X-linked Retinitis Pigmentosa (XLRP) (includes RPGR ORF15) and Choroideremia Panel

Summary and Pricing

Test Method

Exome Sequencing with CNV Detection
Test Code Test Copy Genes Gene CPT Codes Copy CPT Codes
10187 CHM 81479,81479 Order Options and Pricing
OFD1 81479,81479
RP2 81479,81479
RPGR 81479,81479
Test Code Test Copy Genes Panel CPT Code Gene CPT Codes Copy CPT Code Base Price
10187Genes x (4)81479 81479 $1170 Order Options and Pricing

Pricing Comments

We are happy to accommodate requests for testing single genes in this panel or a subset of these genes. The price will remain the list price. If desired, free reflex testing to remaining genes on panel is available. Alternatively, a single gene or subset of genes can also be ordered via our PGxome Custom Panel tool.

A 25% additional charge will be applied to STAT orders. View STAT turnaround times here.

For Reflex to PGxome pricing click here.

Targeted Testing

For ordering sequencing of targeted known variants, go to our Targeted Variants page.

Turnaround Time

18 days on average

EMAIL CONTACTS

Genetic Counselors

Geneticist

Clinical Features and Genetics

Clinical Features

Retinitis pigmentosa (RP) represents a group of hereditary retinal dystrophies with a worldwide prevalence of ~1 in 4000 (Booij 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. 1999). X-linked RP (XLRP) is one of the most severe forms of RP, with early onset and rapid progression in males. Milder symptoms can also present in females, probably due to random X inactivation (Friedrich et al. 1993).

Choroideremia (CHM) is an X-linked retinal dystrophy characterized by progressive degeneration of the choriocapillaris, retinal pigment epithelium and photoreceptors (Coussa and Traboulsi 2012; MacDonald et al. 2003). This blinding disorder typically affects males with a progression from nyctalopia (night blindness) in the first or second decades of life to peripheral visual field loss. Central vision is preserved until age 40-50 years in most CHM cases. Carrier females are usually asymptomatic, but progressive chorioretinal degenerations can occur.

Genetics

Nonsyndromic RP is remarkably heterogeneous both clinically and genetically and exhibits autosomal dominant (AD), autosomal recessive (AR) or X-linked (XL) inheritance. At least five different genetic loci have been linked to XLRP: Xp11.2 (RP2), Xp21.1 (RPGR), Xp21.2-21.3 (RP6), Xp22 (RP23 or OFD1) and Xp26-27 (RP24) (RetNet). To date, only the RPGR, RP2 and OFD1 genes have been identified.

RPGR encodes the retinitis pigmentosa GTPase regulator (Meindl et al. 1996), and RP2 encodes a plasma membrane-associated protein. Pathogenic variants in RPGR account for the vast majority (~80%) of all XL RP cases, with RP2 accounting for about 10% of cases, and the other loci likely accounting for the remaining ~10% (Breuer et al. 2002; Sharon et al. 2003). Males hemizygous for RPGR or RP2 pathogenic variants typically display classic features of RP, such as initial night blindness and loss of peripheral vision (Sharon et al. 2003). However, RPGR pathogenic variants have also been detected in patients presenting with cone and cone-rod dystrophy (Yang et al. 2002; Demirci et al. 2002) or atrophic macular degeneration (Ayyagari et al. 2002). Female carriers of RPGR and RP2 pathogenic variants showed variable manifestation of the phenotypes ranging from asymptomatic to severe retinal degeneration similar to affected male patients (Friedrich et al. 1993; Neidhardt et al. 2008).

The RPGR gene encodes several alternatively spliced isoforms, although RP-causing mutations are only found in isoform C (CCDS35229.1). Isoform C consists of 15 coding exons, with exon 15 (usually referred to as ORF15; see Bader et al. 2003 for a detailed description of ORF15) coding for nearly 50% of the protein. Accordingly, pathogenic variants in ORF15 account for ~50% of all XL RP cases (Vervoort et al. 2000; Sharon et al. 2003). Pathogenic variants in RPGR are a mix of missense, nonsense, splicing, small deletions and insertions (mostly frameshift) and larger deletions.

The RP2 gene consists of 5 exons with pathogenic variants found throughout all five exons; no founder pathogenic variants or mutational hotspots have been reported. Most pathogenic variants result in premature protein termination (frameshift, nonsense and splice-site), although a few causative missense variants have also been identified (Mears et al. 1999; Hardcastle et al. 1999). Patients with pathogenic variants in RP2 appear to retain less visual acuity than patients with pathogenic variants in RPGR (Sharon et al. 2003). Thus, knowledge of which XL RP gene is mutated is useful for making the most accurate long-term visual prognosis.

Exome sequencing has identified that OFD1 is associated with XL RP in one pedigree. The deep intronic variant c.935+706A>G (alternatively known as IVS9+706A>G) was identified in all the affected males and the obligate female carriers were heterozygous for this variant. This variant causes the insertion of a cryptic exon producing an aberrant transcript. In vivo expression of this variant suggested that the normal OFD1 transcript is produced, but at reduced level (39%). They speculated that these levels are sufficient for the other tissues, but not for the photoreceptors. OFD1 is localized to the connecting cilium of photoreceptors, and is probably required for primary cilium biogenesis (Webb et al. 2012).

CHM (Rab Escort Protein 1 - REP-1) has 15 coding exons that encode a protein involved in vesicular trafficking (Cremers et al. 1990; Coussa and Traboulsi 2012; MacDonald et al. 2003). CHM is the only gene to date known to be associated with choroideremia. Nearly all CHM pathogenic variants lead to a null allele or truncated nonfunctional REP-1 protein. The major types of CHM defects are frameshifts (30%), nonsense variants (25%), partial and whole gene deletions (20%), and splicing variants (17%) while missense pathogenic variants are very rare (2%) (Human Gene Mutation Database). Gross insertions and complex rearrangements have been also reported but are uncommon.

