Frequency and phenotype associations of rare variants in five monogenic cerebral small vessel disease genes in 200,000 UK Biobank participants with whole exome sequencing data

Based on previous case reports and disease-based cohorts, a minority of patients with cerebral small vessel disease (cSVD) have a monogenic cause, with many also manifesting extra-cerebral phenotypes. We investigated the frequency, penetrance, and phenotype associations of rare variants in cSVD genes in UK Biobank (UKB), a large population-based study. We used a systematic review of previous literature and ClinVar to identify putative pathogenic rare variants in CTSA, TREX1, HTRA1, COL4A1/2 . We mapped phenotypes previously attributed to these variants (phenotypes-of-interest) to disease coding systems used in UKB’s linked health data from UK hospital admissions, death records and primary care. Among 199,313 exome-sequenced UKB participants, we assessed: the proportion of participants carrying ≥1 variant(s); phenotype-of-interest penetrance; and the association between variant carrier status and phenotypes-of-interest using a binary (any phenotype present/absent) and phenotype burden (linear score of the number of phenotypes a participant possessed) approach. Among UKB participants, 0.5% had ≥1 variant(s) in studied genes. Using hospital admission and death records, 4-20% of variant carriers per gene had an associated phenotype. This increased to 7-55% when including primary care records. Only COL4A1 variant carrier-status was significantly associated with having ≥1 phenotype-of-interest and a higher phenotype score (OR=1.29, p=0.006). While putative pathogenic rare variants in monogenic cSVD genes occur in 1:200 people in the UKB population, only around half of variant carriers have a relevant disease phenotype recorded in their linked health data. We could not replicate most previously reported gene-phenotype associations, suggesting lower penetrance rates, overestimated pathogenicity and/or limited statistical power.