Confirmation of ADAMTSL4 mutations for autosomal recessive isolated bilateral Ectopia Lentis
ABSTRACT Ectopia lentis (EL) is a zonular disease where alteration of the zonular fibers leads progressively to lens dislocation. It is most often associated with systemic diseases such as Marfan syndrome, Weill-Marchesani syndrome or homocystinuria. Isolated non syndromic ectopia lentis (IEL) is reported in families with autosomal inheritance, with dominant forms being more common than recessive. LTBP2 truncating mutations have been described as a cause of autosomal recessive ectopia lentis as a primary or secondary feature in patients showing ocular (eg, glaucoma) or extraocular manifestations (eg, Marfanoid habitus). Recently, ADAMTSL4 has been shown to be responsible for isolated autosomal recessive ectopia lentis in an inbred family. Herein we show a consanguineous family that carries a novel homozygous splice mutation IVS4-1G>A/IVS4-1G>A in ADAMTSL4 responsible for isolated autosomal recessive EL, thus confirming the involvement of this gene in this condition and underlining the major role of ADAMTS proteases in zonular fibers homeostasis.
- SourceAvailable from: Teresa M Neuhann
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- "Elongation of the globes additionally is a risk factor for retinal detachment, which has been described in patients with ADAMTSL4 mutations [Ahram et al., 2009; Neuhann et al., 2011] (this report). Other ocular features that are commonly described are abnormalities of the iris and pupil, especially ectopia pupillae ([Aragon- Martin et al., 2010; Christensen et al., 2010; Sharifi et al., 2013], this report) but also pupillary membranes [Sharifi et al., 2013] (this report) and synechiae [Greene et al., 2010]. Taken together, ADAMTSL4 mutations do not only cause zonular weakness with ensuing lens dislocation but can also manifest with alterations of the lens (cataract, coloboma) as well as anterior segment structures (ectopia pupillae, pupillary membranes). "
ABSTRACT: ADAMTSL4 mutations seem to be the most common cause of isolated ectoplia lentis (EL) and thus are important concerning the differential diagnosis of connective tissue syndromes with EL as main feature. In this study, we describe an additional cohort of patients with apparently isolated EL. All underwent a detailed clinical exam with cardiac evaluation combined with ADAMTSL4 mutation analysis. Mutations were identified in 12/15 patients with EL. Besides the European founder mutation p. (Gln256Profs*38) we identified five further mutations not yet described in the literature: p. (Leu249Tyrfs*21), p. (Ala388Glyfs*8), p. (Arg746His), p. (Gly592Ser), and p. (Arg865His). Clinical evaluation showed common additional ocular features such as high myopia, but no major systemic findings. In particular: no dilatation of the aortic root was reported on. This report increases the total number of patients with ADAMTSL4 mutations reported on today and reviews in detail the clinical findings in all patients reported on to date demonstrate, that these patients have a mainly ocular phenotype. There are no consistent systemic findings. The differentiation between syndromic and isolated EL is crucial for the further surveillance, treatment, and counseling of these patients, especially in young children. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.American Journal of Medical Genetics Part A 05/2015; DOI:10.1002/ajmg.a.37157 · 2.05 Impact Factor
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- "TABLE 3 . Published Mutations in ADAMTSL4 Causing EL Exon / Intron Mutation Reference Exon 11 c . 1785T / G Ahram et al . 13 ( 2009 ) Intron 4 IVS4 - 1G>A Greene et al . 14 ( 2010 ) Exon 5 c . 293delG This study c . 237delC This study Exon 6 c . 767_786del Aragon - Martin et al . 15 ( 2010 ) Neuhann et al . 16 ( 2011 ) Christensen et al . 17 ( 2010 ) c . 826_836del Aragon - Martin et al . 15 ( 2010 ) c . 926G>A Aragon - Martin et al . 15 ( 2010 ) c . 925C>T This study Exon 12 c . 2008C>T Aragon - Martin et al . 1"
ABSTRACT: To describe the genotype-phenotype relationship of a cohort of consecutive patients with isolated ectopia lentis (EL) secondary to ADAMTSL4 and FBN1 mutations. Patients underwent detailed ocular, cardiovascular, and skeletal examination. This was correlated with Sanger sequencing of ADAMTSL4 and FBN1 genes. Seventeen patients were examined, including one with ectopia lentis et pupillae. Echocardiography and skeletal examination revealed no sign of systemic disorders associated with EL, in particular Marfan syndrome (MFS). Nine patients (52.9%) were found to have mutations in ADAMTSL4, including four novel nonsense mutations. Four patients (25%) were found to have novel FBN1 mutations, not previously reported as causing classical Marfan syndrome. One additional patient was found to have an FBN1 mutation previously reported in classical MFS. Four patients (25%) were found to have no mutations in either gene. Median age of diagnosis of EL was 35 years in patients with FBN1 mutations and 2 years in patients with ADAMTSL4 mutations (P < 0.01). Mean axial length was 22.74 mm (95% confidence interval [CI]: 21.3-24.2) (FBN1) and 27.54 mm (95% CI: 24.2-30.9) (ADAMTSL4) (P < 0.01). Other ophthalmic features, including corneal thickness and power, foveal thickness, visual acuity, and direction of lens displacement, were similar for both groups. ADAMTSL4 is the most important known causative gene in isolated EL. Mutations in ADAMTSL4 appear to cause earlier manifestation of EL and are associated with increased axial length as compared to FBN1. We suggest that ADAMTSL4 be screened in all patients with isolated EL and that physicians be vigilant for the more severe ocular phenotype associated with mutations in this gene.Investigative ophthalmology & visual science 06/2012; 53(8):4889-96. DOI:10.1167/iovs.12-9874 · 3.66 Impact Factor
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- "This family showed variable degrees of lens displacement among affected members with deprivation amblyopia, retinal detatchment and cataract but no manifestations in any other system. A second study has identified a distinct ADAMTSL4 mutation in a consanguineous Turkish family affected by isolated EL (Greene, et al., 2010). The mutation abolishes the splice acceptor site in intron 4 leading to deletion of c.79 to c.344 of exon 5 and introduction of a PTC due to a frameshift. "
ABSTRACT: Ectopia lentis (EL) is genetically heterogeneous with both autosomal-dominant and -recessive forms. The dominant disorder can be caused by mutations in FBN1, at the milder end of the type-1 fibrillinopathies spectrum. Recently in a consanguineous Jordanian family, recessive EL was mapped to locus 1q21 containing the ADAMTSL4 gene and a nonsense mutation was found in exon 11 (c.1785T>G, p.Y595X). In this study, 36 consecutive probands with EL who did not fulfill the Ghent criteria for MFS were screened for mutations in FBN1 and ADAMTSL4. Causative FBN1 mutations were identified in 23/36 (64%) of probands while homozygous or compound heterozygous ADAMTSL4 mutations were identified in 6/12 (50%) of the remaining probands. Where available, familial screening of these families confirmed the mutation co-segregated with the EL phenotype. This study confirms that homozygous mutations in ADAMTSL4 are associated with autosomal-recessive EL in British families. Furthermore; the first compound heterozygous mutation is described resulting in a PTC and a missense mutation in the PLAC (protease and lacunin) domain. The identification of a causative mutation in ADAMTSL4 may allow the exclusion of Marfan syndrome in these families and guide the clinical management, of particular relevance in young children affected by EL.Human Mutation 08/2010; 31(8):E1622-31. DOI:10.1002/humu.21305 · 5.05 Impact Factor