Mutation Analysis of a Pakistani Oculocutaneous Albinism Family Identifies a Novel Splice Site Defect in OCA2 Gene

Abstract

Oculocutaneous albinism (OCA) is a multi-systemic and rare genetic disorder of pigmentation. It occurs due to defects in the melanin synthesis pathway. OCA is characterized by hypopigmentation of hair, dermis, and ocular tissue. The clinical consequences of OCA includes whitish skin, whitish to golden hair and photophobia. Genetic studies have so far reported seven non-syndromic OCA genes, among which Pakistani OCA families mostly segregate TYR and OCA2 gene mutations. In the present study we aimed to investigate the genetic factor of OCA in a consanguineous family from Pakistan. Genetic analysis was performed through microarray genotyping and homozygosity-by-descent (HBD) mapping, whole exome sequencing (for mutation identification) and Sanger sequencing (for variant segregation). Homozygosity analysis revealed a 1.2 Mb HBD region on chromosome 15 between markers rs4778147 to rs8036234 (chr15:27752745-28962131bp), which harbors the previously reported OCA2 gene. The subsequent whole exome sequencing identified a novel splice site defect at spice donor site, wherein G was replaced by T at genomic position 28171268 (NM_000275.2:c.2079+5G>T) within intron-19 of the OCA2 gene. This change presumably may either includes few intronic nucleotides or skip exon-20 in the mature mRNA. Our study further supports the evidence of high incidence of OCA2 gene mutations in Pakistani families.