Sarah Hull1, Gavin Arno1, Pia Ostergaard2, Nikolas Pontikos3, Anthony G Robson1, Andrew R Webster1, Chris R Hogg1, Genevieve A Wright1, Robert H H Henderson4, Carol-Anne Martin5, Andrew P Jackson5, Sahar Mansour6, Anthony T Moore7, Michel Michaelides8. 1. UCL Institute of Ophthalmology, University College London, London, United Kingdom; Moorfields Eye Hospital, London, United Kingdom. 2. Genetics Research Centre, Molecular and Clinical Sciences, St George's University of London, London, United Kingdom. 3. UCL Institute of Ophthalmology, University College London, London, United Kingdom. 4. Moorfields Eye Hospital, London, United Kingdom; Ophthalmology Department, Great Ormond Street Hospital for Children, London, United Kingdom. 5. Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom. 6. Genetics Research Centre, Molecular and Clinical Sciences, St George's University of London, London, United Kingdom; South West Thames Regional Genetics Service, St George's Healthcare NHS Trust, London, United Kingdom. 7. UCL Institute of Ophthalmology, University College London, London, United Kingdom; Moorfields Eye Hospital, London, United Kingdom; Ophthalmology Department, University of California, San Francisco, California. 8. UCL Institute of Ophthalmology, University College London, London, United Kingdom; Moorfields Eye Hospital, London, United Kingdom. Electronic address: michel.michaelides@ucl.ac.uk.
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 (10 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 2 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 2 had bilateral retinal folds. Four heterozygous variants were found, including 2 large deletions not identified on Sanger sequencing or WES. Finally, a family of 2 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 7 of 10 families investigated, including a previously unrecognized association with LRP5. WGS enabled molecular diagnosis in 3 families after prior negative Sanger sequencing of the causative gene. This has enabled patient-specific care with targeted investigations and accurate family counseling.
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 (10 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 2 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 2 had bilateral retinal folds. Four heterozygous variants were found, including 2 large deletions not identified on Sanger sequencing or WES. Finally, a family of 2 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 7 of 10 families investigated, including a previously unrecognized association with LRP5. WGS enabled molecular diagnosis in 3 families after prior negative Sanger sequencing of the causative gene. This has enabled patient-specific care with targeted investigations and accurate family counseling.
Authors: Maria F Shurygina; Joseph M Simonett; Maria A Parker; Amanda Mitchell; Florin Grigorian; Jacob Lifton; Aaron Nagiel; Alexander A Shpak; Elena L Dadali; Irina A Mishina; Richard G Weleber; Paul Yang; Mark E Pennesi Journal: Invest Ophthalmol Vis Sci Date: 2020-11-02 Impact factor: 4.799