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一个新的 CCDC88A 基因的纯合无义突变导致沙特血缘家族中的 PEHO 样综合征。

A novel homozygous nonsense mutation in CCDC88A gene cause PEHO-like syndrome in consanguineous Saudi family.

机构信息

Center of Excellence in Genomic Medicine Research (CEGMR), King Abdulaziz University, Jeddah, 21589, Kingdom of Saudi Arabia.

Department of Medical Genetics, King Fahad General Hospital, Jeddah, Saudi Arabia.

出版信息

Neurol Sci. 2019 Feb;40(2):299-303. doi: 10.1007/s10072-018-3626-5. Epub 2018 Nov 3.

Abstract

Progressive encephalopathy, edema, hypsarrhythmia, and optic atrophy (PEHO) syndrome is an unusual Mendelian phenotype of unidentified origin that causes profound intellectual disability, optic nerve/cerebellar atrophy, epileptic seizures, developmental progress, pedal edema, and early death. Uncharacteristic affected individuals are often classified as having PEHO-like syndrome, although they may be misdiagnosed as having epileptic encephalopathy, a potential result of early birth. In this study, we report a consanguineous Saudi family with a novel homozygous nonsense mutation of the CCDC88A gene causing PEHO-like syndrome. The children were suffering from developmental delay, epilepsy, mental disability, optic nerve/cerebellar atrophy, and pedal edema. Whole exome sequencing was conducted for the members of the family who have the disorder to study the novel mutation. Whole exome sequencing data analysis, confirmed by subsequent Sanger sequencing validation, identified a novel homozygous nonsense mutation c. 1292G > A, which was caused by p.Trp431* stop gain. This mutation was ruled out in 100 unrelated healthy controls. The nonsense homozygous mutation detected in this study has not yet been reported as pathogenic in the literature or various databases. In conclusion, a complete loss of protein function due to premature stop gain was caused by a mutation in exon 12 of CCDC88A. This loss may lead to PEHO phenotype. CCDC88A gene may therefore play an important and critical role for multiple aspects of normal human neurodevelopment.

摘要

进行性脑病、水肿、高度失律和视神经萎缩(PEHO)综合征是一种不常见的孟德尔表型,其病因不明,可导致严重的智力障碍、视神经/小脑萎缩、癫痫发作、发育迟缓、足部水肿和早逝。非典型受影响个体通常被归类为具有 PEHO 样综合征,尽管它们可能被误诊为癫痫性脑病,这可能是由于早产的结果。在这项研究中,我们报告了一个沙特阿拉伯的近亲家庭,该家庭存在 CCDC88A 基因的新型纯合无义突变,导致 PEHO 样综合征。患儿表现为发育迟缓、癫痫、智力残疾、视神经/小脑萎缩和足部水肿。对患有该疾病的家庭成员进行全外显子组测序,以研究新的突变。全外显子组测序数据分析,随后通过 Sanger 测序验证,确定了一种新型纯合无义突变 c.1292G>A,导致 p.Trp431* 停止增益。该突变在 100 名无关健康对照中未被发现。本研究中检测到的无义纯合突变在文献或各种数据库中尚未被报道为致病性突变。总之,由于提前终止获得,CCDC88A 基因第 12 外显子的突变导致蛋白功能完全丧失,可能导致 PEHO 表型。因此,CCDC88A 基因可能在人类神经发育的多个方面发挥重要和关键作用。

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