Identification of a functionally significant tri-allelic genotype in the Tyrosinase gene (TYR) causing hypomorphic oculocutaneous albinism (OCA1B)

Abstract

Oculocutaneous albinism (OCA) and ocular albinism (OA) are inherited disorders of melanin biosynthesis, resulting in loss of pigment and severe visual deficits. OCA encompasses a range of subtypes with overlapping, often hypomorphic phenotypes. OCA1 is the most common cause of albinism in European populations and is inherited through autosomal recessive mutations in the Tyrosinase (TYR) gene. However, there is a high level of reported missing heritability, where only a single heterozygous mutation is found in TYR. This is also the case for other OCA subtypes including OCA2 caused by mutations in the OCA2 gene. Here we have interrogated the genetic cause of albinism in a well phenotyped, hypomorphic albinism population by sequencing a broad gene panel and performing segregation studies on phenotyped family members. Of eighteen probands we can confidently diagnose three with OA and OCA2, and one with a PAX6 mutation. Of six probands with only a single heterozygous mutation in TYR, all were found to have the two common variants S192Y and R402Q. Our results suggest that a combination of R402Q and S192Y with a deleterious mutation in a ‘tri-allelic genotype’ can account for missing heritability in some hypomorphic OCA1 albinism phenotypes.

Molecular characterization of a series of 990 index patients with albinism

“…Its prevalence in the homozygous state is about 4.2% in the general population, and patients homozygous for this variant do not present with albinism, which indicates it is not pathogenic per se. Its pathogenicity has been the subject of debate in the literature (Ghodsinejad Kalahroudi et al., ; Kubal, Dagnelie, & Goldberg, ; Norman et al., ; Oetting et al., ). We performed a comparative analysis of the phenotypic features of 69 patients shown by segregation analysis to have the c.1205G>A/p.Arg402Gln variant and a highly pathogenic variant in trans (called “p.Arg402Gln‐OCA1” patients) versus patients harboring two highly pathogenic TYR variants (“classical‐OCA1” patients).…”

“…c.575C>A/p.Ser192Tyr is another common TYR variant thought to have an additive effect when present in cis to c.1205G>A/p.Arg402Gln (Jagirdar et al., ; Norman et al., ). From data in Table , it can be counted that 21.9% of the alleles (61/278; 139 patients) have these variants in cis , a number much higher than the estimated frequency in the general population (1.1%–1.9%; Jagirdar et al., ; Norman et al., ). This suggests a significant involvement of the 192Y‐402Q haplotype in OCA1.…”

Management of nystagmus in children: a review of the literature and current practice in UK specialist services

“…These differing approaches are currently the topic of much debate, and clinicians will increasingly be required to understand the limitations of genetic testing along with its changing role in diagnostics, in many cases through closer collaboration with clinical genetics colleagues. Future directions are likely to be dictated by the cost and speed of genetic testing but will always require detailed clinical assessment in order to confirm or refute putative genetic diagnosis (which can be numerous when many genes are tested at once) [ 42 ] and direct future clinical care.…”

Germline and somatic albinism variants in amelanotic/hypomelanotic melanoma: Increased carriage of TYR and OCA2 variants

“…The TYR common variant double haplotype p.192Y-p.402Q [40][41][42], though at slightly higher frequency in AHM than PM cases (2.8% vs 2.1%), was not significantly different. There were 18 coding variants in OCA2 (S1 Table, gnomAD MAF), two of which, p.R305W (5.05%) and p.R419Q (6.5%), have been described previously as being common [12], with a third variant p.V443I at 1.09% in MGRB controls (Table 1 and S1 Table).…”