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Andrea L Vincent, Will Ikink, Rasha Al Taie; Investigation of the Role of ADAMTSL4 in an atypical Marfan syndrome population. Invest. Ophthalmol. Vis. Sci. 2014;55(13):6436.
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© ARVO (1962-2015); The Authors (2016-present)
To characterise the role of the ADAMTSL4 gene in a population of patients classified as aypical Marfan syndrome (MFS)- i.e.had some Marfanoid features, did not meet the Ghent criteria for MFS, and/or were FBN1 negative.
Subjects were clinically characterised, including corneal topography with both Orbscan and Pentacam. DNA samples were collected. Mutational analysis of the coding exons and bordering intronic regions of ADAMTSL4 was undertaken with PCR and bidirectional Sanger sequencing. Subsequent bioinformatic and in silico analysis of putative changes was performed. Family members were recruited for segregation analysis.
Mutational analysis of ADAMTSL4 in 27 probands with atypical MFS identified autosomal recessive inheritance in 4/27 ( 15%) - 3 homozygous, 1 compound heterozygote. The phenotype was of predominantly ectopia lentis, with lens subluxation inferotemporal in 50% of eyes, and zonules intact. The common 20bp deletion was observed in one patient, in combination with the novel p.Arg746His which affects the TSP1 domain. p.Arg746His was present homozygously in the 3 other probands, of mixed ethnicity, ( Cook Island Maori, NZ Maori and Caucasian) All were diagnosed by the age of 5. In one family, segrgation analysis was possible. A further 4 probands had one pathogenic heterozygous change present.The phenotype in this group was generally mild lens subluxation, with a tendency to flat corneas, and all had a mild cardiac abnormality (Patent ductus ateriosus, mitral valve, aortic valve or both mitral and aortic vlave abnormalitiy)
ADAMTSL4 mutations accounted for recessive inheritance in 15% of the cohort with atypical MFS. The recessive cases tend to have an early onset of significant lens subluxation and a paucity of other systemic features, consistent with previous reports of ADAMTSL4 mutations. A novel mutation occuring in the TSP1 domain occured in multiple ethnic groups. A further 15% with one heterozygous change had a more mild phenotype. ADAMTSL4 may contribute to the atypical Marfanoid phenotype, independent of its role in recessive ectopia lentis.
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