Genetic Causes of Oculocutaneous Albinism in Pakistani Population

Abstract

Melanin pigment helps protect our body from broad wavelength solar radiation and skin cancer. Among other pigmentation disorders in humans, albinism is reported to manifest in both syndromic and nonsyndromic forms as well as with varying inheritance patterns. Oculocutaneous albinism (OCA), an autosomal recessive nonsyndromic form of albinism, presents as partial to complete loss of melanin in the skin, hair, and iris. OCA has been known to be caused by pathogenic variants in seven different genes, so far, according to all the currently published population studies. However, the detection rate of alleles causing OCA varies from 50% to 90%. One of the significant challenges of uncovering the pathological variant underlying disease etiology is inter- and intra-familial locus heterogeneity. This problem is especially pertinent in highly inbred populations. As examples of such familial locus heterogeneity, we present nine consanguineous Pakistani families with segregating OCA due to variants in one or two different known albinism-associated genes. All of the identified variants are predicted to be pathogenic, which was corroborated by several in silico algorithms and association with diverse clinical phenotypes. We report an individual affected with OCA carries heterozygous, likely pathogenic variants in TYR and OCA2, raising the question of a possible digenic inheritance. Altogether, our study highlights the significance of exome sequencing for the complete genetic diagnosis of inbred families and provides the ramifications of potential genetic interaction and digenic inheritance of variants in the TYR and OCA2 genes.

Clinical and Mutation Spectrum of Autosomal Recessive Non-Syndromic Oculocutaneous Albinism (nsOCA) in Pakistan: A Review

“…This type of albinism is more frequent in the population in sub-Saharan Africa, with an approximate rate of 1 in 3900, followed by African–Americans and Americans [ 15 , 16 ]. These two types of OCA are also seen in Pakistani and Indian families with frequent genetic mutations [ 9 , 17 , 21 ]. The prevalence of OCA type 3 and type 4 is 1 in 8500 and 1 in 100,000, respectively.…”

“…Pathogenic TYR mutations are reported widely, and more than 400 variations are documented in this gene. In the Pakistani population, the large cohort of OCA families is linked to TYR mutations [ 21 , 49 , 60 , 61 , 62 , 63 , 64 , 65 ].…”

“…The OCA2 alleles are the most frequent worldwide and are investigated in diverse populations including African, Caucasian, and Asian groups [ 52 , 70 ]. In the Pakistani population, several consanguineous families are reported with OCA2 mutations, and it is categorized as the second most putative factor for OCA development [ 9 , 21 , 42 , 61 , 63 , 64 ].…”

“…Different investigators detected genetic mutations in OCA-associated genes, predominantly TYR and OCA2 . More than ninety consanguineous OCA families have been explored to determine the TYR mutations [ 21 , 42 , 49 , 61 , 63 , 64 , 65 ]. In the TYR gene, a variety of novel, known, and founder mutations have been demonstrated by various research reports.…”

“…This gene is linked to more than fifty OCA families with variable mutation patterns ( Table 3 ). From the reported data, about 17 families are linked to splice-site error c.1045–15 T>G that accounts for 30.3% of total mutations in OCA2 [ 9 , 21 , 64 ]. In a study from Pakistan, it was observed that this mutation was present in a homozygous state in some of the affected individuals, compared with heterozygous form in other individuals with variable OCA phenotypes among these affected family members.…”