Autosomal Recessive Isolated Ectopia Lentis-2 via the ADAMTSL4 Gene

  • Summary and Pricing
  • Clinical Features and Genetics
  • Citations
  • Methods
  • Ordering/Specimens
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Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
1542 ADAMTSL4$1190.00 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

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).

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Deletion/Duplication Testing via aCGH

Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
600 ADAMTSL4$690.00 81479 Add to Order
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Turnaround Time

The great majority of tests are completed within 28 days.

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).


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).

Testing Strategy

This test involves bidirectional DNA Sanger sequencing of all coding exons and ~10 bp of flanking noncoding sequence of the ADAMTSL4 gene. We will also sequence any single exon (Test #100) or pair of exons (Test #200) in family members of patients with known mutations or to confirm research results. 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 (Test #394) (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.


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


Genetic Counselors
  • 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
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Bi-Directional Sanger Sequencing

Test Procedure

Nomenclature for sequence variants was from the Human Genome Variation Society (  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 10 bases of non-coding DNA flanking the exon are sequenced.

Analytical Validity

As of February 2018, we compared 26.8 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 14 years of our lab operation we have Sanger sequenced roughly 14,300 PCR amplicons. Only one error has been identified, and this was an error in analysis of sequence data.

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 10 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.

Deletion/Duplication Testing via Array Comparative Genomic Hybridization

Test Procedure

Equal amounts of genomic DNA from the patient and a gender matched reference sample are amplified and labeled with Cy3 and Cy5 dyes, respectively. To prevent any sample cross contamination, a unique sample tracking control is added into each patient sample. Each labeled patient product is then purified, quantified, and combined with the same amount of reference product. The combined sample is loaded onto the designed array and hybridized for at least 22-42 hours at 65°C. Arrays are then washed and scanned immediately with 2.5 µM resolution. Only data for the gene(s) of interest for each patient are extracted and analyzed.

Analytical Validity

PreventionGenetics' high density gene-centric custom designed aCGH enables the detection of relatively small deletions and duplications within a single exon of a given gene or deletions and duplications encompassing the entire gene. PreventionGenetics has established and verified this test's accuracy and precision.

Analytical Limitations

Our dense probe coverage may allow detection of deletions/duplications down to 100 bp; however due to limitations and probe spacing this cannot be guaranteed across all exons of all genes. Therefore, some copy number changes smaller than 100-300 bp within a targeted large exon may not be detected by our array.

This array may not detect deletions and duplications present at low levels of mosaicism or those present in genes that have pseudogene copies or repeats elsewhere in the genome.

aCGH will not detect balanced translocations, inversions, or point mutations that may be responsible for the clinical phenotype.

Breakpoints, if occurring outside the targeted gene, may be hard to define.

The sensitivity of this assay may be reduced when DNA is extracted by an outside laboratory.

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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.
  • 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.


(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.


(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.


(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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