Clinical Sensitivity - Sequencing with CNV PGxome

This test is predicted to detect a causative variant in over 90% of all patients with presumptive XL RP (Sharon et al. 2003; Hong 2005; Breuer et al. 2002), or ~45% of patients with X-linked cone dystrophy (Demirci et al. 2002). The sensitivity for X-linked atrophic macular degeneration is unknown (Ayyagari et al. 2002). The clinical sensitivity for OFD1 is uncertain. So far, an OFD1 causative variant was only reported in one pedigree (Webb et al. 2012). Direct sequencing of the 15 exons and adjacent splice sites detects CHM pathogenic variants in 60%-95% of affected males with Choroideremia (MacDonald et al. 2003).

Gross deletions and duplications have been reported in the RPGR and RP2 genes (Human Gene Mutation Database; Bader 2003; Pelletier et al. 2007; Vervoort et al. 2000). While an exact frequency of gross deletions and duplications is unknown, they are not a common cause of disease. Large deletions that have been reported in OFD1 are associated with Oral-facial-digital syndrome 1 (Human Gene Mutation Database). Large deletions in CHM are relatively common (Human Gene Mutation Database).

Testing Strategy

This panel provides 100% coverage of all coding exons of the genes 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 coverage as ≥20X NGS reads or Sanger sequencing.

We also sequence the OFD1 intronic c.935+706A>G variant (Webb et al. 2012).

Analysis of the RPGR Exon 15 (ORF15) repetitive region is especially difficult; we utilize special chemistry for this region. It also includes targeted testing of the deep intronic splicing mutation c.314+10127T>A (van den Hurk et al. 2003).

Since this test is performed using exome capture probes, a reflex to any of our exome based tests is available (PGxome, PGxome Custom Panels).

Indications for Test

This test is for patients with X-linked recessive Retinitis Pigmentosa (XLRP), X-linked Cone dystrophy, Cone-Rod Dystrophy and X-linked atrophic macular degeneration.

Genes

Official Gene Symbol OMIM ID
CHM 300390
OFD1 300170
RP2 300757
RPGR 312610
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Related Test

Name
PGxome®

Citations

  • Ayyagari R. et al. 2002. Genomics. 80: 166-71. PubMed ID: 12160730
  • Bader I. 2003. Investigative Ophthalmology & Visual Science. 44: 1458-1463. PubMed ID: 12657579
  • Booij J.C. et al. 2005. Journal of Medical Genetics. 42: e67. PubMed ID: 16272259
  • Breuer D.K. et al. 2002. American Journal of Human Genetics. 70: 1545-54. PubMed ID: 11992260
  • Coussa R.G., Traboulsi E.I. 2012. Ophthalmic Genetics. 33: 57-65. PubMed ID: 22017263
  • Cremers F.P. et al. 1990. American Journal of Human Genetics. 47: 622-8. PubMed ID: 2220804
  • Demirci F. Yesim K. et al. 2002. The American Journal of Human Genetics. 70: 1049–53. PubMed ID: 11857109
  • Friedrich U. et al. 1993. Human Genetics. 92: 359-63. PubMed ID: 8225316
  • Hardcastle A.J. et al. 1999. American Journal of Human Genetics. 64: 1210-5. PubMed ID: 10090907
  • Hong D.H. et al. 2005. Investigative Ophthalmology & Visual Science. 46: 435-41. PubMed ID: 15671266
  • Human Gene Mutation Database (Bio-base).
  • MacDonald I. et al. 2003. Choroideremia. In: Pagon RA, Adam MP, Bird TD, Dolan CR, Fong C-T, Smith RJ, and Stephens K, editors. GeneReviews™, Seattle (WA): University of Washington, Seattle. PubMed ID: 20301511
  • Mears A.J. et al. 1999. American Journal of Human Genetics. 64: 897-900. PubMed ID: 10053026
  • Meindl A. et al. 1996. Nature Genetics. 13: 35-42. PubMed ID: 8673101
  • Neidhardt J. et al. 2008. Molecular Vision. 14: 1081-93. PubMed ID: 18552978
  • Pelletier V. et al. 2007. Human Mutation. 28: 81-91. PubMed ID: 16969763
  • RetNet: Genes and Mapped Loci Causing Retinal Diseases
  • Sharon D. et al. 2003. American Journal of Human Genetics. 73: 1131-46. PubMed ID: 14564670
  • van den Hurk J.A. et al. 2003. Human Genetics. 113: 268-75. PubMed ID: 12827496
  • van Soest S. et al. 1999. Survey of Ophthalmology. 43: 321-34. PubMed ID: 10025514
  • Vervoort R. et al. 2000. Nature Genetics. 25: 462-6. PubMed ID: 10932196
  • Webb T. R. et al. 2012. Human Molecular Genetics. 21: 3647-54. PubMed ID: 22619378
  • Yang Z. et al. 2002. Human Molecular Genetics. 11: 605-11. PubMed ID: 11875055

Ordering/Specimens

Ordering Options

We offer several options when ordering sequencing tests. For more information on these options, see our Ordering Instructions page. To view available options, click on the Order Options button within the test description.

myPrevent - Online Ordering

  • The test can be added to your online orders in the Summary and Pricing section.
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Requisition Form

  • A completed requisition form must accompany all specimens.
  • Billing information along with specimen and shipping instructions are within the requisition form.
  • All testing must be ordered by a qualified healthcare provider.

For Requisition Forms, visit our Forms page


Specimen Types

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