Retinitis Pigmentosa via the PRPF8 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). Genetic heterogeneity is documented within each subgroup. 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 PRPF8 gene. At least 17 heterozygous variants in the PRPF8 gene have been identified in patients with AD-RP. Most of the PRPF8 variants are missense and are clustered in exon 42 (McKie et al. Hum Mol Genet 10:1555-1562, 2001; Martínez-Gimeno et al. Invest Ophthalmol Vis Sci 44:2171-2177, 2003). Patients carrying PRPF8 variants usually present with a severe phenotype and early onset. All PRPF8 variants reported to date occurred in familial cases. PRPF8 encodes the pre-mRNA-processing-splicing factor 8 protein, which participates in the removal of introns from mRNA.

Variants in the PRPF8 gene account for ~3 % of AD-RP (Daiger et al. Adv Exp Med Bio 613:203-209, 2008).

This test provides full coverage of all coding exons of the PRPF8 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).