NOG基因相关指间关节粘连谱系障碍的临床特征和致病变异分析

Clinical characteristics and pathogenic variant analysis of NOG-related symphangism spectrum disorder

杨晓乾;张晓赛;张金慧;孙淑萍;许红恩;陈蓓

1:郑州大学第一附属医院耳科

2:郑州大学医学科学院

3:天健先进生物医学实验室

摘要
目的 分析3个NOG基因相关的指间关节粘连谱系障碍(NOG-related symphangism spectrum disorder,NOG-SSD)家系的临床表型特征及基因变异特点。方法 回顾性分析3个NOG-SSD家系11例家庭成员的临床资料,包括病史采集、体格检查、影像学检查和听力学检查。提取家系成员的外周血基因组DNA,进行全外显子组测序。结果 11例家庭成员中4例表现为混合性或传导性听力损失。家系1和2的先证者均有混合性听力损失及近端指间关节粘连、第5指间关节屈曲障碍及皮肤皱褶缺失,家系3的先证者及其母亲除了传导性/混合性听力损失及近端指间关节粘连外,还有特征性面容(半圆柱形鼻、鼻翼发育不良、上唇薄伴朱红色唇线)。全外显子组测序发现3个家系患者均携带NOG基因(NM_005450.6)致病变异,其中家系1和2分别为错义变异c.236T>A(p.Met79Lys)和无义变异c.666C>G(p.Tyr222Ter),均为新发变异;家系3母女2人均为NOG基因移码变异c.31del(p.Leu11SerfsTer51)。三种变异既往均未曾报道,评级为致病或可能致病。家系1和2患者诊断为近端指关节粘连症1型(proximal symphalangism-1,SYM1),家系3患者诊断为多发性骨性连接综合征1型(multiple synostoses syndrome-1,SYNS1)。结论 NOG基因c.236T>A、c.666C>G和c.31del为本文3个NOG-SSD家系患者的致病原因。
关键词
近端指(趾)骨关节粘连;多发性骨性连接综合征1型;NOG基因;传导性听力损失
基金项目(Foundation):
河南省医学科技攻关计划省部共建项目(SBGJ202102163);; 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)
作者
杨晓乾;张晓赛;张金慧;孙淑萍;许红恩;陈蓓
参考文献

[1] PAN Z,LU W,LI X,et al.Multiple synostoses syndrome:clinical report and retrospective analysis[J].American Journal of Medical Genetics Part A,2020,182(6):1438-1448.

[2] 张文元,毛璐,张金慧.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[J].中华医学遗传学杂志,2023,40(9):1118-1123.

[3] OZA A M,DISTEFANO M T,HEMPHILL S E,et al.Expert specification of the ACMG/AMP variant interpretation guidelines for genetic hearing loss[J].Human Mutation,2018,39(11):1593-1613.

[4] 王蓉蓉,韩士瑞,周宗伟,等.一个中国近端指(趾)骨间关节黏连家系NOG基因新突变鉴定[J].国际遗传学杂志,2017,40(1):1-5.

[5] SHA Y,MA D,ZHANG N,et al.Novel NOG (p.P42S) mutation causes proximal symphalangism in a four-generation Chinese family[J].BMC Medical Genetics,2019,20:1-8.

[6] XIONG J,TU W,YAN Y,et al.Identification of a novel NOG missense mutation in a Chinese family with symphalangism and tarsal coalitions[J].Frontiers in Genetics,2019,10:353.

[7] PANG X,WANG Z,CHAI Y,et al.A novel missense mutation of NOG interferes with the dimerization of NOG and causes proximal symphalangism syndrome in a Chinese family[J].Annals of Otology,Rhinology & Laryngology,2015,124(9):745-751.

[8] PANG X,LUO H,CHAI Y,et al.A 1.6-Mb microdeletion in chromosome 17q22 leads to NOG-related symphalangism spectrum disorder without intellectual disability[J].PLoS One,2015,10(3):e0120816.

[9] SUN H,QIAO Y,CHEN N,et al.Delayed-onset NOG gene-related syndromic conductive deafness:a case report[J].Ear,Nose & Throat Journal,2021,100(3):333S-336S.

[10] 林小云,高利红,章振林.NOG基因新突变导致近端指(趾)骨间关节粘连一家系报告[J].中华内分泌代谢杂志,2020,36(8).711-714.

[11] LIU F,HUANG Y,LIU L,et al.Identification of a novel NOG mutation in a Chinese family with proximal symphalangism[J].Clinica Chimica Acta,2014,429:129-133.

[12] LEE B H,KIM O H,YOON H K,et al.Variable phenotypes of multiple synostosis syndrome in patients with novel NOG mutations[J].Joint Bone Spine,2014,81(6):533-536.

[13] BAYAT A,FIJALKOWSKI I,ANDERSEN T,et al.Further delineation of facioaudiosymphalangism syndrome:description of a family with a novel NOG mutation and without hearing loss[J].American Journal of Medical Genetics Part A,2016,170(6):1479-1484.

[14] GANAHA A,KANAME T,AKAZAWA Y,et al.Identification of two novel mutations in the NOG gene associated with congenital stapes ankylosis and symphalangism[J].Journal of Human Genetics,2015,60(1):27-34.

[15] AYDIN H U,ALTUNOGLU U,UYGUNER Z O,et al.Multiple synostoses syndrome in three members of a family displaying a novel mutation in NOGGIN gene[J].J Plast Reconstr Aes,2013,66(10):e287-e289.

[16] ZHANG Z,LU Y,CAO J Y,et al.Clinical observation and genetic analysis of a SYNS1 family caused by novel NOG gene mutation[J].Mol Genet Genom Med,2022,10(5):e1933.

[17] TAKAHASHI T,TAKAHASHI I,KOMATSU M,et al.Mutations of the NOG gene in individuals with proximal symphalangism and multiple synostosis syndrome[J].Clin Genet,2001,60(6):447-451.

[18] NAKASHIMA T,GANAHA A,TSUMAGARI S,et al.Is the conductive hearing loss in NOG-related symphalangism spectrum disorder congenital?[J].ORL,2021,83(3):196-202.

[19] 赵守琴.先天性中耳畸形的诊断与治疗[J].听力学及言语疾病杂志,2016,24(2):113-115.

[20] 李湘辉,张志钢,郑亿庆,等.耳硬化症患者镫骨底板造孔术后高频感音神经性听力下降原因分析[J].听力学及言语疾病杂志,2010,18(1):26-28.

[21] QUESNEL A M,NADOL JR J B,NIELSEN G P,et al.Temporal bone histopathology in NOG-symphalangism spectrum disorder[J].Otology & Neurotology,2015,36(10):1651-1656.

[22] CARLSON R J,QUESNEL A,WELLS D,et al.Genetic heterogeneity and core clinical features of NOG-related-Symphalangism spectrum disorder[J].Otology & Neurotology,2021,42(8):e1143-e1151.

[23] 谢立,刘爱国,TEJVANSH S I,等.高分辨率CT在耳硬化症诊断中的应用价值[J].听力学及言语疾病杂志,2020,28(6):644-648.