Identification of incompletely penetrant variants and interallelic interactions in autosomal recessive disorders by a population‐genetic approach

Abstract We aimed to identify incompletely penetrant (IP) variants and interallelic interactions in autosomal recessive disorders by a population‐genetic approach. Genotype and clinical data were collected from 9038 patients of European origin with ASL, ATP7B , CAPN3 , CFTR , CTNS , DHCR7 , GAA , GALNS , GALT , IDUA , MUT , NPHS1 , NPHS2 , PAH , PKHD1 , PMM2 , or SLC26A4 ‐related disorders. We calculated the relative allele frequency of each pathogenic variant ( n  = 1936) to the loss‐of‐function (LOF) variants of the corresponding gene in the patient ( A C p t V / A C p t L O F ) and the general population ( AC gnomAD V / AC gnomAD LOF ) and estimated the penetrance of each variant by calculating their ratio:( A C p t V / A C p t L O F ) ( A C g n o m A D V / A C g n o m A D L O F )(V/LOF ratio). We classified all variants as null or hypomorphic based on the associated clinical phenotype. We found 25 variants, 29% of the frequent 85 variants, to be underrepresented in the patient population (V/LOF ratio <30% with p  < 7.22 × 10 −5 ), including 22 novel ones in the ASL , CAPN3 , CFTR , GAA , GALNS , PAH , and  PKHD1 genes. In contrast to the completely penetrant variants (CP), the majority of the IP variants were hypomorphic (IP: 16/18, 88%; CP: 177/933, 19.0%; p  = 5.12 × 10 −10 ). Among them, only the NPHS2 R229Q variant was subject to interallelic interactions. The proposed algorithm identifies frequent IP variants and estimates their penetrance and interallelic interactions in large patient cohorts.