Forms

Autosomal Dominant Stargardt disease (STGD3) via the ELOVL4 Gene

  • Summary and Pricing
  • Clinical Features and Genetics
  • Citations
  • Methods
  • Ordering/Specimens
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TEST METHODS

Sequencing

Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
1848 ELOVL4$610.00 81479 Add to Order
Targeted Testing

For ordering targeted known variants, please proceed to our Targeted Variants landing page.

Turnaround Time

The great majority of tests are completed within 18 days.

Clinical Sensitivity
Clinical sensitivity cannot be precisely estimated as the adSTGD is not very common. Analytical sensitivity should be high because all mutations reported are detectable by this method. No gross deletions or duplications have been reported so far (Human Gene Mutation Database).

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Clinical Features
Stargardt disease (STGD) is a juvenile onset form of macular dystrophy/degeneration (MD) characterized by loss of photoreceptor cells in the macula, resulting in a severe reduction of central vision with a variable phenotype and a variable age of onset and severity. STGD is considered one of the most frequent causes of MD in childhood, accounting for approximately 7% of all retinal degenerative diseases (RDDs) with an estimated prevalence of 1 in 10,000 and a carrier frequency of 2% (Shastry 2008). Clinical features include progressive bilateral degeneration of the macula and retinal pigment epithelium (RPE) with characteristic orange-yellow flecks located around the macula or the mid peripheral retina (Rossi et al. 2012). The hallmark of STGD is massive accumulation of cellular debris, presumably lipofuscin in the RPE (usually seen in normal aging human eyes) (Fishman et al. 1987), which is clinically similar to fundus flavimaculatus (FFM) that has a later age of onset (20-64 years) and slower progression or milder visual loss compared to STGD (Kaplan et al. 1993). Genetic analysis suggests that STGD and FFM are allelic disorders with slightly different clinical manifestations (Shastry 2008).

ELOVL4-associated STGD (STGD3) is clinically similar to STGD, with the exception of the pattern of inheritance (Stone et al. 1994).
Genetics
STGD is usually inherited in an autosomal recessive (ar) manner and, less commonly, as an autosomal dominant (ad) trait (Rossi et al. 2012). The common STGD form is caused by recessive mutations in the ABCA4 gene and the rare ad form STGD3 is due to mutations in the ELOVL4 gene (Vasireddy et al. 2010). A ELOVL4 mutational screening a large independent pedigree affected by an autosomal dominant macular dystrophy detected an ELOVL4 mutation in all affected members, which was absent in in healthy control individuals (Bernstein et al. 2001). Another study in two adSTGD affected patients detected an ELOVL4 mutation in both, which was absent in in 96 healthy control individuals (Maugeri 2004). ELOVL4, which is located on chromosome 6, is predicted to encode an enzyme involved in the elongation of very long-chain fatty acids (ELOVL). This enzyme is highly expressed in photoreceptor cells. Mouse mutant studies suggested that the mutations in ELOVL4 leads to photoreceptor degeneration (Karan et al. 2005). So far, about 5 mutations (Missense/nonsense, small deletions and small indels) have been reported in ELOVL4 that are involved in the STGD phenotype (Human Gene Mutation Database).
Testing Strategy
This test involves bidirectional DNA Sanger sequencing of all coding exons and ~ 20 bp of flanking noncoding sequence of ELOVL4 gene. We will also sequence any single exon (Test #100) in family members of patients with a known mutation or to confirm research results.
Indications for Test
All patients with symptoms suggestive of Stargardt disease (STGD) are candidates.

