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Identification and functional characterisation of genetic variants in OLFM2 in children with developmental eye disorders


Anophthalmia, microphthalmia, and coloboma are a genetically heterogeneous spectrum of developmental eye disorders and affect around 30 per 100,000 live births. OLFM2 encodes a secreted glycoprotein belonging to the noelin family of olfactomedin domain-containing proteins that modulate the timing of neuronal differentiation during development. OLFM2 SNPs have been associated with open angle glaucoma in a case–control study, and knockdown of Olfm2 in zebrafish results in reduced eye size. From a cohort of 258 individuals with developmental eye anomalies, we identified two with heterozygous variants in OLFM2: an individual with bilateral microphthalmia carrying a de novo 19p13.2 microdeletion involving OLFM2 and a second individual with unilateral microphthalmia and contralateral coloboma who had a novel single base change in the 5′ untranslated region. Dual luciferase assays demonstrated that the latter variant causes a significant decrease in expression of OLFM2. Furthermore, RNA in situ hybridisation experiments using human developmental tissue revealed expression in relevant structures, including the lens vesicle and optic cup. Our study indicates that OLFM2 is likely to be important in mammalian eye development and disease and should be considered as a gene for human ocular anomalies.

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We would like to thank the patients and their families for their participation in our study. We are grateful to the following: Youming Zhang, Imperial College London, for contributing vectors; Stephanie Halford, University of Oxford, for providing cDNA and cell lines; Andrew Gallagher (paediatrician), Worcestershire Royal Hospital for initial patient referral; Electrophysiology Department, Great Ormond St Hospital, for electrophysiology studies; M Parulekar (Birmingham Children’s Hospital), K Nischal, Y Abou-Rayyah for clinical care; Thalia Antoniadi (West Midlands Regional Genetics Laboratory) for assistance with the gene panel sequencing. This work was supported by grants from Baillie Gifford, Visually Impaired Children Taking Action (VICTA) (http://www.victa.org.uk/) and Microphthalmia, Anophthalmia and Coloboma Support (MACS) (http://www.macs.org.uk). The human embryonic and fetal material was provided by the Joint Medical Research Council (MRC)/Wellcome Trust (Grant #099175/Z/12/Z) Human Developmental Biology Resource (http://www.hdbr.org).

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Correspondence to Nicola Ragge.

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Holt, R., Ugur Iseri, S.A., Wyatt, A.W. et al. Identification and functional characterisation of genetic variants in OLFM2 in children with developmental eye disorders. Hum Genet 136, 119–127 (2017). https://doi.org/10.1007/s00439-016-1745-8

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  • Open Angle Glaucoma
  • Coloboma
  • Microphthalmia
  • Lens Vesicle
  • OLFM2 Expression