No preferential mode of inheritance for highly constrained genes.

Genetic constraint metrics such as the gnomAD probability of being loss-of-function (LoF) intolerant (pLI) are used to prioritize candidate genes but the mode of inheritance of highly constrained genes has never specifically been studied. We compared 605 genes with a pLI of 1 (pLI1 group) with a random sample of 635 genes from gnomAD (the random group) in terms of genetic constraint metrics, associations with Mendelian disease, modes of inheritance, and two intragenic constraint scores: the percentage of constraint coding regions (CCR) in the 99th percentile and the gene variation intolerance rank (GeVIR). The proportion of genes associated with a Mendelian disease was 35.9% (217/605) in the pLI1 group and 19.5% (124/635) in the random group (p < 0.0001). The modes of inheritance in the random group were autosomal dominant for 35 genes (28.2%), autosomal recessive for 69 (55.6%), mixed for 14 (11.3%) and X-linked for 6 genes (4.8%). The corresponding distribution in the pLI1 group was 150 (69.1%), 26 (12.0%), 14 (6.5%) and 27 (12.4%) (p < 0.0001). The percentage of CCRs in the 99th percentile was 0.3 in the random group versus 1.12 in the pLI1 group (p < 0.0001). The GeVIR score was 50.9 for the random group versus 15.1 for the pLI1 group (p < 0.0001). High genetic constraint does not seem to be associated with a particular mode of inheritance but does seem to be associated with the intragenic constraint scores considered here. Some highly constrained genes are associated with two different modes of inheritance. 2022, International Research and Cooperation Association for Bio & Socio - Sciences Advancement.