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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; Wright, GA; Henderson, RHH; Martin, C-A; et al. Hull, S; Arno, G; Ostergaard, P; Pontikos, N; Robson, AG; Webster, AR; Hogg, CR; Wright, GA; Henderson, RHH; Martin, C-A; Jackson, AP; Mansour, S; Moore, AT; Michaelides, M (2019) Clinical and molecular characterization of familial exudative vitreoretinopathy associated with microcephaly. Am J Ophthalmol, 207. pp. 87-98. ISSN 1879-1891 https://doi.org/10.1016/j.ajo.2019.05.001
SGUL Authors: Ostergaard, Pia Mansour, Sahar

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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.

Item Type: Article
Additional Information: © 2019. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/
Keywords: 1103 Clinical Sciences, 1113 Ophthalmology And Optometry, 1117 Public Health And Health Services, Ophthalmology & Optometry
SGUL Research Institute / Research Centre: Academic Structure > Molecular and Clinical Sciences Research Institute (MCS)
Journal or Publication Title: Am J Ophthalmol
ISSN: 1879-1891
Language: eng
Dates:
DateEvent
November 2019Published
8 May 2019Published Online
1 May 2019Accepted
Publisher License: Creative Commons: Attribution-Noncommercial-No Derivative Works 4.0
Projects:
Project IDFunderFunder ID
1318Fight for Sighthttp://dx.doi.org/10.13039/100002089
1801Fight for Sighthttp://dx.doi.org/10.13039/100002089
ST1109BMoorfields Eye HospitalUNSPECIFIED
GR581Retina UKUNSPECIFIED
C-CL:0710-0505-MEH10-02Foundation Fighting Blindnesshttp://dx.doi.org/10.13039/100001116
BRC2_003National Institute for Health Researchhttp://dx.doi.org/10.13039/501100000272
M184Rosetrees Trusthttp://dx.doi.org/10.13039/501100000833
PubMed ID: 31077665
Go to PubMed abstract
URI: https://openaccess.sgul.ac.uk/id/eprint/110891
Publisher's version: https://doi.org/10.1016/j.ajo.2019.05.001

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