Confirming and Expanding the Phenotypes of Variants: Coloboma, Inferior Chorioretinal Hypoplasia, and High Myopia

Purpose: Two frameshift and two indel variants in have been reported to cause coloboma in two families with incomplete penetrance and in two isolated cases in previous studies, respectively. This study aims to confirm this association and expand related specific phenotypes based on the genotype-phenotype analysis of variants.

Methods: Variants in were collected from our in-house exome sequencing data of 5,845 probands with different eye conditions. Multistep bioinformatics analysis was used to classify the variants. Potential pathogenic variants and phenotypic variations were further evaluated based on family segregation and genotype-phenotype analysis.

Results: In total, 63 rare variants were detected in Multistep bioinformatics and genotype-phenotype analyses suggested that eight rare heterozygous variants in nine families should be considered potential pathogenic variants: three novel frameshift variants (c.350_356delCGCCGCT/p.Ser117*, c.1403_1406dupACCT/p.Tyr470Profs*130, and c.1428delG/p.Ser477Alafs*130) and five novel missense variants (c.388C>A/p.Arg130Ser, c.794G>T/p.Arg265Leu, c.1162G>A/p.Gly388Ser, c.1232A>G/p.Tyr411Cys, and c.1510A>T/p.Met504Leu). Among the nine families, carriers of these variants showed overlapping phenotypes, including typical uveal coloboma (12 eyes of seven patients from four families), inferior chorioretinal hypoplasia (ICH) or optic disc hypoplasia (ODH; 12 eyes of eight patients from six families), and high myopia (10 eyes of five patients from five families) within individual families or among different families.

Conclusions: The data presented in this study confirmed that variants in not only frameshift variants but also missense variants, are a common cause of uveal coloboma. In addition, ICH, ODH, and high myopia may be variant phenotypes that are frequently associated with variants.