A Specific Macula-Predominant Retinal Phenotype Is Associated With the CDHR1 Variant c.783G>A, a Silent Mutation Leading to In-Frame Exon Skipping

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 -