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Clinical and Molecular Characterization of Familial Exudative Vitreoretinopathy Associated With Microcephaly

Hull, S; Arno, G; Ostergaard, P; Pontikos, N; Robson, AG; Webster, AR; Hogg, CR; ... Michaelides, M; + view all (2019) Clinical and Molecular Characterization of Familial Exudative Vitreoretinopathy Associated With Microcephaly. American Journal of Ophthalmology , 207 pp. 87-98. 10.1016/j.ajo.2019.05.001. Green open access

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Abstract

PURPOSE: Familial exudative vitreoretinopathy (FEVR) is a rare finding in patients with genetic forms of microcephaly. This study documents the detailed phenotype and expands the range of genetic heterogeneity. Design; Retrospective case-series METHODS: Twelve patients (ten families) with a diagnosis of FEVR and microcephaly were ascertained from pediatric genetic eye clinics and underwent full clinical assessment including retinal imaging. Molecular investigations included candidate gene Sanger sequencing, whole-exome sequencing (WES) and whole-genome sequencing (WGS). RESULTS: All patients had reduced vision and nystagmus. Six were legally blind. Two probands carried bi-allelic LRP5 variants, both presenting with bilateral retinal folds. A novel homozygous splice variant, and two missense variants were identified. Subsequent bone density measurement, identified osteoporosis in one proband.Four families had heterozygous KIF11 variants. Two probands had a retinal fold in one eye and chorioretinal atrophy in the other; the other two had bilateral retinal folds. Four heterozygous variants were found, including two large deletions not identified on Sanger sequencing or WES.Finally, a family of two children with learning difficulties, abnormal peripheral retinal vasculogenesis and rod-cone dystrophy were investigated. They were found to have bi-allelic splicing variants in TUBGCP6.Three families remain unsolved following WES and WGS. CONCLUSIONS: Molecular diagnosis has been achieved in seven of ten families investigated including a previously unrecognized association with LRP5. WGS enabled molecular diagnosis in three families after prior negative Sanger sequencing of the causative gene. This has enabled patient-specific care with targeted investigations and accurate family counseling.

Type: Article
Title: Clinical and Molecular Characterization of Familial Exudative Vitreoretinopathy Associated With Microcephaly
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.ajo.2019.05.001
Publisher version: https://doi.org/10.1016/j.ajo.2019.05.001
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
URI: https://discovery.ucl.ac.uk/id/eprint/10074496
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