The complexity of simple genetics: oligogenic patterns in albinism

Abstract

Purpose : Albinism is a heterogeneous group of genetically determined conditions characterised by reduced levels of melanin pigment and a range of developmental visual system anomalies. Affected families are generally expected to carry genetic variation disrupting one of 19 albinism-related genes. However, a significant proportion of cases remain without a molecular diagnosis despite comprehensive genomic analysis. It has been speculated that interaction of multiple variants in more than one locus (i.e. digenic/oligogenic patterns) may underlie albinism in these unsolved cases. We sought to gain further insights into this.

Methods : We studied a cohort of 1,120 individuals with albinism. A “control” cohort of 29,451 individuals from the Genomics England 100,000 Genomes Project dataset was also analysed. We assumed a digenic model and utilised a genotype-based approach that focused on two prevalent albinism-related changes, TYR:c.1205G>A (p.Arg402Gln) and OCA2:c.1327G>A (p.Val443Ile). We hypothesised that when these two missense variants are both present in the heterozygous state, their interaction is driving the pathology observed in albinism.

Results : We found that when both TYR:c.1205G>A and OCA2:c.1327G>A are present in the heterozygous state, the probability of receiving a diagnosis of albinism is significantly increased (odds ratio 12.8; 95% confidence interval 6.0 – 24.7; p-value 2.1 x 10^-8). Further analyses in an independent cohort, the UK Biobank, supported this finding and highlighted that heterozygosity for the TYR:c.1205G>A and OCA2:c.1327G>A variant combination is associated with statistically significant alterations in visual acuity and central retinal thickness (traits that are considered albinism endophenotypes)

Conclusions : We have shown that dual heterozygosity for a TYR and an OCA2 variant confers susceptibility to albinism. The outlined approach is likely to be relevant to the study of other rare disorders, and opens up new avenues for the investigation of oligogenic patterns.

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