RHO-Related Disorders via the RHO 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 is genetically and clinically heterogeneous (Koenekoop et al. Clin Exp Ophthalmol 35:473-485, 2007). At least four distinct subgroups are recognized on the basis of the mode of inheritance and age of onset. These include autosomal dominant-RP (AD-RP), autosomal recessive (AR-RP), X-linked, and digenic (Rivolta et al. Hum Mol Genet 11:1219-1227, 2002; 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); and 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. AD-RP affects all ethnic groups, although variants in particular genes have been identified in specific populations. Patients with AD-RP represent 15-25 % of all cases (Fishman Arch Ophthalmol 96:822-826, 1978). Currently, variants in eighteen (18) genes account for at least 58% of AD-RP cases. Variants in the RHO gene represent the most common cause of AD-RP. Over 128 different RHO causative variants were reported. RHO variants are distributed along the entire coding region of the gene. Although most variants are missense resulting in amino acid substitutions, splice variants, and small deletions and insertions were also reported. Rare RHO variants were found in patients with AR-RP, autosomal dominant congenital stationary night blindness (CSNB), and retinitis punctata albescens. The RHO gene encodes the rhodopsin protein, a retinal protein responsible for the formation of photoreceptors.

This test allows the detection of variants in approximately 28% of patients with AD-RP. PreventionGenetics will offer tests for all genes known to cause AD-RP, and is committed to add new tests as the remaining AD-RP genes are discovered.

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