doi: 10.1186/s13023-015-0300-3.
Next-generation sequencing applied to a large French cone and cone-rod dystrophy cohort: mutation spectrum and new genotype-phenotype correlation
Elise Boulanger-Scemama 1 2 3, Said El Shamieh 1 2 3, Vanessa Démontant 1 2 3, Christel Condroyer 1 2 3, Aline Antonio 1 2 3 4, Christelle Michiels 1 2 3, Fiona Boyard 1 2 3, Jean-Paul Saraiva 5, Mélanie Letexier 5, Eric Souied 6, Saddek Mohand-Saïd 1 2 3 4, José-Alain Sahel 1 2 3 4 7 8 9, Christina Zeitz 10 11 12, Isabelle Audo 13 14 15 16 17
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- PMID:26103963
- PMCID: PMC4566196
- DOI: 10.1186/s13023-015-0300-3
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Next-generation sequencing applied to a large French cone and cone-rod dystrophy cohort: mutation spectrum and new genotype-phenotype correlation
Elise Boulanger-Scemama et al. Orphanet J Rare Dis..
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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.
Figures
Percentage of regions with 25-fold coverage per base for each of the 21 known CCRD genes of the panel. The mean and median coverage per gene were 244-fold and 248-fold per base, respectively, with a minimal coverage of 171-fold forRAX2
Gene defect spectrum involved in cone and cone-rod dystrophies. Gene defect prevalence in resolved patients with autosomal recessive inheritance (N = 42 patients including 20 sporadic cases) and autosomal dominant inheritance (N = 17 patients including 5 sporadic cases). *EYS disease association with CCRD should be taken with caution. ** the implication ofROM1 in IRD remains to be elucidated in the future. *** after clinical reassessment, patient’s phenotype was retrospectively more compatible with ADVIRC diagnosis and not CCRD
Phenotype of CIC01571 who carries a homozygous nonsense mutation inC2Orf71, previously reported in RP. (a) Pedigree of family 1932. History of symptoms reveals initial photophobia and bilateral central vision loss. Visual acuity is reduced to hand motion in both eyes. Colour fundus photographs (b), infra-red (c) and blue autofluorescence imaging (d) confirm the predominant central involvement with severe bilateral macular atrophy. SD-OCT (e) shows the disappearance of the photoreceptor layers that extends beyond the vascular arcades. ERG responses (not shown) were undetectable from background noise in both scotopic and photopic conditions
Phenotype of CIC03953 who carries a compound heterozygous mutation inEYS. (a) Pedigree of family 1819. Visual acuity is 20/50 with −2.50 (−0.25)25° in the right eye and 20/80 with −2.50 (−0.75)170° in the left eye. Kinetic perimetry shows a bilateral central scotoma. Color fundus photographs (b) show bilateral optic disc pallor, retinal vessels narrowing and macular pigmentary deposits. Infra-red (c), infra-red autofluorescence (d) and blue autofluorescence imaging (e) highlight macular pigmentary and atrophic changes. SD-OCT (f) reveals a predominant central involvement with a disruption of the outer retinal layers limited in the fovea. ERG (g) revealed unusual features in association forEYS mutations: under scotopic conditions, there was no detectable b-wave in response to a dim (0.01 cd.s.m−2) flash while responses to a bright flash showed some reduction of the a-wave but additional b-wave reduction leading to an electronegative waveform. Photopic responses were severely affected in keeping with cone-rod dysfunction with additional inner retinal dysfunction
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