'Bull's Eye' Macular Dystrophy (BEM), Cone-Rod Dystrophy 12 (CORD12), Retinitis Pigmentosa 41 (RP41) and Stargardt Disease 4 (STGD4) via the PROM1 Gene

Summary and Pricing

Test Method

Exome Sequencing with CNV Detection
Test Code Test Copy GenesTest CPT Code Gene CPT Codes Copy CPT Codes Base Price
11609 PROM1 81479 81479,81479 $890 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
11609PROM181479 81479 $890 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.

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

For Reflex to PGxome pricing click here.

The Sanger Sequencing method for this test is NY State approved.

For Sanger Sequencing 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

'Bull's Eye' Macular Dystrophy or Macular Dystrophy, Retinal 2 (BEM/MCDR2; OMIM 608051) is clinically characterized by mild visual impairment that is usually evident in the first two decades of life. Most prominently, early macular abnormalities include annular retinal pigment epithelium (RPE) atrophy due to the lipofuscin accumulation, sparing the central fovea that gives the distinct BEM appearance. Other symptoms include central scotoma, and flash electroretinogram abnormalities due to cone dysfunction. As the disease progresses, more widespread rod and cone abnormalities are seen in the initially spared central fovea (Michaelides et al. Invest Ophthalmol Vis Sci 44(4):1657-1662, 2003).

Retinitis pigmentosa or rod cone dystrophies (RP/RCDs) represent a group of hereditary retinal dystrophies with a worldwide prevalence of ~1 in 4000 (Booij et al. J Med Genet 42(11): e67, 2005). RP is clinically characterized by retinal pigment deposits visible on fundus examination, night blindness, followed by progressive loss of peripheral vision in daylight, which eventually leads to blindness (van Soest et al. Surv Ophthalmol 43(4):321-34,1999).

Cone rod dystrophies (CORDs/CRDs) are 10 times less common than RP (1/40,000). They are characterized by dysfunction or degeneration of cone photoreceptors with relative preservation of rod function in the initial stages. The most common symptoms are photophobia, reduced 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). 

Stargardt disease (STGD) is the most commonly inherited macular dystrophy with a prevalence of ~1/10,000 and a carrier frequency of 2% (Shastry. Int J Mol Med 21(6):715-720, 2008). Clinically it is characterized by reduced central vision, bilateral, symmetric, atrophic lesions in the macula and underlying RPE and by the presence of prominent flecks in the posterior pole of the retina (Kniazeva et al. Am J Hum Genet 64(5):1394-1399, 1999).

Genetics

A pentaspan membrane glycoprotein prominin-1 (also known as CD133/AC133) encoded by PROM1 was originally classified as a cell surface marker for human hematopoietic stem/progenitor cells, though it is also expressed in some differentiated cells (Yin et al. Blood 90(12):5002-5012, 1997). Missense mutations in PROM1 have been associated with several severe forms of autosomal dominant retinal dystrophies such as BEM (Michaelides et al., 2003), CORD12 (OMIM 612657) (Yang et al. J Clin Invest 118(8):2908-2916, 2008), and STGD4 (OMIM 603786)(Kniazeva et al., 1999). Frameshift mutations in PROM1, resulting in premature stop codons and truncation of the encoded protein and most likely representing null mutations, cause autosomal-recessive RP41 (OMIM 612095) (Zhang et al. Hum Genet 122(3-4):293-299, 2007). Early and severe progressive rod and cone degeneration are the hallmark of PROM1 truncating mutations (Yang et al., 2008; Permanyer et al. Invest Ophthalmol Vis Sci 51(5):2656-63, 2010; Pras et al. Mol Vis 15(5):1709-1716, 2009). Due to alternative splicing, multiple PROM1 protein isoforms have been reported in human tissues (Yang et al., 2008; Permanyer et al., 2010). Two isoforms, s11 and s12, are most prominent in human retina, whereas the s2 isoform spans all the coding exons and is expressed faintly and other isoforms are barely detectable (Permanyer et al., 2010). In the retina, PROM1 is expressed in both rod and cone photoreceptors predominantly at the base of the photoreceptor outer segments (OSs). The photoreceptor OSs comprises a stack of over 1,000 densely packed disks that harbors rhodopsin and the phototransduction machinery. The entire OS is continually renewed by the constant formation of new disks at its base and shedding of older disks from its apex (Young et al. J Cell Biol 33(1):61-72, 1967). The PROM1 protein has prominent function in visual phototransduction and acts as a key regulator of disk morphogenesis during early retinal development (Permanyer et al., 2010).

