Aman Chandra1, Gavin Arno2, Kathleen Williamson3, Panagiotis I Sergouniotis4, Markus N Preising5, David G Charteris6, Dorothy A Thompson7, Graham E Holder8, Arundhati Dev Borman4, Indran Davagnanam9, Andrew R Webster4, Birgit Lorenz5, David R FitzPatrick3, Anthony T Moore10. 1. University College London Institute of Ophthalmology, London, England2Vitreoretinal Department, Moorfields Eye Hospital, London, England3Professorial Unit, Moorfields Eye Hospital, London, England. 2. University College London Institute of Ophthalmology, London, England. 3. Medical Research Council Human Genetics Unit, University of Edinburgh, Western General Hospital, Edinburgh, Scotland. 4. University College London Institute of Ophthalmology, London, England3Professorial Unit, Moorfields Eye Hospital, London, England. 5. Department of Ophthalmology, Justus-Liebig University, Giessen, Germany. 6. Vitreoretinal Department, Moorfields Eye Hospital, London, England. 7. Clinical and Academic Department of Ophthalmology, Great Ormond Street Hospital for Children, London, England. 8. University College London Institute of Ophthalmology, London, England7Electrodiagnostics, Moorfields Eye Hospital, London, England. 9. Radiology, Moorfields Eye Hospital, London, England. 10. University College London Institute of Ophthalmology, London, England3Professorial Unit, Moorfields Eye Hospital, London, England6Clinical and Academic Department of Ophthalmology, Great Ormond Street Hospital for Children, London, England.
Abstract
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.
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.
Authors: Joe Rainger; Kathleen A Williamson; Dinesh C Soares; Julia Truch; Dominic Kurian; Gabriele Gillessen-Kaesbach; Anne Seawright; James Prendergast; Mihail Halachev; Ann Wheeler; Lynn McTeir; Andrew C Gill; Veronica van Heyningen; Megan G Davey; David R FitzPatrick Journal: Hum Mutat Date: 2017-06-06 Impact factor: 4.878
Authors: Valentina Cipriani; Raquel S Silva; Gavin Arno; Nikolas Pontikos; Ambreen Kalhoro; Sandra Valeina; Inna Inashkina; Mareta Audere; Katrina Rutka; Bernard Puech; Michel Michaelides; Veronica van Heyningen; Baiba Lace; Andrew R Webster; Anthony T Moore Journal: Sci Rep Date: 2017-08-08 Impact factor: 4.379
Authors: Bret A Moore; Brian C Leonard; Lionel Sebbag; Sydney G Edwards; Ann Cooper; Denise M Imai; Ewan Straiton; Luis Santos; Christopher Reilly; Stephen M Griffey; Lynette Bower; David Clary; Jeremy Mason; Michel J Roux; Hamid Meziane; Yann Herault; Colin McKerlie; Ann M Flenniken; Lauryl M J Nutter; Zorana Berberovic; Celeste Owen; Susan Newbigging; Hibret Adissu; Mohammed Eskandarian; Chih-Wei Hsu; Sowmya Kalaga; Uchechukwu Udensi; Chinwe Asomugha; Ritu Bohat; Juan J Gallegos; John R Seavitt; Jason D Heaney; Arthur L Beaudet; Mary E Dickinson; Monica J Justice; Vivek Philip; Vivek Kumar; Karen L Svenson; Robert E Braun; Sara Wells; Heather Cater; Michelle Stewart; Sharon Clementson-Mobbs; Russell Joynson; Xiang Gao; Tomohiro Suzuki; Shigeharu Wakana; Damian Smedley; J K Seong; Glauco Tocchini-Valentini; Mark Moore; Colin Fletcher; Natasha Karp; Ramiro Ramirez-Solis; Jacqueline K White; Martin Hrabe de Angelis; Wolfgang Wurst; Sara M Thomasy; Paul Flicek; Helen Parkinson; Steve D M Brown; Terrence F Meehan; Patsy M Nishina; Stephen A Murray; Mark P Krebs; Ann-Marie Mallon; K C Kent Lloyd; Christopher J Murphy; Ala Moshiri Journal: Commun Biol Date: 2018-12-21