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Brief Report |

Expansion of Ocular Phenotypic Features Associated With Mutations in ADAMTS18

Aman Chandra, MRCSEd, FRCOphth, PhD1,2,3; Gavin Arno, PhD1; Kathleen Williamson, PhD4; Panagiotis I. Sergouniotis, PhD1,3; Markus N. Preising, PhD5; David G. Charteris, FRCOphth2; Dorothy A. Thompson, PhD6; Graham E. Holder, PhD1,7; Arundhati Dev Borman, MRCOphth1,3; Indran Davagnanam, FRCR8; Andrew R. Webster, FRCOphth1,3; Birgit Lorenz, FEBO5; David R. FitzPatrick, FRCP (Edin)4; Anthony T. Moore, FRCOphth1,3,6
[+] Author Affiliations
1University College London Institute of Ophthalmology, London, England
2Vitreoretinal Department, Moorfields Eye Hospital, London, England
3Professorial Unit, Moorfields Eye Hospital, London, England
4Medical Research Council Human Genetics Unit, University of Edinburgh, Western General Hospital, Edinburgh, Scotland
5Department of Ophthalmology, Justus-Liebig University, Giessen, Germany
6Clinical and Academic Department of Ophthalmology, Great Ormond Street Hospital for Children, London, England
7Electrodiagnostics, Moorfields Eye Hospital, London, England
8Radiology, Moorfields Eye Hospital, London, England
JAMA Ophthalmol. 2014;132(8):996-1001. doi:10.1001/jamaophthalmol.2014.940.
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Importance  We describe novel ocular phenotypic features caused by mutations in ADAMTS18. The exact role of ADAMTS18 in ocular disease is unclear, and our work further contributes to the understanding of this gene and its protein.

Objective  To expand the phenotypic characterization in patients with homozygous mutations in ADAMTS18 and report novel mutational data.

Design, Setting, and Participants  A case series with genetic investigations was conducted at tertiary referral clinical and university settings. Three families participated.

Main Outcome Measures  Phenotype and genotype description of 3 families.

Results  Four affected patients from 3 families with an unusual ocular phenotype had full ophthalmic and systemic examination. A single affected individual in the first family had bilateral microcornea, ectopic pupils, and cone-rod dystrophy. In a second family, 2 brothers showed bilateral microcornea, childhood cataract, ectopia lentis, rhegmatogenous retinal detachment, and cone-rod dystrophy. In the third family, a single affected individual had the same features as those in family 2, without ectopia lentis. Causative mutations were sought using homozygosity mapping, Sanger sequencing, and massively parallel sequencing of the whole exome. Novel homozygous mutations in ADAMTS18 were identified, consisting of c.1067T>A [p.L356*] in the first proband, c.2159G>C [p.C720S] in the 2 affected brothers, and c.1952G>A [p.R651Q] in the third proband. All 3 mutations are predicted to be pathogenic.

Conclusions and Relevance  Mutations in ADAMTS18 are associated with ocular developmental abnormalities including microcornea, ectopia lentis, and early onset of cone-rod dystrophy. This report provides further evidence that ADAMTS18 plays a key role in ocular development. Physicians should consider screening ADAMTS18 in patients with microcornea and cone-rod dystrophy.

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Figure 1.
Pedigrees and Mutations

Pedigrees and sequence chromatographs demonstrating mutations in family 1 (c.1067T>A [p.L356*]) (A and B), family 2 (c.2159G>C [p.C720S]) (C and D), and family 3 (c.1952G>A [p.R651Q] ) (E and F). In the pedigrees, square symbols indicate males; circles, females; diamond, either sex; slashes within the squares and circles, individuals who have died; and double connecting lines, consanguinity. Black symbols indicate affected individuals and arrowheads indicate probands. The numbers within the circles, squares, and diamonds indicate the number of members of that sex. In the sequence chromatographs, arrowheads indicate mutations. WT indicates wild type.

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Figure 2.
Fundal and Anterior Segment Images of Probands in Family 2 and Family 3

A, Anterior segment of II:1 (family 2), illustrating microcornea. B, Fundus image of II:1 (family 2), illustrating chorioretinal atrophy. C, Anterior segment of II:1 (family 3), illustrating microcornea and central punctate cataracts. D, Fundus image of II:1 (family 3), illustrating chorioretinal atrophy.

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