Systematic Review of CRYAA Pathogenic/Likely Pathogenic Variants Reported in the Literature: Genotype-Phenotype Correlations in Childhood Cataracts

Abstract

Purpose : Variant curation is limited for genes causing childhood cataracts, even for variants in crystallin genes, such as CRYAA, which commonly cause inherited cataracts. The purpose of this study is to review literature reports of CRYAA pathogenic/likely pathogenic (P/LP) variants associated with childhood cataracts.

Methods : A systematic literature review was completed to identify all publications including P/LP CRYAA variants associated with childhood cataracts. Genotype and phenotype data was gathered. Further evaluations of the variants were performed with an online database (Franklin), REVEL score, and alpha missense predictions.

Results : Thirty-one publications reported 26 unique P/LP variants in 186 patients from 41 families (Table 1). Variants were most common in exon 3 (13 variants, 50%), followed by exon 1 (11 variants, 42%). Most variants were missense (18 variants, 68%) and heterozygous (25 variants, 96%). Sixteen variants (62%) involved either substituting arginine for another amino acid or a deletion including arginine. Franklin classifications rated 16 variants as P/LP and 9 were rated variants of uncertain significance (VUS). For the 18 missense variants, all REVEL scores and 16 alpha missense predictions were classified as likely pathogenic. A comparison of genotype-phenotype data identified varying severity, type, and age of onset of bilateral cataracts without systemic manifestations (Table 2), although many reports lacked comprehensive data. Fifty patients also had microcornea and 17 had microphthalmia. The 2 patients with elongation variants had multiple severe ocular abnormalities.

Conclusions : CRYAA-associated childhood cataracts are frequently caused by heterozygous missense variants substituting arginine in exons 1 or 3. When arginine is substituted for an amino acid of a different charge, it alters protein structure and heat shock protein expression, making it less soluble. Cataracts associated with CRYAA variants, even within the same family, vary considerably in type, severity, age of onset and often have other ocular associations, such as microcornea. Elongation variants are associated with the most severe phenotypes. Increased reporting on genotype-phenotype correlations will aid future variant curation and enhance understanding of the pathogenesis of childhood cataracts.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.

 

Table 1

 

Table 2