Heterozygous HTRA1 nonsense or frameshift mutations are pathogenic.

Area of Science:

• Genetics
• Neurology
• Molecular Biology

Background:

• Autosomal dominant cerebral small vessel disease (CSVD) is linked to heterozygous missense mutations in the HTRA1 gene.
• The role of heterozygous HTRA1 stop codon variants in CSVD pathogenesis remains uncertain.

Purpose of the Study:

• To determine the pathogenicity of heterozygous HTRA1 stop codon variants in CSVD.
• To investigate the mechanism underlying CSVD caused by these variants.
• To compare clinical and neuroimaging features with known HTRA1 mutation carriers.

Main Methods:

• Targeted high-throughput sequencing of CSVD genes, including HTRA1, in 3853 CSVD patients.
• Comparison of variant frequencies in patients versus large control databases (gnomAD, TOPMed, 1000 Genomes).
• HTRA1 mRNA analysis in stop codon carrier patients to assess allele degradation.
• Clinical and neuroimaging data characterization of affected individuals.

Main Results:

• Twenty unrelated patients with heterozygous HTRA1 premature stop codon variants were identified.
• A highly significant enrichment of these variants was observed in the patient cohort compared to controls (P < 1.5 × 10-5).
• mRNA analysis indicated degradation of the mutated allele, supporting haploinsufficiency. Clinical features resembled missense mutation carriers, but with potentially lower penetrance.

Conclusions:

• Heterozygous HTRA1 stop codon variants are pathogenic and contribute to CSVD through a haploinsufficiency mechanism.
• These findings expand the known spectrum of pathogenic HTRA1 variants.
• Further research is needed to precisely estimate the penetrance for improved genetic counseling.