ABCMdb

PMID: 23143460

Downes SM, Packham E, Cranston T, Clouston P, Seller A, Nemeth AH
Detection rate of pathogenic mutations in ABCA4 using direct sequencing: clinical and research implications.
Arch Ophthalmol. 2012 Nov;130(11):1486-90. doi: 10.1001/archophthalmol.2012.1697., [PubMed]

Sentences

No. Mutations Sentence Comment

28 ABCA4 p.Gly1961Glu ABCA4 p.Gly863Ala ABCA4 p.Gly863Ala ABCA4 p.Gly863Ala ABCA4 p.Arg212Cys ABCA4 p.Cys54Tyr ABCA4 p.Cys54Tyr ABCA4 p.Cys1490Tyr ABCA4 p.Cys1490Tyr ABCA4 p.Leu2027Phe ABCA4 p.Arg1108Cys ABCA4 p.Arg1108Cys ABCA4 p.Arg2030Gln ABCA4 p.Pro1486Leu ABCA4 p.Leu1201Arg ABCA4 p.Gly991Arg ABCA4 p.Gly991Arg ABCA4 p.Val643Met ABCA4 p.Arg152Gln ABCA4 p.Arg1129Leu ABCA4 p.Gly1441Asp ABCA4 p.Gly885Glu In 5 of the 11 patients, the identification of 2 pathogenic mutations confirmed the historical diagnosis and all had chorioretinal atro- Table. Results From Direct Sequencing of the ABCA4 Gene in 50 Patients Subject No. Change 1 Change 2 Phase Segregation Age at Onset, y Phenotype Grade, Macula Flecks/ Cones/Rodsa Additional Variants Conclusion Nucleotide Amino Acid Nucleotide Amino Acid 1 1Ab0e;G M1V 2588Gb0e;C G863A In trans Unaffected parents carriers 30 STGD maf9;/0/0 R2030Q 3 PVs 2 161Gb0e;A C54Y 2588Gb0e;C G863A In trans Affected sibling with same mutations 12 STGD m/0/0 0 2 PVs 3 161Gb0e;A C54Y 5882Gb0e;A G1961E NK NK 18 STGD m/0/0 0 2 PVs 4 634Cb0e;T R212C 4457Cb0e;T P1486L In trans Unaffected parents carriers 17 STGD m/0/0 0 2 PVs 5 2588Gb0e;C G863A 4469Gb0e;A C1490Y NK NK 48 STGD maf9;/0/1 0 2 PVs 6 2971Gb0e;C G991R 4254-2Ab0e;G Splice NK NK 21 STGD m/0/0 0 2 PVs 7 2971Gb0e;C G991R 3602Tb0e;G L1201R NK NK 18 STGD maf9;af9;/NP/NP V643M (likely), G885E (likely), G1441D (unlikely), V2244V (highly likely) b0e;2 PVs 8 3322Cb0e;T R1108C 768Gb0e;T V256V NK NK 13 STGD maf9;af9;/1/1 0 2 PVs 9 3322Cb0e;T R1108C 6079Cb0e;T L2027F NK NK 26 STGD maf9;/0/0 0 2 PVs 10 3386Gb0e;T R1129L 4469Gb0e;A C1490Y In trans Unaffected parents carriers 15 STGD maf9;/0/0 R152Q (unlikely) 2 PVs (continued) ARCH OPHTHALMOL/VOL 130 (NO. 11), NOV 2012 WWW.ARCHOPHTHALMOL.COM 1486 phy on current clinical examination, consistent with progression of the disorder.5 One of the 11 patients with chorioretinal atrophy (subject 40) had a single stop codon, again strongly supporting the original clinical diagnosis. Six of the 11 patients did not have pathogenic mutations in ABCA4. Login to comment 30 ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Gly863Ala ABCA4 p.Gly863Ala ABCA4 p.Gly863Ala ABCA4 p.Gly863Ala ABCA4 p.Gly863Ala ABCA4 p.Thr1019Met ABCA4 p.Cys1490Tyr ABCA4 p.Glu2131Lys ABCA4 p.Glu2131Lys ABCA4 p.Arg2106Cys ABCA4 p.Val989Ala ABCA4 p.Arg653Cys ABCA4 p.Leu2027Phe ABCA4 p.Leu2027Phe ABCA4 p.Ala1598Asp ABCA4 p.Arg2030Gln ABCA4 p.Arg2030Gln ABCA4 p.Pro1380Leu ABCA4 p.Pro1486Leu ABCA4 p.Pro1486Leu ABCA4 p.Arg152Gln ABCA4 p.Ile1846Thr ABCA4 p.Ile1846Thr ABCA4 p.Glu471Lys ABCA4 p.Glu1022Lys ABCA4 p.Asn1442Lys ABCA4 p.Asn1442Lys ABCA4 p.Phe418Ser ABCA4 p.Tyr1754Asp ABCA4 p.Arg1097Ser In 3 of the 6 patients with a historical diagnosis Table. Results From Direct Sequencing of the ABCA4 Gene in 50 Patients (continued) Subject No. Change 1 Change 2 Phase Segregation Age at Onset, y Phenotype Grade, Macula