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Biallelic mutations in CRB1 underlie autosomal recessive familial foveal retinoschisis


Vincent, Ajoy; Ng, Judith; Gerth-Kahlert, Christina; Tavares, Erika; Maynes, Jason T; Wright, Thomas; Tiwari, Amit; Tumber, Anupreet; Li, Shuning; Hanson, James V M; Bahr, Angela; MacDonald, Heather; Bähr, Luzy; Westall, Carol; Berger, Wolfgang; Cremers, Frans P M; den Hollander, Anneke I; Héon, Elise (2016). Biallelic mutations in CRB1 underlie autosomal recessive familial foveal retinoschisis. Investigative Ophthalmology & Visual Science [IOVS], 57:2637-2646.

Abstract

Purpose: To identify the genetic cause of autosomal recessive familial foveal retinoschisis (FFR).
Methods: A female sibship with FFR was identified (Family-A; 17 and 16 years, respectively); panel based genetic sequencing (132 genes) and comparative genome hybridization (142 genes) were performed. Whole-exome sequencing (WES) was performed on both siblings using the Illumina-HiSeq-2500 platform. A sporadic male (Family-B; 35 years) with FFR underwent WES using Illumina NextSeq500. All three affected subjects underwent detailed ophthalmologic evaluation including fundus photography, autofluorescence imaging, spectral-domain optical coherence tomography (SD-OCT), and full-field electroretinogram (ERG).
Results: Panel-based genetic testing identified two presumed disease causing variants in CRB1 (p.Gly123Cys and p.Cys948Tyr) in Family-A sibship; no deletion or duplication was detected. WES analysis in the sibship identified nine genes with two or more shared nonsynonymous rare coding sequence variants; CRB1 remained a strong candidate gene, and CRB1 variants segregated with the disease. WES in Family-B identified two presumed disease causing variants in CRB1 (p.Ile167_Gly169del and p.Arg764Cys) that segregated with the disease phenotype. Distance visual acuity was 20/40 or better in all three affected except for the left eye of the older subject (Family-B), which showed macular atrophy. Fundus evaluation showed spoke-wheel appearance at the macula in five eyes. The SD-OCT showed macular schitic changes in inner and outer nuclear layers in all cases. The ERG responses were normal in all subjects.
Conclusions: This is the first report to implicate CRB1 as the underlying cause of FFR. This phenotype forms the mildest end of the spectrum of CRB1-related diseases.

Abstract

Purpose: To identify the genetic cause of autosomal recessive familial foveal retinoschisis (FFR).
Methods: A female sibship with FFR was identified (Family-A; 17 and 16 years, respectively); panel based genetic sequencing (132 genes) and comparative genome hybridization (142 genes) were performed. Whole-exome sequencing (WES) was performed on both siblings using the Illumina-HiSeq-2500 platform. A sporadic male (Family-B; 35 years) with FFR underwent WES using Illumina NextSeq500. All three affected subjects underwent detailed ophthalmologic evaluation including fundus photography, autofluorescence imaging, spectral-domain optical coherence tomography (SD-OCT), and full-field electroretinogram (ERG).
Results: Panel-based genetic testing identified two presumed disease causing variants in CRB1 (p.Gly123Cys and p.Cys948Tyr) in Family-A sibship; no deletion or duplication was detected. WES analysis in the sibship identified nine genes with two or more shared nonsynonymous rare coding sequence variants; CRB1 remained a strong candidate gene, and CRB1 variants segregated with the disease. WES in Family-B identified two presumed disease causing variants in CRB1 (p.Ile167_Gly169del and p.Arg764Cys) that segregated with the disease phenotype. Distance visual acuity was 20/40 or better in all three affected except for the left eye of the older subject (Family-B), which showed macular atrophy. Fundus evaluation showed spoke-wheel appearance at the macula in five eyes. The SD-OCT showed macular schitic changes in inner and outer nuclear layers in all cases. The ERG responses were normal in all subjects.
Conclusions: This is the first report to implicate CRB1 as the underlying cause of FFR. This phenotype forms the mildest end of the spectrum of CRB1-related diseases.

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Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Ophthalmology Clinic
04 Faculty of Medicine > Center for Integrative Human Physiology
04 Faculty of Medicine > Institute of Medical Molecular Genetics
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:2016
Deposited On:31 May 2016 16:01
Last Modified:08 Dec 2017 19:37
Publisher:Association for Research in Vision and Ophthalmology
ISSN:0146-0404
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1167/iovs.15-18281
PubMed ID:27258436

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