RPGRIP1-Related Retinal Disorders via the RPGRIP1 Gene
Summary and Pricing 
Test Method
Exome Sequencing with CNV Detection
| Test Code | Test Copy Genes | Test CPT Code | Gene CPT Codes Copy CPT Code | Base Price | |
|---|---|---|---|---|---|
| 11625 | RPGRIP1 | 81479 | 81479,81479 | $990 | Order Options and Pricing |
Pricing Comments
Our favored testing approach is exome based NextGen sequencing with CNV analysis. This will allow cost effective reflexing to PGxome or other exome based tests. However, if full gene Sanger sequencing is desired for STAT turnaround time, insurance, or other reasons, please see link below for Test Code, pricing, and turnaround time information. If the Sanger option is selected, CNV detection may be ordered through Test #600.
An additional 25% charge will be applied to STAT orders. STAT orders are prioritized throughout the testing process.
Click here for costs to reflex to whole PGxome (if original test is on PGxome Sequencing platform).
Click here for costs to reflex to whole PGnome (if original test is on PGnome Sequencing platform).
The Sanger Sequencing method for this test is NY State approved.
For Sanger Sequencing click here.Turnaround Time
3 weeks on average for standard orders or 2 weeks on average for STAT orders.
Please note: Once the testing process begins, an Estimated Report Date (ERD) range will be displayed in the portal. This is the most accurate prediction of when your report will be complete and may differ from the average TAT published on our website. About 85% of our tests will be reported within or before the ERD range. We will notify you of significant delays or holds which will impact the ERD. Learn more about turnaround times here.
Targeted Testing
For ordering sequencing of targeted known variants, go to our Targeted Variants page.
Clinical Features and Genetics
Clinical Features
Leber congenital amaurosis (LCA) is the most severe form of inherited retinal degeneration. LCA is usually evident at birth or during the first months of life. LCA is clinically characterized by poor visual function often accompanied by nystagmus, abnormal pupillary responses, photophobia, high hyperopia, markedly diminished electroretinogram (ERG) and keratoconus condition due to oculo-digital signs of Franceschetti such as eye poking, pressing, and rubbing the eyes with a knuckle or finger (Weleber et al. 2013; Perrault et al. 1996). The estimated prevalence of LCA is 2-3 per 100,000 live births. LCA accounts for 10-18% of congenital blindness cases (Fazzi et al. 2003).
Genetics
LCA is a genetically heterogeneous disorder. To date, approximately 19 genes have been implicated in the pathogenesis of LCA (Weleber et al. 2013; Chen et al. 2013). Together these genes account for 70% of LCA cases. These genes encode proteins that have a wide range of retinal functions, such as photoreceptor morphogenesis, phototransduction, vitamin A cycling, guanine synthesis, and outer segment phagocytosis (den Hollander et al. 2008). Mutations in these genes cause not only LCA, but also other retinal distrophies (Weleber 2002). Genetic variations in RPGRIP1, which encodes the retinitis pigmentosa GTPase regulator (RPGR)-interacting protein 1, are responsible for 4.5–6% of LCA (Won et al. 2009).
RPGRIP1 protein localizes within photoreceptors, predominantly at the connecting cilia and the outer segments (OS), where RPGR protein (majorly associated with X-linked RP) also localizes (Roepman et al. 2005). RPGRIP1 interacts with RPGR, RPGRIP1L (RPGRIP1- like, a protein homolog based on 29% amino acid identity with RPGRIP1) and Nek4 (never in mitosis A (NIMA)-related proteinkinase family protein). This interaction is likely important in photoreceptors; specifically, in regulating ciliary homeostasis. It is likely that RPGRIP1 and RPGRIP1L act as cilium-specific scaffolds in recruiting Nek4 signaling network and in turn regulate cilium integrity and stability (Coene et al. 2011). It has also been reported that RPGRIP1 may be part of the multiprotein complex, which is required for disk morphogenesis, putatively by regulating actin cytoskeleton dynamics (Zhao et al. 2003). Thus far, sequence variations in RPGRIP1 appear to be typically reported in LCA patients (Koenekoop 2005). Due to its interaction with RPGR, it is conceivable that genetic defects in RPGRIP1 that compromise their interaction may cause phenotypes less severe than LCA, such as RP or CRD (cone rod dystrophy) (Cremers et al. 2002; Roepman et al. 2005).
There are about eighty documented pathogenic variations in RPGRIP1 which are associated with autosomal recessive retinal degeneration (Human Gene Mutation Database). Nonsense mutations in RPGRIP1 have been reported in the majority of LCA6 patients (Won et al. 2009). Also, compromised interaction of RPGRIP1 with other proteins may contribute to the pathogenesis of primary open angle glaucoma (Fernández-Martínez et al. 2011).
Clinical Sensitivity - Sequencing with CNV PGxome
A mutation screening in a group of 35 unrelated patients with arRP (17 patients), LCA (9 patients), and isolated RP (9 patients) identified RPGRIP1 pathogenic variations in 6% of the patients (Booij et al. 2005). Genetic screening of 15 genes in eighty-seven unrelated Chinese patients with LCA identified RPGRIP1 pathogenic variations in 8% of their patient cohort (Li et al. 2011).
Testing Strategy
This test provides full coverage of all coding exons of the RPGRIP1 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).
Indications for Test
All patients with symptoms suggestive of LCA, CRD and RP, especially patients with defects in disc morphogenesis. This test may also be considered for the reproductive partners of individuals who carry pathogenic variants in RPGRIP1.
All patients with symptoms suggestive of LCA, CRD and RP, especially patients with defects in disc morphogenesis. This test may also be considered for the reproductive partners of individuals who carry pathogenic variants in RPGRIP1.
