Universität zu Köln

Issa, Peter Charbel, Gliem, Martin, Yusuf, Imran H., Birtel, Johannes, Mueller, Philipp L., Mangold, Elisabeth, Downes, Susan M., MacLaren, Robert E., Betz, Christian and Bolz, Hanno J. (2019). A Specific Macula-Predominant Retinal Phenotype Is Associated With the CDHR1 Variant c.783G > A, a Silent Mutation Leading to In-Frame Exon Skipping. Invest. Ophthalmol. Vis. Sci., 60 (10). S. 3388 - 3398. ROCKVILLE: ASSOC RESEARCH VISION OPHTHALMOLOGY INC. ISSN 1552-5783

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Abstract

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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Issa, Peter Charbel UNSPECIFIED UNSPECIFIED UNSPECIFIED Gliem, Martin UNSPECIFIED UNSPECIFIED UNSPECIFIED Yusuf, Imran H. UNSPECIFIED UNSPECIFIED UNSPECIFIED Birtel, Johannes UNSPECIFIED UNSPECIFIED UNSPECIFIED Mueller, Philipp L. UNSPECIFIED UNSPECIFIED UNSPECIFIED Mangold, Elisabeth UNSPECIFIED UNSPECIFIED UNSPECIFIED Downes, Susan M. UNSPECIFIED UNSPECIFIED UNSPECIFIED MacLaren, Robert E. UNSPECIFIED UNSPECIFIED UNSPECIFIED Betz, Christian UNSPECIFIED UNSPECIFIED UNSPECIFIED Bolz, Hanno J. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-145480
DOI:	10.1167/iovs.18-26415
Journal or Publication Title:	Invest. Ophthalmol. Vis. Sci.
Volume:	60
Number:	10
Page Range:	S. 3388 - 3398
Date:	2019
Publisher:	ASSOC RESEARCH VISION OPHTHALMOLOGY INC
Place of Publication:	ROCKVILLE
ISSN:	1552-5783
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language PROTOCADHERIN-21 PCDH21; OUTER SEGMENT; GENE; IDENTIFICATION; DEGENERATION; FAMILY; CONE; SPECTRUM; CADHERIN Multiple languages Ophthalmology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/14548