| Autor: |
Amy Christina Ferguson, Sophie Thrippleton, David Henshall, Ed Whittaker, Bryan Conway, Malcolm MacLeod, Rainer Malik, Konrad Rawlik, Albert Tenesa, Cathie Sudlow, Kristiina Rannikmae |
| Jazyk: |
angličtina |
| Rok vydání: |
2022 |
| Předmět: |
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| Zdroj: |
Ferguson, A, Thrippleton, S, Henshall, D E, Whittaker, E, Conway, B R, MacLeod, M, Malik, R, Rawlik, K, Tenesa, A, Sudlow, C L M & Rannikmae, K 2022, ' Frequency and phenotype associations of rare variants in 5 monogenic cerebral small vessel disease genes in 200,000 UK Biobank participants ', Neurology Genetics, vol. 8, no. 5, e200015, pp. e200015 . https://doi.org/10.1212/NXG.0000000000200015 |
| DOI: |
10.1212/NXG.0000000000200015 |
| Popis: |
Background and ObjectivesBased 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.MethodsWe 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.ResultsAmong 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).DiscussionWhile 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 gene-phenotype associations, suggesting lower penetrance rates, overestimated pathogenicity, and/or limited statistical power. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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