Retinitis Pigmentosa 38 (RP38) via the MERTK Gene

Retinitis pigmentosa (RP; OMIM # 268000) or rod cone dystrophies (RCDs) represent a group of hereditary retinal dystrophies with a worldwide prevalence of ~1 in 4000 (Booij et al. J Med Genet 42 (11): e67, 2005). RP is clinically characterized by retinal pigment deposits visible on fundus examination, nyctalopia, followed by progressive degeneration of the photoreceptors, which eventually leads to blindness (van Soest et al. Surv Ophthalmol 43(4):321-334, 1999). In the early stages of disease, RP38 (OMIM # 613862) patients have distinct dot-like autofluorescent deposits in the fovea and macula (“bull's eye” pattern on funduscopy), which is a hallmark of RP38. Other salient features of RP38 are nyctalopia in early infancy, reduced visual acuity and decreased rod responses compared to cone at electroretinogram (Ksantini et al. Eur J Ophthalmol 22(4):647-653, 2012).

Nonsyndromic RP is remarkably heterogeneous both clinically and genetically and exhibits autosomal dominant (ad), autosomal recessive (ar) or X-linked (XL) inheritance. To date, over 50 loci have been linked to nonsyndromic RP and 18, 27 and 2 genes have been identified that are involved with adRP, arRP, and XLRP, respectively (RetNet). Mutations in MERTK cause arRP. MERTK (mer proto-oncogene tyrosine kinase; OMIM # 604705), which encodes a transmembrane receptor of tyrosine kinases, is predominantly expressed in retinal pigment epithelium (RPE), and monocytes/macrophages (Strick and Vollrath. Exp Eye Res 91(6):786-787, 2010). MERTK plays an essential role in triggering RPE-mediated phagocytosis for the regeneration/renewal of photoreceptor outer segments (OS) (Conlon et al. Hum Gene Ther Clin Dev 24(1):23-28, 2013). It has been reported in the Royal College of Surgeons (RCS) rat (a widely studied model for arRP) that mutations in MERTK impaired the RPE mediated phagocytic activity and resulted in accumulation of OS debris in the interphotoreceptor space and ultimately lead to retinal degeneration (Gal et al. Nat Genet 26(3):270-271, 2000). MERTK gene replacement therapy using different viral vectors was shown to be effective and safe in the RCS rat (Conlon et al., 2013; D'Cruz et al. Hum Mol Genet 9(4):645-651, 2000). There are about 30 causative mutations reported in MERTK, which include missense mutations, small insertions and deletions (Human Gene Mutation Database).

MERTK mutation screening in a cohort of 328 probands with various retinal dystrophies identified three mutations in three individuals with RP (Gal et al. Nat Genet 26(3):270-271, 2000). A different study showed that MERTK mutations account for about 1% (1/96) of non-syndromic arRP cases (Tschernutter et al. Br J Ophthalmol 90(6):718-723, 2006).

So far, three gross deletions have been reported in MERTK (Human Gene Mutation Database). A gross deletion of exons 1–7 of MERTK is a common founder mutation in the Faroe Islands in Denmark and accounts for ~30% (7/25) of non-syndromic of RP cases in this population (Ostergaard et al. Mol Vis 17:1485-1492, 2011).

This test provides full coverage of all coding exons of the MERTK gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).