Two novel heterozygous HTRA1 mutations in two pedigrees with cerebral small vessel disease families

Area of Science:

• Genetics
• Neurology
• Molecular Biology

Background:

• Hereditary cerebral small vessel disease (CSVD) is increasingly linked to genetic factors.
• Mutations in the High-temperature requirement A serine peptidase 1 (HTRA1) gene are a recently identified cause of autosomal dominant CSVD.

Observation:

• This study details clinical and neuroimaging findings in two families with hereditary CSVD.
• Two distinct heterozygous HTRA1 mutations, a missense variant (p.V176A) and a nonsense variant (p.R197X), were identified in the probands.
• Co-segregation analysis confirmed mutation inheritance within families.

Findings:

• All affected males carrying heterozygous HTRA1 mutations exhibited characteristic CSVD clinical and neuroimaging features.
• Conversely, all affected females with heterozygous HTRA1 mutations were clinically and neuroimaging asymptomatic.
• This suggests a potential male predominance in the manifestation of CSVD associated with heterozygous HTRA1 mutations.

Implications:

• HTRA1 gene screening is recommended for individuals diagnosed with familial CSVD.
• The observed sex-based difference in clinical presentation warrants further investigation.
• Understanding these genetic underpinnings can improve diagnostic strategies and patient management for hereditary CSVD.