DNA icon

Stargardt disease, Fundus Flavimaculatus or Retinal Dystrophy, Early-Onset Severe via the ABCA4 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
11047 ABCA4 81408 81408,81479 $990 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
11047ABCA481408 81408,81479 $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.

EMAIL CONTACTS

Genetic Counselors

Geneticist

  • Dana Talsness, PhD

Clinical Features and Genetics

Clinical Features

Stargardt disease (STGD) is the most common form of juvenile onset inherited macular degeneration. STGD is characterized by loss of photoreceptor cells in the macula and degeneration of the retinal pigment epithelium (RPE), resulting in a severe reduction of central vision with preservation of peripheral vision. STGD has variable phenotype, age of onset, and severity. It accounts for approximately 7% of all retinal disorders with an estimated prevalence of 1 in 10,000 and a carrier frequency of 2% (Shastry. 2008. PubMed ID: 18506364). A characteristic feature of STGD is yellowish flecks surrounding the macula. At advanced stages, a progressive bilateral atrophy of the RPE, photoreceptors, and choroidal vasculature can be found (Rossi et al. 2012. PubMed ID: 23341817; Fishman et al. 1987. PubMed ID: 3658351). Genetic analysis suggests that STGD and Fundus flavimaculatus (FFM) are allelic disorders with slightly different clinical manifestations. FFM has later age of onset (20-64 years) and slower progression or milder visual loss (Kaplan et al. 1993. PubMed ID: 8275096; Shastry. 2008. PubMed ID: 18506364).

With the advent of gene therapy and other types of treatments, the identification of causative genes and variants is becoming increasingly important. Lentiviral gene therapy in mouse model was found to be a potentially efficient tool for treating ABCA4-associated diseases (Kong et al. 2008. PubMed ID: 18463687).

Please see the following links for clinical trials and management options below:

Management

https://clinicaltrials.gov/ct2/show/NCT03772665

https://clinicaltrials.gov/ct2/show/NCT01736592

http://progstar.org/progstar-home/about-the-study/

Genetics

Genetically, STGD is a heterogeneous disorder that is usually inherited in an autosomal recessive (AR) manner and, less commonly, as an autosomal dominant (AD) trait (Rossi et al. 2012. PubMed ID: 23341817). Using homozygosity mapping, the STGD/FFM disease locus was mapped to the short arm of chromosome 1 and the causative gene characterized as ABCA4 (Kaplan et al. 1993. PubMed ID: 8275096; Allikmets et al. 1997. PubMed ID: 9295268). ABCA4 is associated with multiple types of retinal disorders (Rozet et al. 1998. PubMed ID: 9781034; Rivera et al. 2000. PubMed ID: 10958763). Bi-allelic pathogenic variants in ABCA4 are found in the majority of AR STGD (66-80%) (Allikmets et al. 1997. PubMed ID: 9295268), age-related macular degeneration (AMD) (Allikmets et al. 1997. PubMed ID: 9295268), two-thirds of cases with AR cone-rod dystrophy (AR CRD) (Cremers et al. 1998. PubMed ID: 9466990) and a small fraction of patients with AR retinitis pigmentosa (arRP) (Martínez-Mir et al. 1998. PubMed ID: 9425888).

The pathogenic variant spectrum of ABCA4 ranges from single base substitutions to deletions of several exons, although the majority are missense variants followed by protein truncating variants and deep intronic variants (Khan et al. 2020. PubMed ID: 32307445; Briggs et al. 2001. PubMed ID: 11527935). To our knowledge, no de novo variants in ABCA4 have been documented causative. The c.2588G>C (p.[Gly863Ala, Gly863del]) variant was found in more than one-third of patients with STGD in the western European population (Maugeri et al. 1999. PubMed ID: 10090887). c.2588 is the first nucleotide of exon 17. The G>C nucleotide substitution at this position results in a mixture of proteins, some with the p.Gly863Ala substitution, and some with deletion of Gly863 due to a shift in the splice acceptor site (Maugeri et al. 1999. PubMed ID: 10090887). Other common pathogenic variants include c.5882G>A (p.Gln1961Glu), which is likely a founder variant in Somalia (Guymer et al. 2001. PubMed ID: 11346402), and c.5461-10T>C (Sangermano et al. 2016. PubMed ID: 26976702; Cornelis et al. 2017. PubMed ID: 28044389). Although uncommon, uniparental isodisomy has also been reported in AR STGD (Khan et al. 2020. PubMed ID: 32307445; Fingert et al. 2006. PubMed ID: 16682602; Riveiro-Alvarez et al. 2007. PubMed ID: 17277736).

