Biallelic Mutations in CRB1 Underlie Autosomal Recessive Familial Foveal Retinoschisis.
To identify the genetic cause of autosomal recessive familial foveal retinoschisis (FFR).



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).



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.



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.
Program of Genetics and Genome Biology The Hospital for Sick Children, Toronto, Canada 2Department of Ophthalmology and Vision Sciences, The Hospital for Sick Children, University of Toronto, Toronto, Canada 3Department of Ophthalmology and Vision Science.
Ajoy
A
Vincent
Program of Genetics and Genome Biology The Hospital for Sick Children, Toronto, Canada.
Judith
J
Ng
Department of Ophthalmology, University Hospital Zurich, Zurich, Switzerland.
Christina
C
Gerth-Kahlert
Program of Genetics and Genome Biology The Hospital for Sick Children, Toronto, Canada.
Erika
E
Tavares
Department of Anesthesia and Pain Medicine, and Program in Molecular Structure and Function, The Hospital for Sick Children, Toronto, Canada.
Jason T
JT
Maynes
Department of Ophthalmology and Vision Sciences, The Hospital for Sick Children, University of Toronto, Toronto, Canada.
Thomas
T
Wright
Institute of Medical Molecular Genetics, University of Zürich, Wagistrasse 12, Schlieren, Switzerland.
Amit
A
Tiwari
Department of Ophthalmology and Vision Sciences, The Hospital for Sick Children, University of Toronto, Toronto, Canada.
Anupreet
A
Tumber
Program of Genetics and Genome Biology The Hospital for Sick Children, Toronto, Canada.
Shuning
S
Li
Department of Ophthalmology, University Hospital Zurich, Zurich, Switzerland.
James V M
JV
Hanson
Institute of Medical Molecular Genetics, University of Zürich, Wagistrasse 12, Schlieren, Switzerland.
Angela
A
Bahr
Department of Ophthalmology and Vision Sciences, The Hospital for Sick Children, University of Toronto, Toronto, Canada 7Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada 8Division of Clinical and Metabolic Genetics, The Ho.
Heather
H
MacDonald
Institute of Medical Molecular Genetics, University of Zürich, Wagistrasse 12, Schlieren, Switzerland.
Luzy
L
Bähr
Department of Ophthalmology and Vision Sciences, The Hospital for Sick Children, University of Toronto, Toronto, Canada 3Department of Ophthalmology and Vision Sciences, University of Toronto, Toronto, Canada.
Carol
C
Westall
Institute of Medical Molecular Genetics, University of Zürich, Wagistrasse 12, Schlieren, Switzerland 9Zurich Center for Integrative Human Physiology (ZIHP), University of Zürich, Zürich, Switzerland 10Neuroscience Center Zurich (ZNZ), University and ETH.
Wolfgang
W
Berger
Department of Human Genetics, Radboud University Medical Centre, Nijmegen, The Netherlands.
Frans P M
FP
Cremers
Department of Human Genetics, Radboud University Medical Centre, Nijmegen, The Netherlands 12Department of Ophthalmology, Radboud University Medical Centre, Nijmegen, The Netherlands.
Anneke I
AI
den Hollander
Program of Genetics and Genome Biology The Hospital for Sick Children, Toronto, Canada 2Department of Ophthalmology and Vision Sciences, The Hospital for Sick Children, University of Toronto, Toronto, Canada 3Department of Ophthalmology and Vision Science.
Elise
E
Héon
D000293:Adolescent; D000328:Adult; D004247:DNA / Q000235:genetics*; D004252:DNA Mutational Analysis; D005136:Eye Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005451:Fluorescein Angiography; D005584:Fovea Centralis / Q000378:metabolism / Q000473:pathology*; D005654:Fundus Oculi; D005820:Genetic Testing; D005838:Genotype; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D010375:Pedigree; D010641:Phenotype; D041441:Retinoschisis / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D041623:Tomography, Optical Coherence; D014792:Visual Acuity; D055815:Young Adult
C448939:CRB1 protein, human; D005136:Eye Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D004247:DNA