Allele frequency of pathogenic variants related to adult‐onset Mendelian diseases

An increasing number of variants related to Mendelian diseases have been discovered through analyses of next-generation sequencing data, but the results related to adult-onset Mendelian diseases are insufficient. One possible explanation is that the methods commonly used to evaluate pathogenic variants in patients with congenital Mendelian diseases may not be appropriate for adult-onset diseases due to differences in selection pressure, particularly when assessing the frequency of variants in the general population. We established a well-processed and filtered database of pathogenic variants with both phenotype and frequency information based on the ClinVar and GnomAD public database to better explore the genetic features of adult-onset diseases under real-world conditions. Compared with the control group, pathogenic variants related to adult-onset dominant diseases had a higher allele frequency pattern. Further, the allele frequency patterns of both dominant and recessive variants were higher in patients with neurodegenerative diseases than those in patients with intellectual disabilities. Based on the mutation-selection balance model, the above observation of allele frequency described the lower selection pressure on pathogenic variants related to adult-onset Mendelian diseases and suggests a lower effectiveness of population and loss-of-function evidence in investigations of adult-onset Mendelian diseases.