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摘要:
目的 Mohr-Tranebjaerg综合征(MTS)典型症状包括耳聋、肌张力障碍等，本病非常罕见，遵循X连锁遗传模式。本研究对一个罕见MTS家系进行遗传学分析。 方法 收集罕见MTS家系临床资料，同时对先证者Ⅲ6进行全外显子组测序检测，对家族中其他患病个体Ⅲ5和健康人Ⅰ1、Ⅰ2、Ⅱ1、Ⅱ5、Ⅱ7、Ⅱ8、Ⅲ7进行家系验证，将基因检测结果与临床表现反复核实比对。 结果 家族中患者表现为较早期出现的耳聋, 多个患病成员随着年龄增长合并肌张力障碍、精神情绪异常。全外显子组测序检测提示先证者Ⅲ6 TIMM8A (NM_004085.3，又称DDP1)基因内含子存在c.133-2delA变异，目前评级为可能致病(LP)。同时在患病个体Ⅲ5及健康女性Ⅰ1、Ⅱ5、Ⅱ7检出此变异。 结论 TIMM8A检出变异所致MTS与家系患病者临床表现高度吻合，符合家系共分离，是这个罕见MTS患病家族的分子病因。除耳聋外，其他症状在家族中不同个体中可存在差异。针对此类X连锁疾病的基因诊断，还可以明确女性杂合子，给予遗传咨询和生育指导，从而帮助家族成员制订科学的家庭计划。 -
关键词:
- Mohr-Tranebjaerg综合征 /
- TIMM8A基因 /
- 全外显子组测序
Abstract:Objective Mohr-Tranebjaerg syndrome (MTS) is a rare X-linked neurodegenerative disorder which usually involving hearing impairment, gradual dystonia, and other symptoms. In this study, we perform analyzed the genetic makeup of a family with this rare Mohr-Tranebjaerg syndrome. Methods We collected the clinical data of the family, did the whole exome sequencing on the proband Ⅲ6 with a rare mutation, and verified the mutation in another affected family member Ⅲ5 and unaffected members Ⅰ1, Ⅰ2, Ⅱ1, Ⅱ5, Ⅱ7, Ⅱ8, Ⅲ7. Results The patients in the family all showed early-onset deafness. More than a couple of affected male members have dystonia with/without mental disorders. Genetic testing results showed the proband Ⅲ6 had a c.133-2delA in TIMM8A (NM_ 004085.3, DDP1), highly likely pathogenic(LP). This variation was detected in affected Ⅲ5 as well as the unaffected females Ⅰ1, Ⅱ5, Ⅱ7. Conclusions MTS caused by the rare TIMM8A mutation, the molecular etiology of the family with this rare disease, is highly consistent with the clinical manifestations and segregation. Other than the deafness, other symptoms varied among the affected family members. Genetic diagnosis for such X-linked diseases can also identify female heterozygotes. Genetic and reproduction counseling can help families in the family planning. -
Key words:
- Mohr-Tranebjaerg syndrome /
- TIMM8A gene /
- whole exome sequencing
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图 1 Mohr-Tranebjaerg综合征(MTS)家系图
□表示健康男性，○表示健康女性，■表示男性患者，●表示女性患者，WT表示野生型，HET表示杂合子，HEM表示半合子，↗表示先证者，*表示受试者
Figure 1. Pedigree of this family with Mohr-Tranebjaerg syndrome(MTS)
图 2 MTS家系TIMM8A基因测序
A.男性患者Ⅲ5和Ⅲ6检出TIMM8A基因c.133-2delA半合子变异；B.女性健康成员Ⅰ1、Ⅱ5、Ⅱ7检出TIMM8A基因c.133-2delA杂合子变异；C.家族中其他成员Ⅰ2、Ⅱ1、Ⅱ8和Ⅲ7未检出此变异；红色箭头所指为变异位置
Figure 2. Sanger sequencing of MTS family with TIMM8A variation
表 1 TIMM8A基因剪切变异文献回顾
Table 1. Review of TIMM8A gene splicing variation in the literature
基因 位点 临床表现 报道年份(年) HGMD 参考文献 TIMM8A c.133-23A＞C 累及1个家系中2例男性患者，其中1例为31岁男性患者自4岁起患有感音神经性耳聋渐进性至极重度耳聋，11岁开始出现渐进性肌张力障碍，24岁发现视觉异常，另1例为29岁男性患者，11岁诊断为双侧听力损失，20岁出现肌张力障碍和精神情绪症状 2005(是TIMM8A基因报道的首个剪切突变) 已收录 [7] TIMM8A c.132+1G＞A 1例42岁男性患者检出c.132+1G＞A变异，临床表现为8月龄发现的生儿听力损失，25岁出现的肌张力障碍，30岁开始表现有视觉受损 2007 已收录 [8] TIMM8A c.132+1G＞A 1个散发病例检出c.132+1G＞A变异。患者为男性，31岁，4岁因听力损失助听，14岁发现双侧视神经萎缩，23岁出现渐进性肌张力障碍 2008 已收录 [9] TIMM8A c.133-2delA 1个家族中有4例男性患者均检出c.133-2delA变异，表现为2岁发现听力差伴言语欠清，10余岁出现肌力障碍伴姿势异常，其中两例伴有精神情绪异常，1例伴智力水平降低。其中1例行听力检测提示重度感音神经性耳聋。 2013 未收录 [11] TIMM8A c.132+1G＞A 在1例散发男性肌张力障碍病例第3次检出c.132+1G＞A变异，表现为2岁出现的肌张力障碍，未提及该患者其他临床表型 2018 已收录 [10] HGMD: 人类基因突变数据库 
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