Reevaluation of the Retinal Dystrophy Due to Recessive Alleles of RGR With the Discovery of a Cis-Acting Mutation in CDHR1.
Mutation of RGR, encoding retinal G-protein coupled receptor was originally reported in association with retinal dystrophy in 1999. A single convincing recessive variant segregated perfectly in one family of five affected and two unaffected siblings. At least one further individual, homozygous for the same variant has since been reported. The aim of this report was to reevaluate the findings in consideration of data from a whole genome sequencing (WGS) study of a large cohort of retinal dystrophy families.



Whole genome sequencing was performed on 599 unrelated probands with inherited retinal disease. Detailed phenotyping was performed, including clinical evaluation, electroretinography, fundus photography, fundus autofluorescence imaging (FAF) and spectral-domain optical coherence tomography (OCT).



Overall we confirmed that affected individuals from six unrelated families were homozygous for both the reported RGR p.Ser66Arg variant and a nearby frameshifting deletion in CDHR1 (p.Ile841Serfs119*). All had generalized rod and cone dysfunction with severe macular involvement. An additional proband was heterozygous for the same CDHR1/RGR haplotype but also carried a second null CDHR1 mutation on a different haplotype. A comparison of the clinical presentation of the probands reported here with other CDHR1-related retinopathy patients shows the phenotypes to be similar in presentation, severity, and rod/cone involvement.



These data suggest that the recessive retinal disorder previously reported to be due to homozygous mutation in RGR is, at least in part, due to variants in CDHR1 and that the true consequences of RGR knock-out on human retinal structure and function are yet to be determined.
UCL Institute of Ophthalmology, University College London, London, United Kingdom 2Moorfields Eye Hospital, London, United Kingdom.
Gavin
G
Arno
UCL Institute of Ophthalmology, University College London, London, United Kingdom 2Moorfields Eye Hospital, London, United Kingdom.
Sarah
S
Hull
Department of Haematology, University of Cambridge and NHS Blood and Transplant, Cambridge, United Kingdom 4NIHR BioResource - Rare Diseases, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge, United Kingdom.
Keren
K
Carss
UCL Institute of Ophthalmology, University College London, London, United Kingdom 2Moorfields Eye Hospital, London, United Kingdom.
Arundhati
A
Dev-Borman
UCL Institute of Ophthalmology, University College London, London, United Kingdom.
Christina
C
Chakarova
Ocular Genomics Institute, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts, United States.
Kinga
K
Bujakowska
Rotterdam Eye Hospital, Rotterdam, The Netherlands.
L Ingeborgh
LI
van den Born
UCL Institute of Ophthalmology, University College London, London, United Kingdom 2Moorfields Eye Hospital, London, United Kingdom.
Anthony G
AG
Robson
UCL Institute of Ophthalmology, University College London, London, United Kingdom 2Moorfields Eye Hospital, London, United Kingdom.
Graham E
GE
Holder
UCL Institute of Ophthalmology, University College London, London, United Kingdom 2Moorfields Eye Hospital, London, United Kingdom.
Michel
M
Michaelides
Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands 8Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, The Netherlands.
Frans P M
FP
Cremers
Ocular Genomics Institute, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts, United States.
Eric
E
Pierce
NIHR BioResource - Rare Diseases, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge, United Kingdom 9Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom.
F Lucy
FL
Raymond
UCL Institute of Ophthalmology, University College London, London, United Kingdom 2Moorfields Eye Hospital, London, United Kingdom 10Ophthalmology Department, UCSF School of Medicine, Koret Vision Centre, San Francisco, California, United States.
Anthony T
AT
Moore
UCL Institute of Ophthalmology, University College London, London, United Kingdom 2Moorfields Eye Hospital, London, United Kingdom.
Andrew R
AR
Webster
D000483:Alleles; D000070585:Cadherin Related Proteins; D015820:Cadherins / Q000235:genetics* / Q000378:metabolism; D004247:DNA / Q000235:genetics*; D004252:DNA Mutational Analysis; D004596:Electroretinography; D005260:Female; D005451:Fluorescein Angiography; D005654:Fundus Oculi; D005808:Genes, Recessive; D006720:Homozygote; D006801:Humans; D008297:Male; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D010375:Pedigree; D010641:Phenotype; D012160:Retina / Q000378:metabolism* / Q000473:pathology; D058499:Retinal Dystrophies / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D041623:Tomography, Optical Coherence
C442481:CDHR1 protein, human; D000070585:Cadherin Related Proteins; D015820:Cadherins; D009419:Nerve Tissue Proteins; D004247:DNA