Next-generation Sequencing Applied to a Large French Cone and Cone-rod Dystrophy Cohort: Mutation Spectrum and New Genotype-phenotype Correlation

Overview

Journal Orphanet J Rare Dis

Publisher Biomed Central

Specialty General Medicine

Date 2015 Jun 25

PMID 26103963

Citations 59

Authors

Elise Boulanger-Scemama

Said El Shamieh

Vanessa Demontant

Christel Condroyer

Aline Antonio

Christelle Michiels

Fiona Boyard

Jean-Paul Saraiva

Melanie Letexier

Eric Souied

Saddek Mohand-Said

Jose-Alain Sahel

Christina Zeitz

Isabelle Audo

Affiliations

Soon will be listed here.

Abstract

Background: Cone and cone-rod dystrophies are clinically and genetically heterogeneous inherited retinal disorders with predominant cone impairment. They should be distinguished from the more common group of rod-cone dystrophies (retinitis pigmentosa) due to their more severe visual prognosis with early central vision loss. The purpose of our study was to document mutation spectrum of a large French cohort of cone and cone-rod dystrophies.

Methods: We applied Next-Generation Sequencing targeting a panel of 123 genes implicated in retinal diseases to 96 patients. A systematic filtering approach was used to identify likely disease causing variants, subsequently confirmed by Sanger sequencing and co-segregation analysis when possible.

Results: Overall, the likely causative mutations were detected in 62.1 % of cases, revealing 33 known and 35 novel mutations. This rate was higher for autosomal dominant (100 %) than autosomal recessive cases (53.8 %). Mutations in ABCA4 and GUCY2D were responsible for 19.2 % and 29.4 % of resolved cases with recessive and dominant inheritance, respectively. Furthermore, unexpected genotype-phenotype correlations were identified, confirming the complexity of inherited retinal disorders with phenotypic overlap between cone-rod dystrophies and other retinal diseases.

Conclusions: In summary, this time-efficient approach allowed mutation detection in the most important cohort of cone-rod dystrophies investigated so far covering the largest number of genes. Association of known gene defects with novel phenotypes and mode of inheritance were established.

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