Next-generation sequencing applied to a large French cone and cone-rod dystrophy cohort: mutation spectrum and new genotype-phenotype correlation

• Published in: Orphanet journal of rare diseases 2015-06, Vol.10 (1), p.85-85, Article 85
• Main Authors: Boulanger-Scemama, Elise, El Shamieh, Said, Démontant, Vanessa, Condroyer, Christel, Antonio, Aline, Michiels, Christelle, Boyard, Fiona, Saraiva, Jean-Paul, Letexier, Mélanie, Souied, Eric, Mohand-Saïd, Saddek, Sahel, José-Alain, Zeitz, Christina, Audo, Isabelle
• Format: Article
• Language: English
• Subjects: Analysis; Cohort Studies; DNA Copy Number Variations; DNA sequencing; Female; France; Genetic aspects; Genetics; Genotype; High-Throughput Nucleotide Sequencing - utilization; Humans; Life Sciences; Male; Mutation; Nucleotide sequencing; Pedigree; Phenotype; Retinitis Pigmentosa - genetics
• ISSN: 1750-1172; 1750-1172
• DOI: 10.1186/s13023-015-0300-3

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. 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. 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. 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.