Genotype–phenotype correlations of heterozygous HTRA1-related cerebral small vessel disease: case report and systematic review

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.