下颌发育不良及问号耳畸形患者的致病基因突变遗传分析  

The Clinical and Genetic Analysis of Gene Mutations in Mandibular Dysplasia and Question Mark Ear Malformation

作　　者：樊若溪 黎冬梅[1,2] 章锦曼 朱宝生[1,2] FAN Ruoxi;LI Dongmei;ZHANG Jinman;ZHU Baosheng(Department of Pediatrics,The First People’s Hospital of Yunnan Province,Kunming 650032,China;National Health Commission’s Key Laboratory for Western Healthy Birth,Kunming 650032,China;College of Chinese Materia Medica,Yunnan University of Chinese Medicine,Kunming 650032,China)

机构地区：[1]云南省第一人民医院儿科,云南昆明650032 [2]国家卫生健康委员会西部优生重点实验室,云南昆明650032 [3]云南中医药大学中药学院,云南昆明650500

出　　处：《昆明理工大学学报（自然科学版）》2022年第2期105-112,共8页Journal of Kunming University of Science and Technology(Natural Science)

基　　金：云南省科技厅-昆明医科大学应用基础研究联合专项资金项目(2018FE001(-157))。

摘　　要：探讨具有下颌发育不良及问号耳畸形临床表型的患者家系的临床及遗传学特征.分析2个具有下颌发育不良及问号耳畸形患者家系的临床资料,使用全外显子组测序等遗传学检测方法,寻找候选基因并深入分析相关的基因突变.通过全外显子组检测,在两个患者家系中分别发现PLCB4基因纯合错义突变(Chr20:9364985;NM_000933;exon11;c.991T>C;p.Y331H)和EDNRA基因杂合插入造成的移码突变(Chr4:148457092;NM_001957;exon5;c.811_812insT;p.T271fs),这两个突变均未报道过,且与患者的临床表型具有高度相关性.PLCB4和EDNRA均作用于EDN1-EDNRA-DLX信号通路,该通路已报道对人类咽弓发育和下颌骨分化起到至关重要的作用,检测到的两个突变极有可能与患者的临床表现高度相关.本研究发现了两个致病基因中未报道过的疑似致病突变,提出EDNRA基因缺陷同样可能与耳髁突综合征(ACS)表型相关,为研究人类下颌骨发育的致病因素和遗传机制提供了重要的病例和遗传学数据,进一步证明了EDN1-EDNRA-DLX信号通路在人类下颌骨发育过程中的重要作用.This article aims to analyze the clinical features and gene mutations of mandibular dysplasia and question mark ear malformation.We analyzed the clinical data of two families with mandibular dysplasia and question mark ear malformation,and used the whole-exome sequencing to analyze related gene mutations.Through a whole-exome sequencing approach,we found a homozygous missense mutation in PLCB4 gene (Chr20:9364985;NM_000933;exon11;c.991 T>C;p.Y331 H) and a heterozygous frameshift mutation in EDNRA gene(Chr4:148457092;NM_001957;exon5;c.811_812 insT;p.T271 fs) in two families.Both PLCB4 and EDNRA acting on the EDN1-EDNRA-DLX signaling pathway,which has been known to play a crucial role in human pharyngeal arch patterning and mandibular differentiation.Two mutations are likely to develop an auriculocondylar syndrome (ACS) phenotype in patients.We successfully identified two de novo pathogenic variants and suggested that EDNRA defects may also lead to ACS,which provide important evidence and materials for the further genetic investigation and diagnosis.

关 键 词：耳髁突综合征(ACS) EDN1-EDNRA-DLX信号通路 下颌发育不良 问号耳畸形 PLCB4基因 EDNRA基因 

分 类 号：R782[医药卫生—口腔医学] R764.7[医药卫生—临床医学]