Evaluating gene-disease relationship strength in crystallin genes in association with pediatric cataracts

Introduction: Gene curation is the analysis of clinical and experimental evidence to determine the strength of relationship between specific genes and diseases. Gene curations allow for improved genetic testing analysis and downstream clinical outcomes. Although variants in crystallin genes are believed to cause about half of all non-syndromic inherited pediatric cataracts, formal gene curations have not been performed.Methods: Established and publicly available ClinGen protocols  were utilized to perform curations for thirteen crystallin genes to evaluate  strength of their associations with pediatric cataracts using published clinical and experimental evidence.Results: Seven genes (CRYAA, CRYAB, CRYBA1, CRYBB1, CRYBB2, CRYGC, CRYGD) scored as Definitively associated with autosomal dominant (AD) inherited pediatric cataracts. Two genes (CRYGA, CRYGS) as Moderate; and four genes have Limited support (CRYBA2, CRYBA4, CRYBB3 and CRYGB). Experimental evidence, when added to clinical evidence, increased the strength of gene-disease relationship for five genes (CRYAB from Limited to Definitive, CRYAA from Moderate to Definitive, CRYGA and CRYGS from Limited to Moderate and CRYGB from No Known Disease Relationship (given absence of clinical evidence) to Limited).Discussion: Optimization and clarification of these gene-disease relationships will improve harmonization of genetic test options (i.e., inclusion on cataract gene panels) and variant interpretation, ultimately allowing for improved clinical care.