CDHR1 mutations in retinal dystrophies

Katarina Stingl,Günther Rudolph,Pablo Llavona,Bernd Wissinger,Anja K Mayer,Eberhart Zrenner,Lejla Mulahasanovic,Susanne Kohl,Nicole Weisschuh,Samuel G Jacobson

doi:10.1038/s41598-017-07117-8

Abstract

We report ophthalmic and genetic findings in patients with autosomal recessive retinitis pigmentosa (RP), cone-rod dystrophy (CRD) or cone dystrophy (CD) harboring potential pathogenic variants in the CDHR1 gene. Detailed ophthalmic examination was performed in seven sporadic and six familial subjects. Mutation screening was done using a customized next generation sequencing panel targeting 105 genes implicated in inherited retinal disorders. In one family, homozygosity mapping with subsequent candidate gene analysis was performed. Stringent filtering for rare and potentially disease causing variants following a model of autosomal recessive inheritance led to the identification of eleven different CDHR1 variants in nine index cases. All variants were novel at the time of their identification. In silico analyses confirmed their pathogenic potential. Minigene assays were performed for two non-canonical splice site variants and revealed missplicing for the mutant alleles. Mutations in CDHR1 are a rare cause of retinal dystrophy. Our study further expands the mutational spectrum of this gene and the associated clinical presentation.

Highlights

Significant progress has been made over the past two decades in defining the molecular pathogenesis of inherited retinal dystrophies (IRDs), a group of diseases characterized by gradual loss of photoreceptor cells and resulting in compromised vision often leading to patients being registered as blind
Rare and potentially disease-causing variants compatible with a model of autosomal recessive inheritance were only observed in the CDHR1 gene, but not in other genes associated with retinal dystrophies
Compound heterozygosity could not be demonstrated for patient F and we have to point out that her phenotype might not be CDHR1-related, no putative disease-causing variants in other retinal disease genes were identified in the panel sequencing approach

Summary

Introduction

Significant progress has been made over the past two decades in defining the molecular pathogenesis of inherited retinal dystrophies (IRDs), a group of diseases characterized by gradual loss of photoreceptor cells and resulting in compromised vision often leading to patients being registered as blind. Mutations in more than 125 genes have been implicated in non-syndromic forms of IRDs (https://sph.uth.edu/retnet/). The function of these IRD genes is rather diverse, including those that encode proteins of the phototransduction cascade, structural proteins, ciliary proteins, transcription and splicing factors and others. Patients underwent detailed clinical evaluation by multimodal ophthalmological diagnostics (retinal imaging, functional tests and electroretinography techniques)

Methods

Results

Conclusion