Extended Data Table 4 Estimation of genetic prevalence for GoF genetic neurodegenerative diseases
From: Evaluating drug targets through human loss-of-function genetic variation
- Data sources were identified by PubMed and Google Scholar searches. Genetic prevalence was defined as the proportion of the population at birth carrying a mutation and destined to later develop disease, and estimated as described for each gene. The following references are cited in the table: refs. 36,41,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74.
- aIt is important to consider how this figure relates to the penetrance of LRRK2 mutations, as LRRK2 variants appear to occupy a spectrum of penetrance75. Some variants exhibit Mendelian segregation with disease76,77, implying high risk; the G2019S variant is estimated to have approximately 32% penetrance78; and other common variants are risk factors with odds ratios of only around 1.2 estimated through genome-wide association studies (GWAS)79. The GWAS-implicated common variants were not included in the case series on which our estimate is based63, but G2019S does account for most cases in that series. Because the 0.03% estimate here is based on counting symptomatic cases rather than asymptomatic individuals, it will appropriately underestimate the number of G2019S carriers. In essence, in this calculation each G2019S carrier in the population only counts as 1/3 of a person, because they have only a 1/3 probability of developing a disease. It is therefore appropriate that our estimate of genetic prevalence (0.03%) is actually lower than double the allele frequency of G2019S in gnomAD (0.1%).