Gene
| Official Gene Symbol | OMIM ID |
|---|---|
| RPGRIP1 | 605446 |
| Inheritance | Abbreviation |
|---|---|
| Autosomal Dominant | AD |
| Autosomal Recessive | AR |
| X-Linked | XL |
| Mitochondrial | MT |
Diseases
| Name | Inheritance | OMIM ID |
|---|---|---|
| Cone-Rod Dystrophy 13 | 608194 | |
| Leber Congenital Amaurosis 6 | 613826 |
Citations
- Booij JC. et al. 2005. Journal of medical genetics. 42: e67. PubMed ID: 16272259
- Chen Y, Zhang Q, Shen T, Xiao X, Li S, Guan L, Zhang J, Zhu Z, Yin Y, Wang P, Guo X, Wang J, et al. 2013. Comprehensive Mutation Analysis by Whole-Exome Sequencing in 41 Chinese Families With Leber Congenital Amaurosis. Investigative Ophthalmology & Visual Science 54: 4351–4357. PubMed ID: 23661368
- Coene KLM, Mans DA, Boldt K, Gloeckner CJ, Reeuwijk J van, Bolat E, Roosing S, Letteboer SJF, Peters TA, Cremers FPM, Ueffing M, Roepman R. 2011. The ciliopathy-associated protein homologs RPGRIP1 and RPGRIP1L are linked to cilium integrity through interaction with Nek4 serine/threonine kinase. Human Molecular Genetics 20: 3592–3605. PubMed ID: 21685204
- Cremers FP, Hurk JA van den, Hollander AI den. 2002. Molecular genetics of Leber congenital amaurosis. Human molecular genetics 11: 1169–1176. PubMed ID: 12015276
- den Hollander AI, Roepman R, Koenekoop RK, Cremers FPM. 2008. Leber congenital amaurosis: genes, proteins and disease mechanisms. Prog Retin Eye Res 27: 391–419. PubMed ID: 18632300
- Fazzi E, Signorini SG, Scelsa B, Bova SM, Lanzi G. 2003. Leber’s congenital amaurosis: an update. Eur. J. Paediatr. Neurol. 7: 13–22. PubMed ID: 12615170
- Fernández-Martínez L, Letteboer S, Mardin CY, Weisschuh N, Gramer E, Weber BH, Rautenstrauss B, Ferreira PA, Kruse FE, Reis A. 2011. Evidence for RPGRIP1 gene as risk factor for primary open angle glaucoma. European Journal of Human Genetics 19: 445–451. PubMed ID: 21224891
- Human Gene Mutation Database (Bio-base).
- Koenekoop RK. 2005. RPGRIP1 is mutated in Leber congenital amaurosis: a mini-review. Ophthalmic Genet. 26: 175–179. PubMed ID: 16352478
- Li L, Xiao X, Li S, Jia X, Wang P, Guo X, Jiao X, Zhang Q, Hejtmancik JF. 2011. Detection of Variants in 15 Genes in 87 Unrelated Chinese Patients with Leber Congenital Amaurosis. PLoS ONE 6: e19458. PubMed ID: 21602930
- Perrault I, Rozet JM, Calvas P, Gerber S, Camuzat A, Dollfus H, Châtelin S, Souied E, Ghazi I, Leowski C, Bonnemaison M, Paslier D Le, et al. 1996. Retinal-specific guanylate cyclase gene mutations in Leber’s congenital amaurosis. Nat. Genet. 14: 461–464. PubMed ID: 8944027
- Roepman R, Letteboer SJ, Arts HH, Beersum SE van, Lu X, Krieger E, Ferreira PA, Cremers FP. 2005. Interaction of nephrocystin-4 and RPGRIP1 is disrupted by nephronophthisis or Leber congenital amaurosis-associated mutations. Proceedings of the National Academy of Sciences of the United States of America 102: 18520–18525. PubMed ID: 16339905
- Weleber RG, Francis PJ, Trzupek KM, Beattie C. 2013. Leber Congenital Amaurosis. In: Pagon RA, Adam MP, Bird TD, Dolan CR, Fong C-T, and Stephens K, editors. GeneReviews™, Seattle (WA): University of Washington, Seattle. PubMed ID: 20301475
- Weleber RG. 2002. Infantile and childhood retinal blindness: a molecular perspective (The Franceschetti Lecture). Ophthalmic Genet. 23: 71–97. PubMed ID: 12187427
- Won J, Gifford E, Smith RS, Yi H, Ferreira PA, Hicks WL, Li T, Naggert JK, Nishina PM. 2009. RPGRIP1 is essential for normal rod photoreceptor outer segment elaboration and morphogenesis. Human Molecular Genetics 18: 4329–4339. PubMed ID: 19679561
- Zhao Y, Hong D-H, Pawlyk B, Yue G, Adamian M, Grynberg M, Godzik A, Li T. 2003. The retinitis pigmentosa GTPase regulator (RPGR)-interacting protein: subserving RPGR function and participating in disk morphogenesis. Proceedings of the National Academy of Sciences 100: 3965–3970. PubMed ID: 12651948
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.
- Once the test has been added log in to myPrevent to fill out an online requisition form.
- PGnome sequencing panels can be ordered via the myPrevent portal only at this time.
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
If ordering a Duo or Trio test, the proband and all comparator samples are required to initiate testing. If we do not receive all required samples for the test ordered within 21 days, we will convert the order to the most effective testing strategy with the samples available. Prior authorization and/or billing in place may be impacted by a change in test code.
Specimen Types
Specimen Requirements and Shipping Details
PGxome (Exome) Sequencing Panel
PGnome (Genome) Sequencing Panel
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