多发性骨性连接综合征1型一个家系的表型及致病变异分析  

Analysis of phenotype and pathogenic variants in a family with multiple synostoses syndrome type 1

作　　者：张文元 毛璐 张金慧[1] 许红恩 陈蓓[1] Zhang Wenyuan;Mao Lu;Zhang Jinhui;Xu Hongen;Chen Bei(Department of Otology,the First Affiliated Hospital of Zhengzhou University,Zhengzhou,Henan 450052,China;Precision Medicine Center,Academy of Medical Science,Zhengzhou University,Zhengzhou,Henan 450052,China)

机构地区：[1]郑州大学第一附属医院耳科,郑州450052 [2]郑州大学医学科学院精准医学中心,郑州450052

出　　处：《中华医学遗传学杂志》2023年第9期1118-1123,共6页Chinese Journal of Medical Genetics

基　　金：国家卫生健康委出生缺陷预防重点实验室和河南省人口缺陷干预技术研究重点实验室开放课题(ZD202208);河南省医学科技攻关省部共建重点项目(SBGJ202102163);河南省科技攻关计划(212102310610)。

摘　　要：目的探究1个多发性骨性连接综合征1型(SYNS1)家系的临床表型与致病性变异。方法选取2019年8月就诊于郑州大学第一附属医院儿科门诊的1个汉族SYNS1家系为研究对象。采集家系相关临床资料,提取各家系成员的外周血基因组DNA,进行全外显子组测序(WES)和全基因组测序(WGS)。结果该家系共3代14人,其中6人表现为传导性耳聋或混合性耳聋,同时合并近端指间关节粘连、鼻根宽平、鼻翼发育不良、弱视、斜视、短指、足趾分隔不全,与SYNS1的典型症状相符。WES未发现先证者及其父母存在NOG基因编码区致病性单碱基变异与插入缺失变异(InDel),但是先证者及其母亲NOG基因及相邻基因区域存在大片段杂合缺失。WGS进一步确定先证者染色体17q22区存在约1.0 Mb杂合片段缺失(chr17:54171786_55143998),该区域包含NOG基因。参照美国医学遗传学与基因组学学会(ACMG)相关标准与指南,该拷贝数变异(CNV)判定为致病性变异。结论NOG基因及其相邻区域的杂合缺失可能是该SYNS1家系的遗传学病因,丰富了中国人群的NOG基因变异和临床表型图谱。在常规测序方法未发现致病变异的SYNS1患者中,应对CNV进行分析。ObjectiveTo explore the clinical and genetic characteristics of a Chinese pedigree affected with Multiple synostoses syndrome type 1(SYNS1).MethodsClinical data of the proband and her family members were collected.Genomic DNA was extracted from peripheral blood samples.Whole-exome sequencing(WES)and whole-genome sequencing(WGS)were carried out for the proband and her parents.ResultsThe pedigree has comprised of 14 members from three generations,of whom six had manifested hearing loss,with other symptoms including proximal symphalangism,hemicylindrical nose,amblyopia,strabismus,brachydactyly,incomplete syndactyly,which fulfilled the diagnostic criteria for SYNS1.WES had detected no pathogenic single nucleotide variants and insertion-deletion(InDel)in the coding region of the NOG gene,whilst copy number variation(CNV)analysis indicated that there was a heterozygous deletion involving the NOG gene.WGS revealed a heterozygous deletion(54171786_55143998)in 17q22 of the proband.The CNV was classified as pathogenic based on the guidelines from the American College of Medical Genetics and Genomics(ACMG).ConclusionThe heterozygous deletion in 17p22 involving the NOG gene probably underlay the pathogenesis of SYNS1 in this pedigree.Above finding has enriched the mutational spectrum of NOG.CNV should be considered when conventional sequencing has failed to detect any pathogenic variants in such patients.

关 键 词：多发性骨性连接综合征1型 NOG基因 综合征型耳聋 拷贝数变异 

分 类 号：R725[医药卫生—儿科]