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Leber Congenital Amaurosis 1 (LCA1) and Cone-Rod dystrophy 6 (CORD6) via the GUCY2D Gene

Summary and Pricing

Test Method

Sequencing and CNV Detection via NextGen Sequencing using PG-Select Capture Probes
Test Code Test Copy GenesTest CPT Code Gene CPT Codes Copy CPT Codes Base Price
7127 GUCY2D 81479 81479,81479 $640 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
7127GUCY2D81479 81479,81479 $640 Order Options and Pricing

Pricing Comments

This test is also offered via our exome backbone with CNV detection (click here). The exome-based test may be higher priced, but permits reflex to the entire exome or to any other set of clinically relevant genes.

An additional 25% charge will be applied to STAT orders. STAT orders are prioritized throughout the testing process.

Turnaround Time

18 days on average for standard orders or 13 days 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.

EMAIL CONTACTS

Genetic Counselors

Geneticist

  • Dana Talsness, PhD

Clinical Features and Genetics

Clinical Features

Leber congenital amaurosis (LCA, OMIM 204000) is the most severe form of inherited retinal degeneration that 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. GeneReviews, 2013; Perrault et al. Nat Genet 14(4):461-464, 1996). The estimated prevalence of LCA is 2-3 per 100,000 live births and accounts for 10-18% of congenital blindness (Fazzi et al. Eur J Paediatr Neurol 7(1):13-22, 2003). The less severe forms of inherited retinal degeneration are usually considered juvenile retinitis pigmentosa (RP) (Gu et al. Nature Genetics 17(2): 194 -197, 1997), which represents a group of hereditary retinal dystrophies with a worldwide prevalence of ~1 in 4000 ((Booij et al. J Med Genet 42(11): e67, 2005). LCA and juvenile RP overlap both phenotypically and genotypically, and the intermediate phenotypes are described as Cone rod dystrophies (CORDs/CRDs) or early onset retinal degeneration (Booij et al., 2005). CORDs are 10 times less common than RP (1/40,000). One of the forms, CORD6 (OMIM 601777), is characterized by dysfunction or degeneration of cone photoreceptors with relative preservation of rod function in the initial stages. The most common symptoms are photophobia, decreased visual acuity, and dyschromatopsia. Fundus changes may vary from mild pigment granularity to a distinct atrophic lesion in the central macula. As the disease progresses, degeneration of rod photoreceptors also occurs and leads to progressive night blindness and peripheral visual field loss (Hamel. Orphanet J Rare Dis 2:7, 2007).

Genetics

LCA is a genetically heterogeneous disorder and is often inherited in an autosomal recessive manner. To date, approximately 19 genes have been implicated in the pathogenesis of different types of LCA (Weleber et al., 2013; Chen et al. Invest Ophthalmol Vis Sci 54(6):4351-4357, 2013). Together these genes account for 70% of the 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. Prog Retin Eye Res 27(4):391-419, 2008). Mutations in these genes cause not only LCA but also other retinal disorders (Weleber. Ophthalmic Genet 23(2):71-97, 2002).

GUCY2D (also known as RetGC-1), which encodes the membrane-bound retinal guanylyl cyclase, is a major causative gene for LCA, and is also known to be causative for CORD6. GUCY2D is expressed in both cone and rod photoreceptors, but primarily in the cone outer segments (Dizhoor et al. Neuron 12(6):1345-1352, 1994). GUCY2D catalyzes visual photransduction, which is a biochemical process responsible for light conversion into electrical signals in the rod and cone cells. In this process, the GUCY2D protein helps in restoring photoreceptor sensitivity by synthesizing cyclic guanosine monophosphate (cGMP), which is regulated by guanylate cyclase activator proteins (GCAPs). GCAPs are sensitive to changes in the cytoplasmic Ca++ concentrations. At lower cytoplasmic Ca++ concentrations, the GCAPs bind to the GUCY2D dimerization domain and stimulate it, and in consequence, the cGMP level is restored. Due to genetic or environmental factors, if the Ca++ homeostasis is disrupted in the photoreceptor cells it would lead to the apoptosis of the cells (Baehr and Palczewski. Subcell Biochem 45:71-91, 2007; Garcia-Hoyos et al. Mol Vis 17:1103-1109, 2011). Recessive mutations in GUCY2D cause LCA, whereas dominant mutations result in a less severe form, CORD6. The majority of the identified GUCY2D mutations in CORD6 patients localize to codon 838 on exon 13 (dimerization domain), indicating a mutation hotspot. LCA1-associated mutations were dispersed throughout the gene but none were identified at exon 13. These mutations have a more damaging effect on GUCY2D function than CORD6 mutations (Kitiratschky et al. Invest Ophthalmol Vis Sci 49(11):5015-5023, 2008; Hamel, 2007), which explains the severity of the LCA.

