面具有异质性。尽管已经描述了许多 ASD 易感基因，但它们仅占估计遗传力的一小部分，支持识别更多风险变异的需要。本研究报告了 24 个具有散发性 ASD 病例的单纯性家庭的整个外显子组测序。这些家庭是在严格的家族史研究后选择的，该研究旨在排除有任何神经发育或精神疾病史的家庭。鉴定了 13 个家族中的 15 个罕见的从头变体，包括 14 个错义变体和一个剪接变体。我们描述了 XRCC6 中的一个剪接变体，预计会破坏 5' 在内含子 9 中的剪接位点并引入过早终止密码子。我们观察到 XRCC6 转录本中的内含子 9 保留和先证者中 XRCC6 表达降低。由于 XRCC6 在非同源 DNA 修复中的作用以及 C 末端 SAP 结构域与 DEAF1 的相互作用，XRCC6 活性和功能的降低可能与 ASD 病因有关，DEAF1 是胚胎发育过程中重要的核转录调节因子。

更新日期：2019-12-13

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