FLNA基因p.A267T变异首发与中国汉族人群耳-腭-指综合征相关  

FLNA Gene p.A267T Variant First Identified in a Chinese Han Family with Oto-palato-digital Syndrome

作　　者：王静[2] 郑好 胡清强 张玉婷 孔旭辉 汪羽 储九圣 庞秀红 WANG Jing;ZHENG Hao;HU Qingqiang;ZHANG Yuting;KONG Xuhui;WANG Yu;CHU Jiusheng;PANG Xiuhong(Department of Otorhinolaryngology-Head and Neck Surgery,Taizhou People’s Hospital,Nanjing Medical University,Taizhou,Jiangsu Province 225300,China;Dalian Medical University,Dalian,Liaoning Province 116027,China;Nantong University School of Medicine,Nantong,Jiangsu Province 226019,China)

机构地区：[1]南京医科大学附属泰州市人民医院耳鼻咽喉-头颈外科,江苏225300 [2]大连医科大学,辽宁116027 [3]南通大学医学院,江苏226019

出　　处：《中华耳科学杂志》2022年第4期543-548,共6页Chinese Journal of Otology

基　　金：江苏省基础研究计划(自然科学基金)面上项目(BK20191229);江苏省第五期“333工程”科研项目(BRA2019192);国家自然科学基金青年基金(81700920);江苏省卫生计生委科研课题项目(H201666);泰州市科技支撑(社会发展)项目(TS201733)。

摘　　要：目的 耳-腭-指(趾)综合征(Oto-palato-digital syndrome,OPDS)为一类罕见X连锁显性遗传综合征型耳聋,主要表型涉及耳聋、颅面畸形及指趾畸形等多个方面。本研究拟对前期所收集的疑似OPDS综合征性耳聋家系进行遗传性病因探寻,并对该家系进行婚育指导,从而实现OPDS综合征型耳聋的一级预防。方法 收集家系成员临床资料;采集外周静脉血;抽提DNA;利用一代测序技术对三大常见耳聋基因进行全序列筛查排除致病突变后,利用靶向外显子捕获二代测序技术对所有已知耳聋基因进行筛查;对可疑致病突变利用Sanger测序技术进行家系内成员验证,并利用生物信息学蛋白预测功能软件对可疑致病突变位点进行致病性预测。结果 既往报道一次的与OPDS相关FLNA基因可疑致病突变c.799G>A (p.A267T)在本研究家系内呈现基因型-表型共分离。工具软件预测结果提示该位点致病可能性大。结论 本研究首次在中国汉族OPDS家系中发现FLNA基因p.A267T突变,该突变二次重现及工具软件预测结果提示其很可能为OPDS致病性突变,很可能为本研究家系的遗传致病性因素。氨基酸改变所致功能增益效应很可能为该突变潜在致病机制。本研究为FLNA基因p.A267T突变导致OPDS进一步提供了依据。Objective Oto-palato-digital syndrome(OPDS),characterized with deafness,facial dysmorphism and digital anomalies,is a series of rare dominant X-linked syndromes.In this study,we aim to identify the genetic etiology of suspected OPDS in a Chinese Han family to provide genetic counselling for the primary prevention of OPDS.Methods Clinical data of family members were collected and genomic DNA extracted from peripheral venous blood.After excluding pathogenic mutations in three common deafness genes by first generation sequencing,406 known deafness genes were screened by targeted next-generation sequencing(NGS).Potential pathogenic variants discovered by NGS were verified by Sanger sequencing.Their pathogenicity was predicted by computational tools.Results A suspected pathogenic mutation,c.799G>A(p.A267T) in the FLNA gene reported in one previously reported OPDS family,was showed to have genotypic-phenotypic co-segregation in this family.It was very likely to be a disease-causing mutation based on computational pathogenic prediction.Conclusion This is the first report of the p.A267T variant in FLNA in a Chinese Han family as a likely pathogenic mutation associated with OPDS as supported by its recurrence and by computational prediction.The pathogenic mechanism may be related to the gain-of-function effect.Our study provides additional evidence for p.A267T in FLNA as a disease-causing mutation in OPDS.

关 键 词：耳-腭-指综合征 FLNA基因 p.A267T 功能增益效应 遗传咨询 

分 类 号：R764[医药卫生—耳鼻咽喉科]