Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is caused by biallelic HTRA1 pathogenic variants. Recent studies have shown that heterozygous HTRA1 mutations are associated with autosomal dominant cerebral small vessel disease (CSVD). However, large studies evaluating heterozygous HTRA1 carriers are lacking and the genotype–phenotype correlation is unknown. This study aimed to describe these mutations to clarify factors playing a role in the clinical phenotype amongst these patients. We reported two unrelated families and performed a systematic review of all published cases of heterozygous HTRA1-related CSVD. The clinical phenotype severity was independently related to the pathogenicity score (CADD score; p < 0.05) and mutation in the loop 3/loop D domains (p = 0.05); the pathogenicity score was also associated with exon distribution. More importantly, patients with mutations in exon 4 (p = 0.0001) or vascular risk factors (p < 0.05) presented with more severe clinical symptoms. Thus, clinical phenotype severity is influenced by the mutation domain and vascular risk factors. Applying the pathogenicity score to predict clinical outcomes and adopting preventive measures against cerebral vascular risk factors is advantageous.

伴有皮质下梗死和白质脑病的常染色体隐性脑动脉病 (CARASIL) 是由双等位基因HTRA1致病性变异引起的。最近的研究表明，杂合HTRA1突变与常染色体显性脑小血管病 (CSVD) 相关。然而，缺乏评估杂合HTRA1携带者的大型研究，并且基因型-表型相关性尚不清楚。本研究旨在描述这些突变，以阐明在这些患者的临床表型中发挥作用的因素。我们报告了两个不相关的家庭，并对所有已发表的杂合HTRA1相关 CSVD 病例进行了系统回顾。临床表型严重程度与致病性评分（CADD 评分； p < 0.05）和环 3/环 D 结构域的突变独立相关（ p = 0.05）；致病性评分也与外显子分布相关。更重要的是，具有外显子4突变（ p =0.0001）或血管危险因素（ p <0.05）的患者表现出更严重的临床症状。因此，临床表型的严重程度受到突变域和血管危险因素的影响。应用致病性评分来预测临床结果并对脑血管危险因素采取预防措施是有利的。