Heterozygous HTRA1 nonsense or frameshift mutations are pathogenic

AbstractHeterozygous missenseHTRA1 mutations have been associated with an autosomal dominant cerebral small vessel disease (CSVD) whereas the pathogenicity of heterozygousHTRA1 stop codon variants is unclear. We performed a targeted high throughput sequencing of all known CSVD genes, includingHTRA1, in 3853 unrelated consecutive CSVD patients referred for molecular diagnosis. The frequency of heterozygousHTRA1 mutations leading to a premature stop codon in this patient cohort was compared with their frequency in large control databases. An analysis of HTRA1 mRNA was performed in several stop codon carrier patients. Clinical and neuroimaging features were characterized in all probands. Twenty unrelated patients carrying a heterozygousHTRA1 variant leading to a premature stop codon were identified. A highly significant difference was observed when comparing our patient cohort with control databases: gnomAD v3.1.1 [P = 3.12 × 10−17, odds ratio (OR) = 21.9], TOPMed freeze 5 (P = 7.6 × 10−18, OR = 27.1) and 1000 Genomes (P = 1.5 × 10−5). Messenger RNA analysis performed in eight patients showed a degradation of the mutated allele strongly suggesting a haploinsufficiency. Clinical and neuroimaging features are similar to those previously reported in heterozygous missense mutation carriers, except for penetrance, which seems lower. Altogether, our findings strongly suggest that heterozygousHTRA1 stop codons are pathogenic through a haploinsufficiency mechanism. ...

Source: Brain - July 16, 2021 Category: Neurology Source Type: research