Frequency and Phenotype Associations of Rare Variants in 5 Monogenic Cerebral Small Vessel Disease Genes in 200,000 UK Biobank Participants

Ferguson, Amy Christina; Thrippleton, Sophie; Henshall, David; Whittaker, Ed; Conway, Bryan; MacLeod, Malcolm; Malik, Rainer; Rawlik, Konrad; Tenesa, Albert; Sudlow, Cathie und Rannikmae, Kristiina (2022): Frequency and Phenotype Associations of Rare Variants in 5 Monogenic Cerebral Small Vessel Disease Genes in 200,000 UK Biobank Participants. In: Neurology - Genetics, Bd. 8, Nr. 5, e200015

Abstract

Background and Objectives 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 extracerebral phenotypes. We investigated the frequency, penetrance, and phenotype associations of putative pathogenic variants in cSVD genes in the UK Biobank (UKB), a large population-based study. Methods We used a systematic review of previous literature and ClinVar to identify putative pathogenic rare variants in CTSA, TREX1, HTRA1, and COL4A1/2. We mapped phenotypes previously attributed to these variants (phenotypes-of-interest) to disease coding systems used in the UKB's linked health data from UK hospital admissions, death records, and primary care. Among 199,313 exome-sequenced UKB participants, we assessed the following: 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. Results 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). Discussion While putative pathogenic rare variants in monogenic cSVD genes occur in 1:200 people in the UKB population, only approximately half of variant carriers have a relevant disease phenotype recorded in their linked health data. We could not replicate most previously reported genephenotype associations, suggesting lower penetrance rates, overestimated pathogenicity, and/or limited statistical power.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 2376-7839
• Sprache: Englisch