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A clinical and molecular characterisation of CRB1-associated maculopathy.

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cam.issuedOnline2018-02
dc.contributor.authorKhan, Kamron N
dc.contributor.authorRobson, Anthony
dc.contributor.authorMahroo, Omar AR
dc.contributor.authorArno, Gavin
dc.contributor.authorInglehearn, Chris F
dc.contributor.authorArmengol, Monica
dc.contributor.authorWaseem, Naushin
dc.contributor.authorHolder, Graham E
dc.contributor.authorCarss, Keren J
dc.contributor.authorRaymond, Lucy F
dc.contributor.authorWebster, Andrew R
dc.contributor.authorMoore, Anthony T
dc.contributor.authorMcKibbin, Martin
dc.contributor.authorvan Genderen, Maria M
dc.contributor.authorPoulter, James A
dc.contributor.authorMichaelides, Michel
dc.contributor.authorUK Inherited Retinal Disease Consortium
dc.contributor.orcidPoulter, James A [0000-0003-2048-5693]
dc.date.accessioned2018-11-23T00:32:23Z
dc.date.available2018-11-23T00:32:23Z
dc.date.issued2018-05
dc.description.abstractTo date, over 150 disease-associated variants in CRB1 have been described, resulting in a range of retinal disease phenotypes including Leber congenital amaurosis and retinitis pigmentosa. Despite this, no genotype-phenotype correlations are currently recognised. We performed a retrospective review of electronic patient records to identify patients with macular dystrophy due to bi-allelic variants in CRB1. In total, seven unrelated individuals were identified. The median age at presentation was 21 years, with a median acuity of 0.55 decimalised Snellen units (IQR = 0.43). The follow-up period ranged from 0 to 19 years (median = 2.0 years), with a median final decimalised Snellen acuity of 0.65 (IQR = 0.70). Fundoscopy revealed only a subtly altered foveal reflex, which evolved into a bull's-eye pattern of outer retinal atrophy. Optical coherence tomography identified structural changes-intraretinal cysts in the early stages of disease, and later outer retinal atrophy. Genetic testing revealed that one rare allele (c.498_506del, p.(Ile167_Gly169del)) was present in all patients, with one patient being homozygous for the variant and six being heterozygous. In trans with this, one variant recurred twice (p.(Cys896Ter)), while the four remaining alleles were each observed once (p.(Pro1381Thr), p.(Ser478ProfsTer24), p.(Cys195Phe) and p.(Arg764Cys)). These findings show that the rare CRB1 variant, c.498_506del, is strongly associated with localised retinal dysfunction. The clinical findings are much milder than those observed with bi-allelic, loss-of-function variants in CRB1, suggesting this in-frame deletion acts as a hypomorphic allele. This is the most prevalent disease-causing CRB1 variant identified in the non-Asian population to date.
dc.format.mediumPrint-Electronic
dc.identifier.doi10.17863/CAM.33160
dc.identifier.eissn1476-5438
dc.identifier.issn1018-4813
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/285816
dc.languageeng
dc.language.isoeng
dc.publisherSpringer Science and Business Media LLC
dc.publisher.urlhttp://dx.doi.org/10.1038/s41431-017-0082-2
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectAdolescent
dc.subjectAdult
dc.subjectAlleles
dc.subjectChild
dc.subjectChild, Preschool
dc.subjectElectronic Health Records
dc.subjectEye Proteins
dc.subjectFemale
dc.subjectGenetic Association Studies
dc.subjectGenetic Predisposition to Disease
dc.subjectGenetic Testing
dc.subjectHumans
dc.subjectInfant
dc.subjectInfant, Newborn
dc.subjectMacular Degeneration
dc.subjectMale
dc.subjectMembrane Proteins
dc.subjectNerve Tissue Proteins
dc.subjectRetinal Photoreceptor Cell Outer Segment
dc.subjectYoung Adult
dc.titleA clinical and molecular characterisation of CRB1-associated maculopathy.
dc.typeArticle
dcterms.dateAccepted2017-12-05
prism.endingPage694
prism.issueIdentifier5
prism.publicationDate2018
prism.publicationNameEur J Hum Genet
prism.startingPage687
prism.volume26
rioxxterms.licenseref.startdate2018-05
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.typeJournal Article/Review
rioxxterms.versionVoR
rioxxterms.versionofrecord10.1038/s41431-017-0082-2

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