Biallelic WDR19 Variants: Systematic Analysis of Genotype–Phenotype Correlations
TL;DR
Genotype–phenotype analyses indicated that the presence of a truncating variant was associated with increased likelihood of skeletal involvement and reduced likelihood of hepatobiliary disease compared with individuals harbouring only missense variants, and variants located outside repeat protein domains were associated with early symptom onset and with ocular manifestations.
Abstract
Ciliopathies represent a diverse group of inherited disorders resulting from dysfunctional cilia. A rare subset is associated with biallelic variants in WDR19, with fewer than 100 affected individuals reported worldwide. This study is aimed at reviewing the clinical and molecular spectrum of WDR19‐associated ciliopathies, with a particular focus on genotype–phenotype correlations. We report a 32‐year‐old woman with renal, ocular and hepatic manifestations attributed to compound heterozygous variants in WDR19, and reviewed available data from 93 previously published cases. Missense, truncating, splice‐site and copy number variants have all been reported, with renal, ocular, skeletal and hepatic involvement most frequently observed. Genotype–phenotype analyses indicated that the presence of a truncating variant was associated with increased likelihood of skeletal involvement and reduced likelihood of hepatobiliary disease compared with individuals harbouring only missense variants. Amongst individuals with only missense variants, variants located outside repeat protein domains were associated with early symptom onset (before 16 years of age) and with ocular manifestations. Notably, recurrent variants demonstrated considerable phenotypic variability. This study represents the largest review of WDR19 variants to date and contributes to current understanding of WDR19‐related disease.