Testing Strategy

This test provides full coverage of all coding exons of the PROM1 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.

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

Clinical Sensitivity - Sequencing with CNV PGxome

PROM1 mutations are a relatively rare cause of blindness. In a study done in a large family, where all six affected individuals had homozygous PROM1 mutations, five of the six unaffected family members were heterozygous carriers (Zhang et al. Hum Genet 122(3-4):293-299, 2007). Another study identified homozygous PROM1 frameshift mutations in three siblings from a consanguineous Arab family, who had prominent axial myopia (Pras et al. Mol Vis 15:1709-1716 2009). A third study done in 41 individuals from five unrelated families with autosomal dominant BEM, revealed heterozygous c.1117C>T mutations in PROM1 in all affected family members (in family C all 8 affected individuals had this variant and unaffected individuals did not) (Michaelides et al. Invest Ophthalmol Vis Sci 51(9):4771-4780, 2010).

To date, no gross deletions or duplications have been reported in PROM1 (Human Gene Mutation Database).

Indications for Test

Patients with early and severe progressive rod and cone degeneration, particularly with high myopia are candidates for this test. Patients with symptoms consistent of BEM, CORD12, RP41 and STGD4 are also candidates. This test may also be considered for the reproductive partners of individuals who carry pathogenic variants in PROM1.

Gene

Official Gene Symbol OMIM ID
PROM1 604365
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Citations

  • 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
  • Hamel CP. 2007. Cone rod dystrophies. Orphanet J Rare Dis 1;2:7. PubMed ID: 17270046
  • Human Gene Mutation Database (Bio-base).
  • Kniazeva, M. et al. (1999). "A new locus for autosomal dominant stargardt-like disease maps to chromosome 4." Am J Hum Genet 64(5):1394-1399. PubMed ID: 10205271
  • Michaelides, M. et al. (2003). "An autosomal dominant bull's-eye macular dystrophy (MCDR2) that maps to the short arm of chromosome 4." Invest Ophthalmol Vis Sci 44(4):1657-1662. PubMed ID: 12657606
  • Michaelides, M. et al. (2010). "The PROM1 mutation p.R373C causes an autosomal dominant bull's eye maculopathy associated with rod, rod-cone, and macular dystrophy." Invest Ophthalmol Vis Sci 51(9):4771-4780. PubMed ID: 20393116
  • Permanyer, J. et al. (2010). "Autosomal recessive retinitis pigmentosa with early macular affectation caused by premature truncation in PROM1." Invest Ophthalmol Vis Sci 51(5):2656-2663. PubMed ID: 20042663
  • Pras, E. et al. (2009). "Cone-rod dystrophy and a frameshift mutation in the PROM1 gene." Mol Vis 15:1709-1716. PubMed ID: 19718270
  • Shastry BS. 2008. Evaluation of the common variants of the ABCA4 gene in families with Stargardt disease and autosomal recessive retinitis pigmentosa. International journal of molecular medicine 21: 715–720. PubMed ID: 18506364
  • Van Soest S., Westerveld A. 1999. Survey of ophthalmology. 43: 321-34. PubMed ID: 10025514
  • Yang, Z. et al. (2008). "Mutant prominin 1 found in patients with macular degeneration disrupts photoreceptor disk morphogenesis in mice." J Clin Invest 118(8):2908-2916. PubMed ID: 18654668
  • Yin, A.H. et al. (1997). "AC133, a novel marker for human hematopoietic stem and progenitor cells." Blood 90(12):5002-5012. PubMed ID: 9389720
  • Young, R.W. et al. (1967). "The renewal of photoreceptor cell outer segments." J Cell Biol 33(1):61-72. PubMed ID: 6033942
  • Zhang, Q. et al. (2007). "Severe retinitis pigmentosa mapped to 4p15 and associated with a novel mutation in the PROM1 gene." Hum Genet 122(3-4):293-299. PubMed ID: 17605048

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.

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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