STOML1 as an Exploratory Candidate Gene for Autosomal Dominant Iris and Chorioretinal Coloboma in a British Family.

BACKGROUND

Ocular coloboma is a congenital eye defect with high genetic heterogeneity. This study investigated a four-generation pedigree to identify candidate variants underlying autosomal dominant iris and chorioretinal coloboma.

METHODS

Whole-exome sequencing (WES) was performed on a single affected family member. Variants were prioritised using the Phenopolis pipeline, filtered for rarity across multiple population databases, and retained where CADD indicated predicted deleteriousness. Candidate variants were then validated by Sanger sequencing in the four family members from whom DNA was available. Variants were classified according to ACMG/AMP criteria.

RESULTS

Five rare heterozygous variants were identified: STOML1 (NM_004809.5:c.1100T>C; p.(Leu367Pro)), MTIF2 (NM_002453.3:c.1337G>A; p.(Trp446Ter)), CDH23 (NM_022124.6:c.8906G>A; p.(Arg2969His)), CDON (NM_001378964.1:c.3276+1G>T; p.?), and ERCC6L2 (NM_020207.7:c.19C>T; p.(Gln7Ter)). Four are classified as of uncertain significance; the ERCC6L2 variant is classified as pathogenic in ClinVar.

CONCLUSIONS

STOML1 is proposed as an exploratory candidate gene for isolated ocular coloboma, requiring replication in independent families and functional validation. The recurrent ERCC6L2 nonsense variant is reported as an incidental finding of potential haematological relevance.