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.

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ABCA4 p.Val26Met 26103963:124:2108

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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)).

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ABCA4 p.Val26Met 26103963:148:132

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208 CIC05272 carried a missense mutation in BEST1 (c.76G > A p.(V26M)) already associated with Autosomal Dominant Vitreoretinochoridopathy (ADVIRC) [50].

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ABCA4 p.Val26Met 26103963:208:60

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