Whole-exome sequencing combined with in silico protein analysis identifies rare truncating variants in the TYR gene associated with oculocutaneous albinism IA (OCA1A) in an Iranian patient

Abstract

Oculocutaneous albinism type IA (OCA1A) is an autosomal recessive tyrosinase-negative condition caused by deleterious variants in the TYR gene. Using whole-exome sequencing (WES) followed by Sanger sequencing, we detected rare pathogenic variants (c.286dupA and c.763C > T) within the TYR gene in a 12-year-old Iranian female who met the clinical criteria proposed for OCA. Through comprehensive in silico protein analysis, we elucidated the functional impact of these two variants. c.286dupA induced a frameshift, leading to the loss of the entire copper-binding tyrosinase domain and the only transmembrane melanosome-bound tyrosinase helix. Similarly, c.763C > T introduced a premature stop codon, resulting in the loss of approximately two-thirds of the copper-binding tyrosinase domain and the transmembrane helix. These findings signified a substantial disturbance in the normal function of tyrosinase. Our study presents the first report of co-occurring pathogenic c.286dupA and c.763C > T variants, comprehensively investigating their functional impact using in silico protein tools.