Gene

Official Gene Symbol OMIM ID
ELOVL4 605512
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Disease

Name Inheritance OMIM ID
Stargardt Disease 3 600110

CONTACTS

Genetic Counselors
Geneticist
Citations
  • Bernstein PS, Tammur J, Singh N, Hutchinson A, Dixon M, Pappas CM, Zabriskie NA, Zhang K, Petrukhin K, Leppert M, others. 2001. Diverse macular dystrophy phenotype caused by a novel complex mutation in the ELOVL4 gene. Investigative ophthalmology & visual science 42: 3331–3336. PubMed ID: 11726641
  • Fishman GA, Farber M, Patel BS, Derlacki DJ. 1987. Visual acuity loss in patients with Stargardt’s macular dystrophy. Ophthalmology 94: 809–814. PubMed ID: 3658351
  • Human Gene Mutation Database (Bio-base).
  • Kaplan J, Gerber S, Larget-Piet D, Rozet JM, Dollfus H, Dufier JL, Odent S, Postel-Vinay A, Janin N, Briard ML. 1993. A gene for Stargardt’s disease (fundus flavimaculatus) maps to the short arm of chromosome 1. Nat. Genet. 5: 308–311. PubMed ID: 8275096
  • Karan G, Lillo C, Yang Z, Cameron DJ, Locke KG, Zhao Y, Thirumalaichary S, Li C, Birch DG, Vollmer-Snarr HR, others. 2005. Lipofuscin accumulation, abnormal electrophysiology, and photoreceptor degeneration in mutant ELOVL4 transgenic mice: a model for macular degeneration. Proceedings of the National Academy of Sciences of the United States of America 102: 4164–4169. PubMed ID: 15749821
  • Maugeri A. 2004. A Novel Mutation in the ELOVL4 Gene Causes Autosomal Dominant Stargardt-like Macular Dystrophy. Investigative Ophthalmology & Visual Science 45: 4263–4267. PubMed ID: 15557430
  • Rossi S, Testa F, Attanasio M, Orrico A, Benedictis A de, Della Corte M, Simonelli F. 2012. Subretinal Fibrosis in Stargardt’s Disease with Fundus Flavimaculatus and ABCA4 Gene Mutation. Case reports in ophthalmology 3: 410–417. PubMed ID: 23341817
  • 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
  • Stone EM, Nichols BE, Kimura AE, Weingeist TA, Drack A, Sheffield VC. 1994. Clinical features of a Stargardt-like dominant progressive macular dystrophy with genetic linkage to chromosome 6q. Arch. Ophthalmol. 112: 765–772. PubMed ID: 8002834
  • Vasireddy V, Wong P, Ayyagari R. 2010. Genetics and molecular pathology of Stargardt-like macular degeneration. Progress in Retinal and Eye Research 29: 191–207. PubMed ID: 20096366
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TEST METHODS

Bi-Directional Sanger Sequencing

Test Procedure

Nomenclature for sequence variants was from the Human Genome Variation Society (http://www.hgvs.org).  As required, DNA is extracted from the patient specimen.  PCR is used to amplify the indicated exons plus additional flanking non-coding sequence.  After cleaning of the PCR products, cycle sequencing is carried out using the ABI Big Dye Terminator v.3.0 kit.  Products are resolved by electrophoresis on an ABI 3730xl capillary sequencer.  In most cases, sequencing is performed in both forward and reverse directions; in some cases, sequencing is performed twice in either the forward or reverse directions.  In nearly all cases, the full coding region of each exon as well as 20 bases of non-coding DNA flanking the exon are sequenced.

Analytical Validity

As of March 2016, we compared 17.37 Mb of Sanger DNA sequence generated at PreventionGenetics to NextGen sequence generated in other labs. We detected only 4 errors in our Sanger sequences, and these were all due to allele dropout during PCR. For Proficiency Testing, both external and internal, in the 12 years of our lab operation we have Sanger sequenced roughly 8,800 PCR amplicons. Only one error has been identified, and this was due to sequence analysis error.

