Abstract
GCNT2-related cataracts is a disorder characterized by bilateral congenital cataracts (CC) of various types (with or without the adult i blood phenotype) and is caused by biallelic variants in GCNT2, which has 3 major isoforms, differentiated by alternative splicing of the first exon (known as exon 1A, B, and C). While the transcript that includes exon 1C is thought to be key for the adult i blood phenotype, it is not clear which transcript(s) are clinically relevant for the CC disease phenotype. We report a proband with CC and a truncating variant in exon 1B (NM_001491.3: c.760dup p.H254Pfs*2) found in trans with a 75 kilobase (kb) copy-number deletion encompassing exon 1B and 1C. To our knowledge, c.760dup is the first reported disease-associated variant limited to exon 1B of GCNT2. This report strongly suggests that NM_001491.3, which includes exon 1B, is a clinically relevant transcript for GCNT2-related cataracts and adds to the variant spectrum for this understudied gene-disease relationship. This finding has implications for genotype-phenotype correlations of GCNT2 related CC and variant classification, particularly for truncations in exon 1B, which should likely receive strong pro-pathogenic weight based on this being a clinically relevant exon.

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