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Autosomal Recessive Isolated Ectopia Lentis-2 via the ADAMTSL4 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
8051 ADAMTSL4 81479 81479,81479 $990 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
8051ADAMTSL481479 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.

EMAIL CONTACTS

Genetic Counselors

Geneticist

  • Dana Talsness, PhD

Clinical Features and Genetics

Clinical Features

Ectopia lentis (EL) is a clinically heterogeneous disorder. EL is characterized by lens subluxation (dislocation) due to instability of the zonular fibers. In the absence of traumatic injury, it occurs with systemic or syndromal diseases such as Marfan syndrome (MFS), homocystinuria, ectopia lentis et pupillae (ELeP) and Weill-Marchesani syndrome (WMS), or can also occur as an isolated condition (Sadiq and Vanderveen 2013). Usually, patients with isolated EL (IEL) have significant loss of visual acuity. Severity depends on the degree of lens subluxation. Other complications include myopia, retinal detachment, cataract and glaucoma (Noble et al. 1993; Dagi and Walton 2006).

EleP is a rare congenital inherited ocular disorder without systemic manifestations. Typically bilateral, with the lens and pupil displaced in opposite directions. Prevalence of this disorder has been reported to be ~ 7% of all IEL. Additional symptoms include megalocornea, increased corneal astigmatism, increased anterior chamber depth, iris transillumination, angle malformation caused by enlarged iris processes, persistent pupillary membrane, loss of zonular fibers, tilted disc, increased axial length and optic nerve hypoplasia (Gupta et al. 1989). Secondary ocular defects include refractive errors, glaucoma, retinal detachment, and early-onset of cataracts (Goldberg 1988).

Genetics

IEL is genetically heterogeneous with both autosomal-dominant (ad) and autosomal–recessive (ar) inheritance. adIEL occurs most frequently and is associated with pathogenic variations in FBN1 (fibrillin-1) gene, which is a major gene for MFS (Please see Test #394). Ectopia Lentis-2 (ECTOL2, arIEL) is caused by pathogenic variations in ADAMTSL4, which encodes A Disintegrin And Metalloproteinase with ThromboSpondin type 1 repeats-Like protease that belongs to the ADAMTS family but lacks proteolytic activity (Apte 2009). ADAMTSL4 is a secreted glycoprotein that localizes to cells and fibrillar extracellular matrix structures of the eye. It binds with fibrillin-1 and may have a role in the development or maintenance of the homeostasis of zonule fibers, which is affected in EL patients (Gabriel et al. 2011). There are ~15 pathogenic variations in ADAMTSL4 that have been associated with ECTOL2 (Human Gene Mutation Database). Genotype-phenotype correlation of IEL patients with sequence variations in FBN1 and ADAMTSL4 indicated that the ADAMTSL4-pathogenic variations produce a more severe ocular phenotype with earlier onset and carry lower cardiovascular risk than those with FBN1 (Chandra et al. 2012).

Clinical Sensitivity - Sequencing with CNV PGxome

FBN1 and ADAMTSL4 mutation screening in a cohort of 36 EL probands (who did not fulfill the Ghent criteria for MFS) identified causative FBN1 variations in 23/36 (64%) and homozygous or compound heterozygous ADAMTSL4 causative variations in 6/36 (17%) (Aragon-Martin et al. 2010). Another mutation screening with four candidate genes (ANXA9, MAN1A2, ADAM30 and ADAMTSL4) revealed a homozygous nonsense mutation in exon 11 of ADAMTSL4 (c.1785T>G) in all affected individuals, which was absent in 380 control chromosomes (Ahram et al. 2009). The presence of a founder mutation (c.759_778del20) in the European population, suggests that screening of ADAMTSL4 should be considered in all patients with isolated ectopia lentis, with or without family history (Neuhann et al. 2010).

Testing Strategy

This test provides full coverage of all coding exons of the ADAMTSL4 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).