Our Sanger sequencing is capable of detecting virtually all nucleotide substitutions within the PCR amplicons. Similarly, we detect essentially all heterozygous or homozygous deletions within the amplicons. Homozygous deletions which overlap one or more PCR primer annealing sites are detectable as PCR failure. Heterozygous deletions which overlap one or more PCR primer annealing sites are usually not detected (see Analytical Limitations). All heterozygous insertions within the amplicons up to about 100 nucleotides in length appear to be detectable. Larger heterozygous insertions may not be detected. All homozygous insertions within the amplicons up to about 300 nucleotides in length appear to be detectable. Larger homozygous insertions may masquerade as homozygous deletions (PCR failure).

Analytical Limitations

In exons where our sequencing did not reveal any variation between the two alleles, we cannot be certain that we were able to PCR amplify both of the patient’s alleles. Occasionally, a patient may carry an allele which does not amplify, due for example to a deletion or a large insertion. In these cases, the report contains no information about the second allele.

Similarly, our sequencing tests have almost no power to detect duplications, triplications, etc. of the gene sequences.

In most cases, only the indicated exons and roughly 20 bp of flanking non-coding sequence on each side are analyzed. Test reports contain little or no information about other portions of the gene, including many regulatory regions.

In nearly all cases, we are unable to determine the phase of sequence variants. In particular, when we find two likely causative mutations for recessive disorders, we cannot be certain that the mutations are on different alleles.

Our ability to detect minor sequence variants, due for example to somatic mosaicism is limited. Sequence variants that are present in less than 50% of the patient’s nucleated cells may not be detected.

Runs of mononucleotide repeats (eg (A)n or (T)n) with n >8 in the reference sequence are generally not analyzed because of strand slippage during PCR and cycle sequencing.

Unless otherwise indicated, the sequence data that we report are based on DNA isolated from a specific tissue (usually leukocytes). Test reports contain no information about gene sequences in other tissues.

Order Kits

Ordering Options


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.

SPECIMEN TYPES
WHOLE BLOOD

(Delivery accepted Monday - Saturday)

  • Collect 3 ml -5 ml (5 ml preferred) of whole blood in EDTA (purple top tube) or ACD (yellow top tube). For Test #500-DNA Banking only, collect 10 ml -20 ml of whole blood.
  • For small babies, we require a minimum of 1 ml of blood.
  • Only one blood tube is required for multiple tests.
  • Ship blood tubes at room temperature in an insulated container. Do not freeze blood.
  • During hot weather, include a frozen ice pack in the shipping container. Place a paper towel or other thin material between the ice pack and the blood tube.
  • In cold weather, include an unfrozen ice pack in the shipping container as insulation.
  • At room temperature, blood specimen is stable for up to 48 hours.
  • If refrigerated, blood specimen is stable for up to one week.
  • Label the tube with the patient name, date of birth and/or ID number.

DNA

(Delivery accepted Monday - Saturday)

  • Send in screw cap tube at least 5 µg -10 µg of purified DNA at a concentration of at least 20 µg/ml for NGS and Sanger tests and at least 5 µg of purified DNA at a concentration of at least 100 µg/ml for gene-centric aCGH, MLPA, and CMA tests, minimum 2 µg for limited specimens.
  • For requests requiring more than one test, send an additional 5 µg DNA per test ordered when possible.
  • DNA may be shipped at room temperature.
  • Label the tube with the composition of the solute, DNA concentration as well as the patient’s name, date of birth, and/or ID number.
  • We only accept genomic DNA for testing. We do NOT accept products of whole genome amplification reactions or other amplification reactions.

CELL CULTURE

(Delivery preferred Monday - Thursday)

  • PreventionGenetics should be notified in advance of arrival of a cell culture.
  • Culture and send at least two T25 flasks of confluent cells.
  • Some panels may require additional flasks (dependent on size of genes, amount of Sanger sequencing required, etc.). Multiple test requests may also require additional flasks. Please contact us for details.
  • Send specimens in insulated, shatterproof container overnight.
  • Cell cultures may be shipped at room temperature or refrigerated.
  • Label the flasks with the patient name, date of birth, and/or ID number.
  • We strongly recommend maintaining a local back-up culture. We do not culture cells.
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