Retinitis Pigmentosa via the IMPDH1 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, eventually, 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 an 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 (Koenekoop et al. Clin Experiment 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). 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 18 genes account for at least 58% of AD-RP cases. These include the IMPDH1 gene. At least 8 different IMPDH1 variants have been reported in patients with AD-RP. The most common disease-causing variant, Asp226Asn, accounts for at ~ 1% of all cases of AD-RP (Bowne et al. Invest Ophthalmol Vis Sci 47:34-42, 2006). Notably, the variant Arg231Pro was associated with a severe form of AD-RP in one family in which all patients presented with early-onset, severe loss of visual acuity and nondetectable ERG signals (Groveret al. Ophthalmology 111:1910-1916, 2004). These observations led the authors to suggest that patients with a severe form of AD-RP should be investigated for variants in the IMPDH1 gene. In addition to AD-RP, heterozygous variants in the IMPDH1 gene were found in isolated cases of Leber congenital amaurosis (LCA, OMIM 146690; Bowne et al. 2006).

The IMPDH1 gene encodes the inosine monophosphate dehydrogenase type1 enzyme, which catalyzes the rate-limiting step of de novo guanine nucleotide biosynthesis.

This test allows the detection of variants in approximately 2.8 % of patients with AD-RP (Daiger Adv Exp Med Bio 613:203-209, 2008) and rare isolated cases of LCA.

This test provides full coverage of all coding exons of the IMPDH1 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).