Segregation of novel p.(Ser270Tyr) MAF mutation and p.(Tyr56*) CRYGD variant in a family with dominantly inherited congenital cataracts

Abstract

Purpose To identify the molecular genetic cause in a three generation family with the occurrence of congenital cataracts, variably associated with iris colobomata and microcornea. Methods Whole‐exome sequencing was performed in three affected family members, one unaffected first degree relative, and one spouse. Sequence variants previously reported as disease‐causing, and novel sequence variants within genes listed in CatMap (http://cat-map.wustl.edu/) were given a priority for further evaluation. Verification of possibly pathogenic sequence variants was performed by conventional Sanger sequencing. Results Sequence variant c.168C>G; p.(Tyr56*) in CRYGD, previously reported as pathogenic, and a novel mutation c.809C>A; p.(Ser270Tyr) in MAF, were identified in two affected family members; the grandmother, and half‐brother of the proband. The proband inherited only the MAF mutation, whereas her clinically unaffected sister had the CRYGD change. In silico analysis supported a pathogenic role of p.(Ser270Tyr) in MAF, which was absent from publicly available whole‐exome datasets, and 1,161 Czech individuals. The frequency of CRYGD p.(Tyr56*) in the ExAC dataset was higher than the estimated incidence of congenital cataract in the general population. Conclusions Our study highlights that patients with genetically heterogeneous conditions may exhibit rare variants in more than one disease‐associated gene, warranting caution with data interpretation, and supporting parallel screening of all genes known to harbour pathogenic mutations for a given phenotype. The pathogenicity of sequence variants previously reported as cataract‐causing may require re‐assessment in light of recently released datasets of human genomic variation. Supported by AZV 17‐30500A.