Analysis Of Clinical Features And Genotype-phenotype Correlations In Patients With Heterozygous HTRA1-related Cerebral Small Vessel Disease

ObjectiveCerebral 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 among these patients.MethodsClinical and imaging features of two familial cerebral small vessel disease involving different heterozygous HTRA1 mutations were evaluated.Additionally,we performed a systematic review of all published cases of heterozygous HTRA1 mutations in Pub Med,Cochrane,Embase,VIP,Chinese Biomedical Medical,Chinese National Knowledge Infrastructure databases(CNKI)and Wanfang Databases,and assessed the mutation pathogenicity in cases with detailed data and investigated possible phenotype-genotype correlations.Results1.We found two families with heterozygous HTRA1 mutations: p.P275 L and p.V175 M.2.In this review,73 patients from 46 unrelated families met the inclusion criteria,involving 38 different mutations.3.Among these 46 unrelated families,the majority of mutations were found in exon 4(48%)and exon 2(22%).Mutations that cause amino acid changes in Loop D (LD)and Loop 3(L3)were present in 10(22%)and 6(13%)of the probands,respectively.4.In these 73 patients(47 males and 26 females),62 patients were symptomatic and the median age at onset was 53.Thirty-four of the 46 probands was recorded with a family history of stroke and/or dementia.5.Half of the 64 patients who evaluated vascular risk factors presented with these factors such as hypertension,smoking,dyslipidaemia and/or diabetes.6.In these 73 patients,common clinical symptoms included cognitive decline(74%,50/68),stroke(68%,48/71),gait disturbance(63%,43/68),spinal lesions(40%,27/67),and alopecia(11/71,15%).Of the 5 main symptoms,19 patients(26%)presented with none or one symptom,17(23%)Patients presented with two symptoms,15(21%)Patients presented with 3 symptoms,22 Patients(30%)presented with 4 or 5 symptoms.7.Moderate or severe leukoencephalopathy was shown in 55 out of 56patients(98%);the anterior temporal pole was involved in 17 out of 40 patients(43%),and the external capsule was involved in 32 out of 39 patients(82%).Lacunar infarcts was showed in 48 out of 51 patients.Cerebral microbleeds were revealed in 65% of patients(22/34),and cerebral haemorrhage was reported in 5 patients.8.In univariate analyses,the phenotype severity was significantly associated with the Combined Annotation Dependent Depletion(CADD)score of the mutation(p < 0.001;Spearman’s rho =0.564).Additionally,those harbouring mutations involved in amino acid changes located at the LD or L3 had a more severe phenotype than those with mutations in other regions(p = 0.05;Spearman’s rho =0.23).We also found that the pathogenicity scores differed in different exons of the mutation(p <0.05;Spearman’s rho =0.24).9.Ordinal logistic analyses indicated that smoking(p=0.011),hyperlipidaemia(p=0.005),and exon position of the mutation(p=0.0001)were determinants of the clinical phenotype severity.Regarding a more severe clinical phenotype,patients who smoked had a >10-fold risk compared with nonsmokers(OR=10.76;95% CI,1.73 to 66.69);those with hyperlipidemia had a46-fold risk compared with nonhyperlipidaemia patients(OR=46.24;95% CI,3.25 to659.18);those carrying mutations in exon 4 had a > 17-fold risk compared with patients with mutations in exon 2(OR=17.20;95% CI,3.48 to 85.03).Conclusions1.Patients with heterozygous HTRA1 mutations show the elderly onset,milder clinical presentation,lower frequency of extraneurological complications compared to those in cerebral autosomal recessive arteriopathy with subcortical infarcts and lecoencephalopathy(CARASIL).Thus,many patients may be misdiagnosed or never diagnosed.2.To some extent,the CADD score is associated with the severity of the clinical phenotype.3.Applying the CADD score to predict clinical outcomes and adopting preventive measures against vascular risk factors are advantageous.