ABCA4 encodes a retina-specific ATP-binding transmembrane transporter, located in the discs of rod and foveal cone outer segments. The protein transports retinoids from photoreceptors to the retinal pigment epithelium (RPE) (Sun and Nathans. 1997. PubMed ID: 9288089). Pathogenic variants in this gene result in failure to transport and lead to the accumulation of lipofuscin fluorophore A2-E (N-retinylidene-N-retinylethanolamine). This product could be deleterious to the RPE, with consequent secondary photoreceptor degeneration due to loss of the RPE support role (Weng et al. 1999. PubMed ID: 10412977). 

Clinical Sensitivity - Sequencing with CNV PGxome

Shroyer et al. (Shroyer. 2001. PubMed ID: 11726554) screened 22 families with both STGD and AMD and detected causative ABCA4 pathogenic variants in 37/46 (80%), which is higher than previous reports (~63%) (Yatsenko et al. 2003. PubMed ID: 12754711). According to Maugeri et al. (2000), ABCA4 also plays a major role in arCRD. Their study detected ABCA4 pathogenic variants in 65% of the patients (13/20), of which 6 had a pathogenic variant in both ABCA4 alleles and 7 had a pathogenic variant in only one of the alleles (Maugeri et al. 2000. PubMed ID: 10958761). Yatsenko et al. (2003) evaluated 192 chromosomes to detect genomic rearrangements and observed one large deletion in ABCA4, IVS17-905_IVS18+35del, which eliminates exon 18. This study suggests that large deletions account for <1% of causative pathogenic variants in ABCA4 (Yatsenko et al. 2003. PubMed ID: 12754711).

Testing Strategy

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This test provides full coverage of all coding exons of the ABCA4 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).

Of note, the following list of deep intronic variants in ABCA4 are tested when a single pathogenic or likely pathogenic variant is identified:

c.161-23T>A, c.570+1798A>G, c.769-784C>T, c.859-506G>C, c.859-540C>G, c.1937+435C>G, c.1938-619A>G, c.2160+584A>G, c.2919-826T>A, c.3050+370C>T, c.4253+43G>A, c.4539+1100A>G, c.4539+2001G>A, c.4539+2028C>T, c.4539+2064C>T, c.5196+1056A>G, c.5196+1136C>A, c.5196+1137G>T, c.5196+1159G>A, c.5196+1216C>A, c. 6006-609T>A, c.6148-471C>T.

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 Stargardt disease (STGD) and fundus flavimaculatus (FFM) are candidates for this test. Also, patients with autosomal (AR) cone-rod dystrophy (arCRD), AR retinitis pigmentosa (ARRP), and age-related macular degeneration (AMD) are candidates. This test may also be considered for the reproductive partners of individuals who carry pathogenic variants in ABCA4.

Gene

Official Gene Symbol OMIM ID
ABCA4 601691
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Citations

  • Allikmets et al. 1997. PubMed ID: 9295268
  • Briggs et al. 2001. PubMed ID: 11527935
  • Cornelis et al. 2017. PubMed ID: 28044389
  • Cremers et al. 1998. PubMed ID: 9466990
  • Fingert et al. 2006. PubMed ID: 16682602
  • Fishman et al. 1987. PubMed ID: 3658351
  • Guymer et al. 2001. PubMed ID: 11346402
  • Kaplan et al. 1993. PubMed ID: 8275096
  • Khan et al. 2020. PubMed ID: 32307445
  • Kong et al. 2008. PubMed ID: 18463687
  • Martínez-Mir et al. 1998. PubMed ID: 9425888
  • Maugeri et al. 1999. PubMed ID: 10090887
  • Riveiro-Alvarez et al. 2007. PubMed ID: 17277736
  • Rivera et al. 2000. PubMed ID: 10958763
  • Rossi et al. 2012. PubMed ID: 23341817
  • Rozet et al. 1998. PubMed ID: 9781034
  • Sangermano et al. 2016. PubMed ID: 26976702
  • Shastry. 2008. PubMed ID: 18506364
  • Shroyer. 2001. PubMed ID: 11726554
  • Sun and Nathans. 1997. PubMed ID: 9288089
  • Weng et al. 1999. PubMed ID: 10412977
  • Yatsenko et al. 2003. PubMed ID: 12754711

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

Specimen Requirements and Shipping Details

PGxome (Exome) Sequencing Panel

PGnome (Genome) Sequencing Panel

loading Loading... ×

ORDER OPTIONS

An error has occurred while calculating the price. Please try again or contact us for assistance.

View Ordering Instructions

1) Select Test Method (Platform)


1) Select Test Type


2) Select Additional Test Options

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

No Additional Test Options are available for this test.

Note: acceptable specimen types are whole blood and DNA from whole blood only.
Total Price: loading
Patient Prompt Pay Price: loading
A patient prompt pay discount is available if payment is made by the patient and received prior to the time of reporting.
Show Patient Prompt Pay Price
×
Copy Text to Clipboard
×