Submission Details

The relationship between MERTK and an autosomal recessive inherited retinal dystrophy, MERTK-related retinopathy, was evaluated using the ClinGen Clinical Validity Framework as of July 7, 2022. The disease entity has previously been described as retinitis pigmentosa 38. To encompass a range of phenotypes and to account for the genetic heterogeneity in inherited retinopathy, the disease entity used for this curation is MERTK-related retinopathy (MONDO:0800394).

MERTK (MER proto-oncogene, tyrosine kinase) (MIM*604705) is localized to chromosome 2q14.1 and consists of 19 exons (Weier, Fung, & Lersch, 1999). It encodes the tyrosine-protein kinase Mer, a 999-amino-acid transmembrane protein (Uniprot#Q12866) belonging to the TAM (TYRO3/AXL/MER) receptor kinase family. MERTK is highly expressed in monocyte/macrophages, and in epithelial cells including the Retina Pigment Epithelium (RPE). It plays a critical role in the shedding of photoreceptor outer segments prior to phagocytosis, a circadian process essential for photoreceptor homeostasis (Feng et al., 2002).

MERTK was first associated with retinopathy after the identification of a deletion in the gene causing the naturally occurring autosomal recessive (AR) retinal degeneration of the Royal College of Surgeons (RCS) rat (D'Cruz et al., 2000), a retinal dystrophy model secondary to a phagocytic defect of the RPE.

Biallelic variants in MERTK underlying retinopathy in humans were first reported by Gal et al. (2000). The associated retinopathy phenotype is usually severe, characterized by an early onset of the disease, with night blindness and progressive visual field constriction due to loss of rod photoreceptors, and rapid macular involvement.

A total of 79 variants have already been identified underlying rod-cone dystrophy. The variant spectrum in MERTK includes 33 missense, 12 nonsense, 12 splice defects, 12 small deletions, 2 small insertion–deletions, 3 small duplications, and 2 exonic and 3 gross deletions (PMID: 29659094). Altogether, variants in MERTK account for ∼2% of retinopathy cases with a severe phenotype. No specific phenotype/genotype correlations have been reported, most likely due to the diversity of the variant spectrum in a yet limited number of patients.

In this curation, data from 3 consanguineous families with multiple patients and 3 isolated individuals with 8 unique variants (nonsense, frameshift, missense), were collected from 6 publications (Ksantini M, et al., 2012, PMID: 22180149, Bhatia S, et al., 2019, PMID: 30851773, McHenry CL, et al., 2004, PMID: 15111602, Lukovic D, et al., 2015, PMID: 26263531, Mackay DS, et al., 2010, PMID: 20300561, Biswas P, et al., 2021, PMID: 33252167). More data is available in the literature but the maximum score for genetic evidence (12 points) has been reached.

This gene-disease relationship is supported by functional studies and model systems, described above (D'Cruz PM, et al., 2000, PMID: 10699188, Lukovic D, et al., 2015, PMID: 26263531, McHenry CL, et al., 2004, PMID: 15111602, Duncan JL, et al., 2003, PMID: 12556419). Results described by D'Cruz PM, et al., 2000, PMID: 10699188, provide genetic evidence for an essential role of a receptor tyrosine kinase in a specialized form of phagocytosis and suggest a molecular model for ingestion of outer segments by RPE cells.

In summary, ΜΕRΤΚ is definitively associated with the autosomal recessive inherited retinal dystrophy, MERTK-related retinopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This clinical validity classification was approved by the ClinGen Retina Gene Curation Expert Panel on July 7, 2022.