ABCMdb

ABCA4 p.Val26Met

Predicted by SNAP2:	A: N (66%), C: N (66%), D: D (63%), E: N (61%), F: N (53%), G: D (63%), H: N (57%), I: N (93%), K: D (53%), L: N (82%), M: N (72%), N: N (53%), P: N (53%), Q: N (57%), R: D (53%), S: N (57%), T: N (72%), W: D (75%), Y: D (53%),
Predicted by PROVEAN:	A: N, C: N, D: D, E: D, F: N, G: D, H: D, I: N, K: D, L: N, M: N, N: D, P: D, Q: D, R: D, S: D, T: N, W: D, Y: N,

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[hide] Next-generation sequencing applied to a large Fren... Orphanet J Rare Dis. 2015 Jun 24;10:85. doi: 10.1186/s13023-015-0300-3. Boulanger-Scemama E, El Shamieh S, Demontant V, Condroyer C, Antonio A, Michiels C, Boyard F, Saraiva JP, Letexier M, Souied E, Mohand-Said S, Sahel JA, Zeitz C, Audo I
Next-generation sequencing applied to a large French cone and cone-rod dystrophy cohort: mutation spectrum and new genotype-phenotype correlation.
Orphanet J Rare Dis. 2015 Jun 24;10:85. doi: 10.1186/s13023-015-0300-3., [PMID:26103963]

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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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124 Table 2 Summary of 19 patients carrying pathogenic or likely pathogenic mutations in other retinal disease genes ID Type Consang. Gene NM Allele State Exon cDNA Protein Coseg. Conservation Polyphen2 Sift Mutation Taster References High confidence CIC01571 Ar C2Orf71 NM_001029883.2 Ho 1 c.2950C>T p.(R984*) + - - - - (Audo et al. 2011) (RP) CIC00643 Ar + C2Orf71 NM_001029883.2 Ho 1 c.1949G>A p.(W650*) Np - - - - Novel (rs371289954) CIC03112 Ar + MERTK NM_006343.2 Ho 17 c.2214del p.(C738Wfs*32) Np - - - - (Tschernutter et al. 2006) (RP) CIC01242 Ar MERTK NM_006343.2 Ho 3_19 c.483-?_c.3000+?del - + - - - - Novel CIC06514 Ar + RLBP1 NM_000326.4 Ho 7_9 c.526-?_c.954+?del - Np - - - - Novel CIC03953 simplex EYS NM_001292009.1 Het 11 c.1673G>A p.(W558*) + - - - - (Audo et al. 2010) (RP) (rs201823777) EYS NM_001292009.1 Het 14 c.2234A>G p.(N745S) + Not B - Poly (Audo et al. 2010) (RP) (rs201652272) CIC05012 simplex NMNAT1 NM_022787.3 Het 5 c.619C>T p.(R207W) Np Weakly B D Dc (Perrault et al. 2012) (LCA) (rs142968179) NMNAT1 NM_022787.3 Het 5 c.769G>A p.(E257K) Np Moderately B T Dc (Chiang et al. 2012) (LCA) (rs150726175) CIC06499 simplex NMNAT1 NM_022787.3 Het 5 c.619C>T p.(R207W) + Weakly B D Dc (Perrault et al. 2012) (LCA) (rs142968179) NMNAT1 NM_022787.3 Het 5 c.769G>A p.(E257K) + Moderately B T Dc (Chiang et al. 2012) (LCA) (rs150726175) CIC05394 Ar + RDH12 NM_152443.2 Ho 8 c.806_810del p.(A269Gfs*2) Np - - - - (Janecke et al 2004) (LCA (rs386834261)) CIC07241 Ar + RDH12 NM_152443.2 Ho 7 c.464C>T p.(T155I) Np Highly Pr D Dc (Thompson et al 2005) (LCA) (rs121434337) CIC07447 Ar RDH12 NM_152443.2 Het 8 c.806_810del p.(A269Gfs*2) + - - - (Janecke et al 2004) (LCA) (rs386834261)) RDH12 NM_152443.2 Het 8 c.403A>G p.(K135E) + Highly Prd T Dc Novel CIC00953 simplex IQCB1 NM_001023570.2 Het 6 c.424_425del p.(F142Pfs*5) + - - - - (Otto et al. 2005) (Senior-Loken/LCA) IQCB1 NM_001023570.2 Het 8 c.686del p.(T229Mfs*8) + - - - - Novel CIC01300 Ar + RP1 NM_006269.1 Ho 4 c.1719_1723del p.(S574Cfs*7) Np - - - - (El Shamieh et al 2015) (arRP) CIC05272 Ad BEST1 NM_001139443.1 Het 4 c.76G>A p.(V26M) + Highly Prd D Dc (Yardley et al. 2004) (ADVIRC) (rs121918289) CIC01380 Ar + CRB1 NM_201253.2 Ho 11 c.3994T>G p.(C1332G) + Highly Prd D Dc Novel (LCA) CIC00963 Ar + TULP1 NM_003322.4 Ho 11 c.1087G>A p.(G363R) + Highly Pd D Dc Novel (LCA and arRP) Lower confidence CIC05007 Ad ROM1 NM_000327.3 Het 1 c.339del p.(L114Sfs*8) + - - - - Novel (adRP) Most likely not pathogenic CIC05379 simplex FSCN2 NM_001077182.2 Het 1 c.574C>T p.(R192C) + Highly Prd D Dc Novel (adRP and adMD but questionable) (rs377025075) CIC05604 simplex FSCN2 NM_001077182.2 Het Partial 1 Partial deletion - Np - - - - Novel (adRP and adMD but questionable) RP: Retinitis Pigmentosa; MD: macular dystrophy; LCA: Leber Congenital Amaurosis; ADVIRC: Autosomal Dominant Vitreoretinochoroidopathy; Ad:autosomal dominant; Ar: autosomal recessive; Consang.: Consangunity; Coseg.: Cosegregation; Np: Not possible; Poly: Polymorphism ; Het: heterozygous; Ho: homozygous; B: Benign; T: Tolerated; Prd: Proabably damaging, Pd: Possible disease causing; D: Damaging; Dc: Disease causing We re-assessed pathogenic prediction for the published and novel variants we identified herein and all of them remain convincing except one on EYS (p.N745S) [23, 39], which now appears not conserved with a poor pathogenic prediction profile (Table 2), most likely due to novel sequenced species showing also the S amino acid at position 745. Login to comment
148 For the remaining 2 patients, mutations were identified in genes not classically associated with CCRD (Table 2: BEST1 c.76G > A, p.(V26M) and ROM1 c.339del, p.(L114Sfs*8)). Login to comment
208 CIC05272 carried a missense mutation in BEST1 (c.76G > A p.(V26M)) already associated with Autosomal Dominant Vitreoretinochoridopathy (ADVIRC) [50]. Login to comment