GPR143

Inheritance Pattern: XL

Disease ID:MONDO:0021019

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: XL

Disease ID:MONDO:0010435

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: XL

Disease ID:MONDO:0021019

Submitter: Orphanet

Inheritance Pattern: XL

Disease ID:MONDO:0700230

Submitter: PanelApp Australia

Inheritance Pattern: XL

Disease ID:MONDO:0017304

Submitter: G2P

Inheritance Pattern: XL

Disease ID:MONDO:0700230

Submitter: ClinGen

The *GPR143* gene was first reported in relation to X-linked ocular albinism in 1995 (Bassi et al., PMID: 7647783). Affected males with causal hemizygous variants in *GPR143* have since been identified in a number of other publications, diagnosed with either X-linked ocular albinism 1 or X-linked congenital nystagmus 6 (PMID: 17516023). Patients from both groups generally present initially with nystagmus or reduced visual acuity, while additional phenotypes include foveal hypoplasia, amblyopia, and/or photophobia. Cases diagnosed as ocular albinism in particular can exhibit hypopigmentation of the fundus, iris transillumination defects, optic nerve misrouting, and/or melanocytes harboring giant melanosomes. This latter group of features associated with ocular albinism has been reported more consistently among the subset of patients of European descent and less commonly among those of East Asian descent, leading to a higher proportion of congenital nystagmus diagnoses among the East Asian subset of patients. Hypopigmentation in particular may be milder or absent in affected individuals with darker eye color (PMID: 26061757). While most heterozygous female carriers are reportedly unaffected, some exhibit features such as mild hypopigmentation of the iris (PMID: 18978956) or fundus (PMID: 28211458). Per criteria outlined by the ClinGen Lumping & Splitting Working Group, we found the molecular mechanism (hemizygous loss of function in the GPR143 gene product) and mode of inheritance (X-linked) to be consistent among unrelated patients diagnosed with either ocular albinism type 1 (MIM#: 300500) or X-linked congenital nystagmus 6 (MIM#: 300814). The phenotypic variability between the two diagnoses appeared to represent a spectrum of disease rather than separate disease entities. Therefore, these cases have been lumped into a single disease entity, referred to as *GPR143*-related foveal hypoplasia. Twelve suspected disease-causing variants were scored as part of this curation (one missense, seven frameshift, two nonsense, and two disrupting canonical splice sites), which have been collectively reported in twelve probands in ten publications (PMID: 7647783, PMID: 17516023, PMID: 18523664, PMID: 19390656, PMID: 12515581, PMID: 8634705, PMID: 29847651, PMID: 28211458, PMID: 11520764, PMID: 18978956). The mechanism of pathogenicity appears to be hemizygous loss of function, characterized in some cases by suspected null variants predicted to trigger the absence of the gene product. All probands scored for this curation harbored a single variant allele within the *GPR143* locus. A large family with co-segregation of the variant with the affected phenotype was scored from one of these publications (PMID: 17516023), while other families were available but not scored as part of this curation as the maximum scoring for this evidence type had already been reached. This gene-disease association is also supported by experimental evidence that GPR143 shows subcellular localization to melanosomes (PMID: 10471510) and interacts with the TYR enzyme involved in melanin biogenesis (PMID: 27720922). This matches the finding that *GPR143* expression reaches its highest levels within the retinal pigment epithelium (PMID: 30239781). *GPR143* silencing in melanoma cells results in a reduction of mature melanosomes (PMID: 19717472), while *GPR143* over-expression in neuroendocrine cells indicates a role in negative regulation of neuron projection development that may be consistent with the optic nerve misrouting observed in human patients (PMID: 31606330). These cellular features are recapitulated by both zebrafish (PMID: 25690007) and mouse (PMID: 11092754, PMID: 16303920, PMID: 18697795) models of *GPR143* loss of function. The mouse model in particular matches the human patient phenotypes of normal hair color, hypopigmentation of the fundus, optic nerve misrouting, and giant melanosomes within melanocytes and retinal pigment epithelial cells, while revealing an underlying defect in microtubule-based melanosome motility (PMID: 18697795). Additional experimental evidence was available but not included in this curation as the maximum scoring for this evidence type had already been reached. In summary, *GPR143* is definitively associated with *GPR143*-related foveal hypoplasia. This has been repeatedly demonstrated in both research and diagnostic settings, and has been upheld over time without the emergence of contradictory evidence, leading to a Definitive classification. This classification has been approved by the Retina GCEP on October 6th, 2022 (SOP Version 9).