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Colin E Willoughby, Chitra Sambare, Judith Lechner, Vidya Chelerkar, Kalyani Sodimall, Milind Killedar, Sangeeta Malani, Sagarika Patyal, David Armstrong, Madan Deshpande; Genetically-directed targeted clinical surveillance in juvenile open angle glaucoma.. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):2543.
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The aim of this study was to determine the mutational load associated with myocilin (MYOC; MIM*601652) mutations in patients with juvenile open angle glaucoma (JOAG).
JOAG patients and normal ethnically and age-matched control subjects were recruited following careful phenotyping from the Departments of Ophthalmology in Belfast (UK) and Pune (India). All of the 3 coding exons and flanking introns of the MYOC gene were Sanger sequenced in 23 JOAG patients and 89 control subjects. Deleterious structural effects of amino acid substitutions on protein function were assessed using a suite of bioinformatics approaches. In patients with a family history of JOAG potential disease-causing variants were assessed for segregation.
2/23 (8.7%) JOAG had pathogenic MYOC mutations. In one three generation Northern Irish family a previously identified myocilin mutation (c.1109C>T; p.P370L) was detected in all affected family members. This mutation accounts for 3.9% of myocilin related JOAG and POAG. In a two generation Indian family the proband, a 32yr old female patient with severe JOAG phenotype, had two MYOC mutations (compound heterozygote) (absent from 156 control chromosomes); one previously reported as pathogenic (c.1279G>A; p.Ala427Thr) and one novel MYOC change (c.1129A>G; p.Thr377Ala). Pathogenic mutations at codon 377 in MYOC have been previously reported in JOAG (p. Thr377Met, p.Thr377Lys and p.Thr377Arg). The affected patient had three children and MYOC was sequenced within the family. The compound heterozygote MYOC mutation (p.Ala427Thr/p.Thr377Ala) was inherited by two children (sisters aged 9 and 11) and these children are now under closer clinical surveillance to detect the onset of glaucoma early, instigate timely and appropriate treatment, and hopefully prevent blindness.
Cascade screening following the detection of these MYOC mutations in JOAG has identified at risk family members and directed targeted clinical surveillance. Genetic screening for myocilin mutations in JOAG can direct health care, especially in India where access to clinics and doctors can be limited. We feel myocilin genetic testing should form part of the routine clinical care of JOAG patients and their families.
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