Clinical Sensitivity - Sequencing with CNV PG-Select

A study by Rozet et al. (2001) identified GUCY2D mutations in ~20% (25/130) of their LCA patients, whereas Kitiratschky et al. (2008) identified mutations in ~40% (11/27) of their CORD families. All CORD mutations affected codon 838 (Rozet et al. Invest Ophthalmol Vis Sci 42(6):1190-1192, 2001; Kitiratschky et al. Invest Ophthalmol Vis Sci 49(11):5015-5023, 2008). Another study identified GUCY2D mutations in 11% of the patients with juvenile RP (Booij et al. J Med Genet 42(11): e67, 2005). Ugur Iseri et al. (2010) identified GUCY2D mutations in 12% of all LCA cases and up to 40% of dominant CORD6 cases (Ugur Iseri et al. Eur J Hum Genet 18(10):1121-1126, 2010).

A study by Perrault et al. (2000) identified two gross deletions and one duplication in GUCY2D out of 118 patients affected with LCA (Perrault et al. Eur J Hum Genet 8(8):578-582, 2000).

Testing Strategy

This test provides full coverage of all coding exons of the GUCY2D gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.

Indications for Test

Candidates for this test are all LCA and CORD patients, patients with symptoms consistent with LCA1 and CORD6, family members of patients who have known mutations and carrier testing for at-risk family members.

Gene

Official Gene Symbol OMIM ID
GUCY2D 600179
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Diseases

Name Inheritance OMIM ID
Cone-Rod Dystrophy 6 AR, AD 601777
Leber Congenital Amaurosis 1 AR 204000

Related Tests

Name
Cone-Rod Dystrophy Panel
Leber Congenital Amaurosis 14 (LCA14) or Early Onset Retinal Dystrophy (EORD) and Juvenile Retinitis Pigmentosa via the LRAT Gene
Leber Congenital Amaurosis 4 (LCA4) via the AIPL1 Gene
Leber Congenital Amaurosis Panel
Leber Congenital Amaurosis via the CRX Gene
Retinitis Pigmentosa (includes RPGR ORF15) Panel

Citations

  • Baehr W and Palczewski K. 2007. Guanylate cyclase-activating proteins and retina disease. Subcell Biochem 45:71-91. PubMed ID: 18193635
  • Booij JC. 2005. Identification of mutations in the AIPL1, CRB1, GUCY2D, RPE65, and RPGRIP1 genes in patients with juvenile retinitis pigmentosa. Journal of Medical Genetics 42: e67–e67. PubMed ID: 16272259
  • Chen, Y. et al. (2013). "Comprehensive mutation analysis by whole-exome sequencing in 41 Chinese families with Leber congenital amaurosis." Invest Ophthalmol Vis Sci 54(6):4351-4357. PubMed ID: 23661368
  • 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
  • Dizhoor, A.M. et al. (1994). " The human photoreceptor membrane guanylyl cyclase, RetGC, is present in outer segments and is regulated by calcium and a soluble activator." Neuron 12(6):1345-1352. PubMed ID: 7912093
  • Fazzi, E. et al. (2003). "Leber's congenital amaurosis: an update." Eur J Paediatr Neurol 7(1):13-22. PubMed ID: 12615170
  • Garcia-Hoyos M, Auz-Alexandre CL, Almoguera B, Cantalapiedra D, Riveiro-Alvarez R, Lopez-Martinez MA, Gimenez A, Blanco-Kelly F, Avila-Fernandez A, Trujillo-Tiebas MJ, Garcia-Sandoval B, Ramos C, Ayuso C. 2011. Mutation analysis at codon 838 of the Guanylate Cyclase 2D gene in Spanish families with autosomal dominant cone, cone-rod, and macular dystrophies. Mol. Vis. 17:1103-1109. PubMed ID: 21552474
  • Gu, S. M. et.al. (1997). "Mutations in RPE65 cause autosomal recessive childhood-onset severe retinal dystrophy." Nat Genet 17(2): 194-197. PubMed ID: 9326941
  • Hamel CP. 2007. Cone rod dystrophies. Orphanet J Rare Dis 1;2:7. PubMed ID: 17270046
  • Kitiratschky, V.B. et al (2008). "Mutation analysis identifies GUCY2D as the major gene responsible for autosomal dominant progressive cone degeneration." Invest Ophthalmol Vis Sci 49(11):5015-5023. PubMed ID: 18487367
  • 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
  • Perrault, I. et al. (2000). "Spectrum of retGC1 mutations in Leber's congenital amaurosis." Eur J Hum Genet 8(8):578-582. PubMed ID: 10951519
  • Rozet, J.M. et al (2001). "Complete abolition of the retinal-specific guanylyl cyclase (retGC-1) catalytic ability consistently leads to leber congenital amaurosis (LCA)." Invest Ophthalmol Vis Sci 42(6):1190-1192. PubMed ID: 11328726
  • Ugur Iseri, S.A., et al (2010). "A novel recessive GUCY2D mutation causing cone-rod dystrophy and not Leber's congenital amaurosis." Eur J Hum Genet 18(10):1121-1126. PubMed ID: 20517349
  • 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

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


Specimen Types

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STAT and Prenatal Test Options are not available with Patient Plus.

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Note: acceptable specimen types are whole blood and DNA from whole blood only.
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