Autosomal Recessive Isolated Ectopia Lentis-2 via the ADAMTSL4 Gene

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).

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).

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).