Evidence that the Ser192Tyr/Arg402Gln in cis Tyrosinase gene haplotype is a disease-causing allele in oculocutaneous albinism type 1B (OCA1B).

Oculocutaneous albinism type 1 (OCA1) is caused by pathogenic variants in the TYR (tyrosinase) gene which encodes the critical and rate-limiting enzyme in melanin synthesis. It is the most common OCA subtype found in Caucasians, accounting for ~50% of cases worldwide. The apparent 'missing heritability' in OCA is well described, with ~25-30% of clinically diagnosed individuals lacking two clearly pathogenic variants. Here we undertook empowered genetic studies in an extensive multigenerational Amish family, alongside a review of previously published literature, a retrospective analysis of in-house datasets, and tyrosinase activity studies. Together this provides irrefutable evidence of the pathogenicity of two common TYR variants, p.(Ser192Tyr) and p.(Arg402Gln) when inherited in cis alongside a pathogenic TYR variant in trans. We also show that homozygosity for the p.(Ser192Tyr)/p.(Arg402Gln) TYR haplotype results in a very mild, but fully penetrant, albinism phenotype. Together these data underscore the importance of including the TYR p.(Ser192Tyr)/p.(Arg402Gln) in cis haplotype as a pathogenic allele causative of OCA, which would likely increase molecular diagnoses in this missing heritability albinism cohort by 25-50%.

A small gene sequencing panel realises a high diagnostic rate in patients with congenital nystagmus following basic phenotyping.

Nystagmus is a disorder of uncontrolled eye movement and can occur as an isolated trait (idiopathic INS, IINS) or as part of multisystem disorders such as albinism, significant visual disorders or neurological disease. Eighty-one unrelated patients with nystagmus underwent routine ocular phenotyping using commonly available phenotyping methods and were grouped into four sub-cohorts according to the level of phenotyping information gained and their findings. DNA was extracted and sequenced using a broad utility next generation sequencing (NGS) gene panel. A clinical subpanel of genes for nystagmus/albinism was utilised and likely causal variants were prioritised according to methods currently employed by clinical diagnostic laboratories. We determine the likely underlying genetic cause for 43.2% of participants with similar yields regardless of prior phenotyping. This study demonstrates that a diagnostic workflow combining basic ocular phenotyping and a clinically available targeted NGS panel, can provide a high diagnostic yield for patients with infantile nystagmus, enabling access to disease specific management at a young age and reducing the need for multiple costly, often invasive tests. By describing diagnostic yield for groups of patients with incomplete phenotyping data, it also permits the subsequent design of 'real-world' diagnostic workflows and illustrates the changing role of genetic testing in modern diagnostic workflows for heterogeneous ophthalmic disorders.

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

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.