Estimation of carrier frequencies of variants in genes associated with autosomal recessive diseases to form a gene list for expanded carrier screening

Abstract

For expanded carrier screening (ECS) of pathogenic variants (PV) in genes associated with autosomal recessive diseases (ARD), ACMG proposed an approach that takes into account both the severity of diseases and the carrier frequencies (CF) of PV in genes associated with autosomal recessive diseases. The aim was to assess the CF of PV in genes associated with ARD which are not included in the ACMG recommendations in the Russian population (RP). An assessment of the CF of PV in 303 candidate genes was carried out in a sample of patients of the NMRC TPM (n=1126). Among the genes with the PV frequency exceeding the threshold value of 0.005, genes were selected for the assessment of the PV frequency in the RP, carried out using the «Database of population frequencies of genetic variants of the population of the Russian Federation». Of these, the CF of PV exceeded the threshold value in the SBDS gene (CF=0.01171; p_adj 0,001), associated with the Shwachman–Diamond syndrome, and the ALOX12B gene associated with autosomal recessive congenital ichthyosis (CF=0.005845; p_adj< 0,001). These genes can be considered as candidates for ECS in the RP.