ABCMdb

PMID: 26103963

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., [PubMed]

Sentences

No. Mutations Sentence Comment

99 ABCA4 p.Ala1598Asp ABCA4 p.Phe642Ile ABCA4 p.Glu2132Lys ABCA4 p.Phe642Leu Table 1 Summary of 43 patients carrying pathogenic and likely pathogenic mutations in known CCRD genes ID Type Consang. Gene NM Allele State Exon cDNA Protein Coseg. Conservation Polyphen2 Sift Mutation taster References High confidence CIC00137 simplex ABCA4 NM_000350.2 Ho 47 c.6394G>A p.(E2132K) + Highly Prd D Dc Novel CIC00765 Ar + ABCA4 NM_000350.2 Ho 47 c.6445C>T p.(R2149*) + - - - - (Lewis et al. 1999) (rs61750654) CIC03436 Ar + ABCA4 NM_000350.2 Ho 42 c.5892del p.(G1965Efs*9) Np - - - - a CIC04412 simplex ABC4A NM_000350.2 Het 34 c.4793C>A p.(A1598D) + Weakly Pd T Dc (Maugeri et al. 2000) (rs61750155) ABCA4 NM_000350.2 Het 28 c.4234C>T p.(Q1412*) + - - - - (Maugeri et al. 2000) (rs61750137) CIC04645 Ar + ABCA4 NM_000350.2 Ho 13 c.1924T>C p.(F642L) Np Moderately B D Dc Novel, but c.1924T>A p.F642I in (Jin et al. 2014) [80] CIC05087 simplex ABCA4 NM_000350.2 Ho IVS 11 c.1554+1G>C r.(spl?) Login to comment 100 ABCA4 p.Arg1640Gln ABCA4 p.Arg2030Gln ABCA4 p.Glu1087Lys ABCA4 p.Ala1773Val ABCA4 p.Asp1613Asn Np Highly - - - Novel CIC05853 simplex + ABC4A NM_000350.2 Ho 22 c.3259G>A p.E1087K Np Highly Prd D Dc (Allikmets et al. 1997) (rs61751398) [81] CIC05854 Ar + ABC4A NM_000350.2 Ho 35 c.4919G>A p.(R1640Q) + Highly Prd D Dc (Simonelli et al. 2000) (rs61751403) [82] CIC05989 simplex ABC4A NM_000350.2 Het 34 c.4837G>A p.(D1613N) + Not B D Dc Novel ABC4A NM_000350.2 Het 10 c.1302del p.(Q437Rfs*12) + - - - - Novel ABCA4 NM_000350.2 Het 38 c.5318C>T p.(A1773V) + Moderately Prd D Dc (Stenirri et al. 2008) [83] CIC06170 simplex ABC4A NM_000350.2 Het 44 c.6089G>A p.(R2030Q) + Highly Prd D Dc (Lewis et al. 1999) (rs61750641) ABC4A NM_000350.2 Het IVS 24 c.3607+3A>T r.(spl?) Login to comment 101 ABCA4 p.Thr1019Met ABCA4 p.Lys678Asn + Moderately - - - Novel ABCA4 NM_000350.2 Het 14 c.2034G>T p.(K678N) + Highly Prd Des Dc (Huang et al. 2014) [84] CIC06735 Ar + ABC4A NM_000350.2 Ho 42 c.5892del p.(G1965Efs*9) Np - - - - a CIC06913 Ar + ABCA4 NM_000350.2 Ho 21 c.3056C>T p.(T1019M) + Highly Prd D Dc (Rozet et al. 1998) (rs201855602) [85] CIC04239 Ar + CDHR1 NM_033100.3 Ho 9 c.838C>T p.(R280*) Np - - - Novel CIC06568 Ar + CERKL NM_001030311.2 Ho 8 c.1090C>T p.(R364*) Np - - - - Thesis (Sergouniotis P. 2012) b CIC07299 simplex + PDE6C NM_006204.3 Ho 2 c.542del p.(A181Efs*13) Np - - - - Novel CIC05218 Ar + PDE6C NM_006204.3 Ho IVS 10 c.1413+3A>T r.(spl?) Login to comment 104 ABCA4 p.Arg1108Cys ABCA4 p.Ser1099Pro + Highly - - - Novel CIC04965 Ad CRX NM_000554.4 Het 4 c.608_609del p.(S203Ffs*32) + - - - - Novel CIC3750 simplex CRX NM_000554.4 Het 3 c.121C>T p.(R41W) + Highly Prd D Dc (Swain et al. 1997) (rs104894672) CIC06321 simplex + RPGRIP1 NM_020366.3 Ho 14 c.2021C>A p.(P674H) + Highly Prd T Dc Novel CIC00190 simplex AIPL1 NM_014336.4 Het 5 c.769C>T p.(L257F) + Moderately Prd D Dc Novel AIPL1 NM_014336.4 Het 5 c.767T>G p.(I256S) + Moderately B D Dc Novel Lower confidence d CIC00162 Ar ABCA4 NM_000350.2 Het 31 c.4546_4547del p.(Q1516Afs*38) + - - - - Novel ABCA4 NM_000350.2 Het 16 c.2463G>A p.(W821*) + - - - - Novel CIC05987 Ar ABC4A NM_000350.2 Het 22 c.3295T>C p.(S1099P) + Highly Pd D Dc (Fumagalli et al. 2001) (rs61750119) [87] ABC4A NM_000350.2 Het 22 c.3322C>T p.(R1108C) Np - - - - (Briggs et al. 2001) [88] CIC06694 simplex ABC4A NM_000350.2 Het IVS36 c.5196+1G>A r.(spl?) Login to comment 105 ABCA4 p.Arg1108Cys Np - - - - (Kitiratschky et al. 2008) ABC4A NM_000350.2 Het 22 c.3322C>T p.(R1108C) Np - - - - (Briggs et al. 2001) [86] CIC02712 simplex + PDE6C NM_006204.3 Het 10 c.1325T>A p.(M442K) Np Moderately Pd D Dc Novel PDE6C NM_006204.3 Het 10 c.1375C>G p.(Q459E) Weakly B T Dc Novel CIC00597 simplex GUCY2D NM_000180.3 Het 14 c.2747T>C p.(I916T) + Moderately Prd D Dc (De Castro-Mir&#f3; et al. 2014) [89] CIC06352 simplex GUCA1A NM_000409.3 Het 3 c.149C>T p.(P50L) Np Moderately B T Dc (Downes et al. 2001) (rs104893968) [90] CIC07188 simplex PROM1 NM_006017.2 Het 12 c.1354dup p.(Y452Lfs*13) Np - - - - (Pras et al. 2009) PROM1 NM_006017.2 Het IVS 12 c.1454+2>C r.(spl?) Login to comment 124 ABCA4 p.Val26Met 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 ABCA4 p.Val26Met 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 ABCA4 p.Val26Met CIC05272 carried a missense mutation in BEST1 (c.76G > A p.(V26M)) already associated with Autosomal Dominant Vitreoretinochoridopathy (ADVIRC) [50]. Login to comment