Evidence of the role of ADAMTS18 in ocular development

Abstract

Purpose: To investigate the molecular pathology of two subjects with atypical Knobloch syndrome (KNO) and to describe the detailed ocular phenotype.

Methods: Detailed phenotype data was collected from affected members of one consanguineous Pakistani family with a rare developmental ocular abnormality. Autozygosity mapping and candidate gene sequencing was undertaken.

Results: Two brothers were identified as having with congenital lens opacities. One sibling developed axial myopia and had electrophysiological evidence of a cone rod dystrophy. The other had ectopia lentis, unilateral posterior Staphyloma with contralateral hypermetropia. He subsequently developed bilateral rhegmatogenous retinal detachments. No skull defects were present. Genotyping with Affymetrix SNP6 array© was performed and analysis highlighted 40mB of autozygous DNA with a 6.9mB region in 16q22.2-23.2, a region which included ADAMTS18. Bidirectional sequencing of this gene revealed a novel missense mutation (c.536C>T (p.Ser179Leu) predicted to be pathogenic (SIFT, PolyPhen, Mutation Taster). This is the second report of mutations in ADAMTS18 causing a developmental eye phenotype confirming the role of this gene in Knoblock syndrome.

Conclusions: We report the second ADAMTS18 mutation causing human disease, thus confirming the importance of its role and broadening the understanding of this family of proteins in ocular development.

Keywords: 534 gene mapping