A Specific Macula-Predominant Retinal Phenotype Is Associated With the CDHR1 Variant c.783G>A, a Silent Mutation Leading to In-Frame Exon Skipping
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A Specific Macula-Predominant Retinal Phenotype Is Associated With the CDHR1 Variant c.783G>A, a Silent Mutation Leading to In-Frame Exon Skipping. / Charbel Issa, Peter; Gliem, Martin; Yusuf, Imran H; Birtel, Johannes; Müller, Philipp L; Mangold, Elisabeth; Downes, Susan M; MacLaren, Robert E; Betz, Christian; Bolz, Hanno J.
in: INVEST OPHTH VIS SCI, Jahrgang 60, Nr. 10, 01.08.2019, S. 3388-3397.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - A Specific Macula-Predominant Retinal Phenotype Is Associated With the CDHR1 Variant c.783G>A, a Silent Mutation Leading to In-Frame Exon Skipping
AU - Charbel Issa, Peter
AU - Gliem, Martin
AU - Yusuf, Imran H
AU - Birtel, Johannes
AU - Müller, Philipp L
AU - Mangold, Elisabeth
AU - Downes, Susan M
AU - MacLaren, Robert E
AU - Betz, Christian
AU - Bolz, Hanno J
PY - 2019/8/1
Y1 - 2019/8/1
N2 - PURPOSE: To report the clinical and molecular findings in patients with retinal dystrophy associated with the c.783G>A variant in CDHR1.METHODS: The retinal phenotype of 10 patients with CDHR1-related retinopathy was characterized by multimodal imaging including color fundus photography, optical coherence tomography (OCT), and blue- and near-infrared fundus autofluorescence imaging. Functional testing included electroretinography, visual acuity, and visual field testing.RESULTS: Six patients homozygous for the c.783G>A variant in CDHR1 showed a retinal phenotype resembling central areolar choroidal dystrophy (CACD) on multimodal imaging. Retinal function outside an area of slowly progressive macular atrophy remained relatively preserved. In contrast, biallelic severe/truncating CDHR1 mutations result in retina-wide retinal degeneration in addition to macular atrophy, with overall severely reduced retinal function. Patients compound heterozygous for the c.783G>A mutation and a truncating mutation in CDHR1 showed an intermediate phenotype. All patients except one with biallelic severe CDHR1 mutations were asymptomatic in the first four decades of life, irrespective of their individual CDHR1 mutations. Analysis of blood RNA from patients with the c.783G>A variant revealed in-frame skipping of exon 8 in vivo, predicting a partial deletion of CDHR1 ectodomains 2 and 3.CONCLUSIONS: Patients with biallelic c.783G>A CDHR1 mutations demonstrate a retinal phenotype consistent with autosomal recessive CACD. The apparently silent dbSNP-annotated c.783G>A CDHR1 variant (rs147346345) has a relatively high minor allele frequency (0.31%), with homozygous individuals annotated in the general population, and it may therefore have been disregarded in many next-generation sequencing (NGS)-based studies. The differential diagnosis includes PRPH2-associated CACD and age-related macular degeneration.
AB - PURPOSE: To report the clinical and molecular findings in patients with retinal dystrophy associated with the c.783G>A variant in CDHR1.METHODS: The retinal phenotype of 10 patients with CDHR1-related retinopathy was characterized by multimodal imaging including color fundus photography, optical coherence tomography (OCT), and blue- and near-infrared fundus autofluorescence imaging. Functional testing included electroretinography, visual acuity, and visual field testing.RESULTS: Six patients homozygous for the c.783G>A variant in CDHR1 showed a retinal phenotype resembling central areolar choroidal dystrophy (CACD) on multimodal imaging. Retinal function outside an area of slowly progressive macular atrophy remained relatively preserved. In contrast, biallelic severe/truncating CDHR1 mutations result in retina-wide retinal degeneration in addition to macular atrophy, with overall severely reduced retinal function. Patients compound heterozygous for the c.783G>A mutation and a truncating mutation in CDHR1 showed an intermediate phenotype. All patients except one with biallelic severe CDHR1 mutations were asymptomatic in the first four decades of life, irrespective of their individual CDHR1 mutations. Analysis of blood RNA from patients with the c.783G>A variant revealed in-frame skipping of exon 8 in vivo, predicting a partial deletion of CDHR1 ectodomains 2 and 3.CONCLUSIONS: Patients with biallelic c.783G>A CDHR1 mutations demonstrate a retinal phenotype consistent with autosomal recessive CACD. The apparently silent dbSNP-annotated c.783G>A CDHR1 variant (rs147346345) has a relatively high minor allele frequency (0.31%), with homozygous individuals annotated in the general population, and it may therefore have been disregarded in many next-generation sequencing (NGS)-based studies. The differential diagnosis includes PRPH2-associated CACD and age-related macular degeneration.
KW - Aged
KW - Cadherin Related Proteins
KW - Cadherins/genetics
KW - Electroretinography
KW - Exons/genetics
KW - Female
KW - High-Throughput Nucleotide Sequencing
KW - Humans
KW - Male
KW - Middle Aged
KW - Multimodal Imaging
KW - Nerve Tissue Proteins/genetics
KW - Optical Imaging
KW - Pedigree
KW - Phenotype
KW - Photography
KW - Retina/pathology
KW - Retinal Dystrophies/diagnostic imaging
KW - Sequence Deletion/genetics
KW - Silent Mutation
KW - Tomography, Optical Coherence
KW - Visual Acuity/physiology
KW - Visual Field Tests
KW - Visual Fields/physiology
U2 - 10.1167/iovs.18-26415
DO - 10.1167/iovs.18-26415
M3 - SCORING: Journal article
C2 - 31387115
VL - 60
SP - 3388
EP - 3397
JO - INVEST OPHTH VIS SCI
JF - INVEST OPHTH VIS SCI
SN - 0146-0404
IS - 10
ER -