Retinitis Pigmentosa via the PRPF31 Gene

Nonsyndromic retinitis pigmentosa (RP, OMIM 268000) is a large group of inherited degenerative diseases of the retina characterized by abnormalities of the photoreceptors or the retinal pigment epithelium. It is a progressive disease. Symptoms usually begin with night blindness, progressing to constriction of the peripheral visual field and eventual to loss of central vision. The age of onset varies from childhood to middle age (Gu et al. J Med Genet 36:705-707, 1999). The clinical hallmarks are abnormal fundus with bone-spicule deposits and attenuated retinal vessels, abnormal electroretinographic findings, and reduced visual fields (Daiger et al. Arch Ophthalmol 125:151-158, 2007). RP affects 1 in 3,000 people worldwide (Farrar et al. EMBO J 21:857-864, 2002). Genetic abnormalities are the primary cause of RP.

Retinitis pigmentosa (RP) is genetically and clinically heterogeneous. At least four distinct subgroups are recognized on the basis of the mode of inheritance and age of onset. These include autosomal dominant (AD-RP), autosomal recessive (AR-RP), X-linked, and digenic (Kajiwara et al. Science 264:1604-1608, 1994). In addition, RP can be inherited as a mitochondrial trait (Mansergh et al. Am J Hum Genet 64:971-985, 1999). About 50% of patients with RP are isolated cases with no known affected relatives. It is unclear how many of these are real isolated cases caused by de novo variants or inherited with low penetrance. RP affects all ethnic groups. Currently, variants in 18 genes are known to cause AD-RP. These include the PRPF31 gene. At least 40 heterozygous variants in the PRPF31 gene have been identified in patients with RP (Rio Frio et al. J Clin Invest 118:1519-1531, 2008), including familial and sporadic cases (Vithana et al. Mol Cell 8:375-381, 2001; Martínez-Gimeno et al. Invest Ophthalmol Vis Sci 44:2171-2177, 2003; Wang et al. Am J Med Genet 121A:235-239, 2003). The PRPF31 variants, most of which are novel, are distributed throughout the gene and are of various types. These variants are associated with a wide clinical variability in terms of age of onset, disease severity, and progression. PRPF31 variants have been detected in patients of various ethnic groups; however, the c.1142delG variant has been found only in Japanese patients and accounts for the majority of Japanese RP (Taira et al. Jpn J Opthalmol 51:45-48, 2007).

PRPF31 encodes the pre-mRNA-processing factor 31 protein, which participates in the removal of introns from mRNA. Variants in such proteins are expected to affect the splicing process of photoreceptor-specific genes resulting in abnormal gene products and ultimately retinal degeneration.

Variants in the PRPF31 gene account for ~ 8% of RP (Daiger et al. Adv Exp Med Bio 613:203-209, 2008). PreventionGenetics plans to offer tests for all genes known to cause RP and is committed to add new tests as the remaining RP genes are discovered.

This test provides full coverage of all coding exons of the PRPF31 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).

This test will also sequence the region encompassing the deep intronic variant c.1374+654C>G.

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).