Identified novel heterozygous HTRA1 pathogenic variants in Chinese patients with HTRA1-associated dominant cerebral small vessel disease

Abstract

Background: Homozygous and compound heterozygous mutations in HTRA1 cause cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL). Recently, heterozygous pathogenic variants in HTRA1 were described in patients with autosomal dominant cerebral small vessel disease (CSVD). Here, we investigated the genetic variants in a cohort of Chinese patients with CSVD.Methods: A total of 95 Chinese index patients with typical characteristics of CSVD were collected. Whole exome sequencing was performed in the probands, followed by Sanger sequencing. Pathogenicity prediction software was applied to evaluate the pathogenicity of the identified variants.Results: We detected five heterozygous HTRA1 pathogenic variants in five index patients. These pathogenic variants included four known variants (c.543delT, c.854C>T, c.889G>A, and c.824C>T) and one novel variant (c.472 + 1G>A). Among them, c.854C>T, c.824C>T, and c.472 + 1G>A have never been reported in China and c.889G>A was once reported in homozygous but never in heterozygous. Three of them were distributed in exon 4, one in exon 2, and another splicing variant in intron 1. Four out of five probands presented typical features of CARASIL but less severe. The common clinical features included lacunar infarction, cognitive decline, alopecia, and spondylosis. All of them showed leukoencephalopathy, and the main involved cerebral area include periventricular and frontal area, centrum semiovale, thalamus, and corpus callosum. Anterior temporal lobes and external capsule involvement were also observed. Three probands had intracranial microbleeds.Conclusion: Our study expanded the mutation spectrum of HTRA1, especially in Chinese populations, and provided further evidence for “hot regions” in exon 1–4, especially in exon 4, in heterozygous HTRA1 pathogenic variants. Our work further supported that patients with heterozygous HTRA1 pathogenic variants presented with similar but less-severe features than CARASIL but in an autosomal dominantly inherited pattern.

Exploring HTRA1-Autosomal Dominant Disease: Literature Review of Clinical Features and Molecular Mechanisms

“…Extra-neurological symptoms also vary between the diseases. Several investigations indicated high occurrences of early-onset alopecia (20%~30%) and spondylosis (70%~100%) (Chen et al, 2022;Lee et al, 2018;Nozaki et al, 2016) in HTRA1-autosomal dominant disease, while others reported absence of such symptoms (Di Donato et al, 2017;Verdura et al, 2015). Nonetheless, the overall proportion of extra-neurological features of HTRA1-autosomal dominant disease is still lower than CARASIL, which demonstrates alopecia in more than 90% of patients and spinal lesions in almost 100% of patients (Mancuso et al, 2020).…”

Heterozygous Pathogenic and Likely Pathogenic Symptomatic HTRA1 Variant Carriers in Cerebral Small Vessel Disease

“…Most pathogenic and likely pathogenic heterozygous HTRA1 gene variants of symptomatic carriers were missense variants, and some of them were nonsense variants, 30–35 frameshift variants, 27 , 30 , 36 and splice site variants. 6 , 36 , 37 The variant sites of the heterozygous HTRA1 gene were mostly located in exon 4 (50.91%), and the trypsin-like serine protease domain was the most common domain in HtrA1 protease (61.82%). Moreover, we found two variant site aggregation regions (166–182 aa and 276–302 aa).…”