摘要
目的:报道一组新发现的HTRA1基因致病变异家系病例，并结合既往文献总结本HTRA1相关常染色体显性脑小血管病家系的临床表型及遗传学特点。方法:收集HTRA1相关染色体显性脑小血管病先证者及其家系成员的临床资料，总结其临床特点，采用高通量测序方法捕获变异位点，应用Sanger测序进行家系验证，功能预测软件进行致病性分析，并查阅相关文献，探讨此新发现变异的表型及遗传学特点。结果:先证者为51岁男性，临床表现为50岁时突发左侧肢体麻木、认知功能障碍，无脱发、腰痛等神经系统外症状。头颅MRI包括磁敏感加权成像序列显示右侧基底节脑梗死，双侧脑白质弥漫性、对称性高信号，微出血。基因检测发现HTRA1基因c.941T＞G杂合错义变异，功能预测提示为致病性变异。先证者母亲60岁时出现脑梗死及认知功能障碍，70岁时去世；先证者哥哥携带相同杂合变异，32岁时患脑梗死导致右侧肢体偏瘫、言语障碍及认知障碍，影像学特征符合脑小血管病特点；先证者儿子携带相同杂合变异，目前无临床症状。结论:HTRA1基因c.941T＞G（p.M314R）杂合变异为致病变异，其临床表型及遗传学特点与既往报道的HTRA1相关常染色体显性脑小血管病类似。
Abstract
Objective:To report a novel HTRA1 gene mutation and summarize the clinical phenotypes and genetic characteristics of the family with this heterozygous HTRA1 mutation associated with autosomal dominant cerebral small vessel disease (CSVD).Methods:Clinical data of the proband and his family members were collected. The mutation loci were captured by high-throughput sequencing and validated by Sanger sequencing, and the pathogenicity was predicted by in silico tools. The literature was reviewed.Results:The proband was a 51-year-old male whose clinical manifestations included sudden numbness of left limbs and cognitive impairment at the age of 50, without typical symptoms of cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) such as alopecia and spondylosis. Brain MRI revealed right basal ganglia infarction, symmetric lesions in white matter, and microbleeds. Genetic testing revealed a heterozygous missense mutation of HTRA1 gene (c.941T＞G). Function prediction suggested pathogenicity. His mother suffered from cerebral infarction in her sixties, which resulted in cognitive impairment, and died at the age of 70. His brother carries the same heterozygous mutation, and he suffered from cerebral infarction at the age of 32, resulting in right hemiplegia, speech disorder, and cognitive impairment. His neuroimaging findings were consistent with the imaging features of CSVD. His son carried the same heterozygous mutation but is currently asymptomatic, possibly due to his age.Conclusion:HTRA1 c. 941T＞G (p.M314R) heterozygous variant is pathogenic, and its clinical phenotype and genetic characteristics are similar to those of HTRA1 gene heterozygous mutation associated autosomal dominant cerebral small vascular disease previously reported.
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