In individuals with IEL, who represent simplex cases (i.e. a single occurrence in a family) with unknown mode of inheritance, testing should begin with FBN1 (Rødahl et al. 1993).

Indications for Test

Candidates for this test are patients with symptoms consistent with arIEL/ECTOL2, family members of patients who have known mutations and carrier testing for at-risk family members.

Gene

Official Gene Symbol OMIM ID
ADAMTSL4 610113
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Citations

  • Ahram D, Sato TS, Kohilan A, Tayeh M, Chen S, Leal S, Al-Salem M, El-Shanti H. 2009. A Homozygous Mutation in ADAMTSL4 Causes Autosomal-Recessive Isolated Ectopia Lentis. The American Journal of Human Genetics 84: 274–278. PubMed ID: 19200529
  • Apte SS. 2009. A Disintegrin-like and Metalloprotease (Reprolysin-type) with Thrombospondin Type 1 Motif (ADAMTS) Superfamily: Functions and Mechanisms. Journal of Biological Chemistry 284: 31493–31497. PubMed ID: 19734141
  • Aragon-Martin JA, Ahnood D, Charteris DG, Saggar A, Nischal KK, Comeglio P, Chandra A, Child AH, Arno G. 2010. Role of ADAMTSL4 mutations in FBN1 mutation-negative ectopia lentis patients. Human Mutation 31: E1622–E1631. PubMed ID: 20564469
  • Chandra A, Aragon-Martin JA, Hughes K, Gati S, Reddy MA, Deshpande C, Cormack G, Child AH, Charteris DG, Arno G. 2012. A Genotype-Phenotype Comparison of ADAMTSL4 and FBN1 in Isolated Ectopia Lentis. Investigative Ophthalmology & Visual Science 53: 4889–4896. PubMed ID: 22736615
  • Dagi LR, Walton DS. 2006. Anterior axial lens subluxation, progressive myopia, and angle-closure glaucoma: recognition and treatment of atypical presentation of ectopia lentis. J AAPOS 10: 345–350. PubMed ID: 16935236
  • Gabriel LAR, Wang LW, Bader H, Ho JC, Majors AK, Hollyfield JG, Traboulsi EI, Apte SS. 2011. ADAMTSL4, a Secreted Glycoprotein Widely Distributed in the Eye, Binds Fibrillin-1 Microfibrils and Accelerates Microfibril Biogenesis. Investigative Ophthalmology & Visual Science 53: 461–469. PubMed ID: 21989719
  • Goldberg MF. 1988. Clinical manifestations of ectopia lentis et pupillae in 16 patients. Transactions of the American Ophthalmological Society 86: 158. PubMed ID: 2979048
  • Gupta NK, Ayra AV, Azad R. 1989. Ectopia lentis et pupillae. Indian J Ophthalmol 37: 32–34. PubMed ID: 2807501
  • Human Gene Mutation Database (Bio-base).
  • Neuhann TM, Artelt J, Neuhann TF, Tinschert S, Rump A. 2010. A Homozygous Microdeletion within ADAMTSL4 in Patients with Isolated Ectopia Lentis: Evidence of a Founder Mutation. Investigative Ophthalmology & Visual Science 52: 695–700. PubMed ID: 21051722
  • Noble KG, Bass S, Sherman J. 1993. Ectopia lentis, chorioretinal dystrophy and myopia. A new autosomal recessive syndrome. Doc Ophthalmol 83: 97–102. PubMed ID: 8334934
  • Rødahl E, Christensen AE, Fiskerstrand T, Knappskog PM, Boman H. 2012. ADAMTSL4-Related Eye Disorders. In: Pagon RA, Adam MP, Bird TD, Dolan CR, Fong C-T, and Stephens K, editors. GeneReviewsTM, Seattle (WA): University of Washington, Seattle. PubMed ID: 22338190
  • Sadiq MA, Vanderveen D. 2013. Genetics of ectopia lentis. Semin Ophthalmol 28: 313–320. PubMed ID: 24138040

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

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