Flecks/ Cones/Rodsa Additional Variants Conclusion Nucleotide Amino Acid Nucleotide Amino Acid 11 4139Cb0e;T P1380L 5714 af9; 5Gb0e;A Splice NK NK 19 STGD m/0/0 0 2 PVs 12 4457Cb0e;T P1486L 4457Cb0e;T P1486L In trans Unaffected sibling carries 1 mutation 25 STGD maf9;af9;/1/1 0 2 PVs 13 4537dupC Q1513fs 6391Gb0e;A E2131K In trans Unaffected parents carriers 10 STGD maf9;/0/0 R152Q in cis with Q1513fs, E2131K in cis with E471K 2 PVs 14 6079Cb0e;T L2027F 6079Cb0e;T L2027F In trans Unaffected sibling carrier 28 STGD maf9;af9;/0/0 0 2 PVs 15 5018 af9; 2Tb0e;C NA 6316Cb0e;T R2106C In trans Affected sibling with same mutations 17 STGD m/0/1 0 2 PVs 16 3004Cb0e;T R1002Wb 1957Cb0e;T R653C In trans NK 16 STGD m/0/1 0 2 PVs 17 1253Tb0e;C F418S 2588Gb0e;C G863A NK NK 52 STGD maf9;/0/0 0 2 PVs 18 6709Ab0e;C T2237Pb 3064Gb0e;A E1022K In trans 2 Affected siblings with same mutations 6 STGD maf9;af9;/0/0 0 2 PVs 19 5260Tb0e;G Y1754D 4469Gb0e;A C1490Y In trans NK 12 STGD maf9;af9;/0/0 0 2 PVs 20 551Cb0e;T S184Fb 4793Cb0e;A A1598D NK 2 Affected siblings with same mutations 58 STGD m/NP/NP 0 2 PVs 21 550-551TCb0e;CG S184Rb 5882Gb0e;A G1961E In trans Affected sibling with same mutations 25 STGD maf9;af9;/0/0 0 2 PVs 22 5313-3Cb0e;G Spliceb 5882Gb0e;A G1961E In trans Unaffected parents carriers 47 STGD m/0/1 0 2 PVs 23 2588Gb0e;C G863A 5461-10Tb0e;C Disease-associated allele, unknown mechanism In trans NA 26 STGD maf9;af9;/3/1 1 In cis with G863A 2 PVs 24 5537Tb0e;C I1846T 5461-10Tb0e;C Disease-associated allele, unknown mechanism In trans Unaffected son carries I1846T only 17 STGD maf9;af9;/3/3 0 2 PVs 25 6089Gb0e;A R2030Q 5461-10Tb0e;C Disease-associated allele, unknown mechanism In trans Unaffected sibling carries R2030Q 4 STGD m/NP/NP 0 2 PVs 26 6730-1Gb0e;C Spliceb 2588Gb0e;C G863A NK NK 15 STGD NP/NP/NP 0 2 PVs 27 3291Ab0e;T R1097Sb 3056Cb0e;T T1019M In trans NK 9 STGD NP/NP/NP 1 In cis with R1097S 2 PVs 28 498delT L167HisfsX2b Not present NA NA NK 28 STGD m/1/1 0 1 PV 29 2345Gb0e;A W782Xb Not present NA NA Unaffected mother carries mutation 25 STGD m/1/1 0 1 PV 30 2588Gb0e;C G863A 4326Cb0e;A N1442K NK NK 36 STGD maf9;/0/0 0 1 PV af9; N1442K (unlikely) 31 2966Tb0e;C V989A Not present NA NA NK 49 STGD m/1/1 0 1 PV (continued) ARCH OPHTHALMOL/VOL 130 (NO. 11), NOV 2012 WWW.ARCHOPHTHALMOL.COM 1487 (c)2012 American Medical Association. All rights reserved. Downloaded From: http://archopht.jamanetwork.com/ by a Semmelweis University Budapest User on 12/06/2015 lopathy is genetically heterogeneous. A total of 10 novel mutations were identified (Table). Login to comment 41 ABCA4 p.Asp576His Table. Results From Direct Sequencing of the ABCA4 Gene in 50 Patients (continued) Subject No. Change 1 Change 2 Phase Segregation Age at Onset, y Phenotype Grade, Macula Flecks/ Cones/Rodsa Additional Variants Conclusion Nucleotide Amino Acid Nucleotide Amino Acid 48 NA NA NA NA NA NA 16 Vitelliform (historical diagnosis of STGD) maf9;af9;/0/1 0 0 PVs 49 5461-10Tb0e;C Disease-associated allele, unknown mechanism 1726Gb0e;C D576H NA NA 50 Pattern dystrophy (historical diagnosis of STGD) maf9;af9;/1/2 0 1 Splice and 1 uncertain 50 NA NA NA NA NA Unaffected sibling 45 Atypical pattern dystrophy (historical diagnosis of STGD) maf9;af9;/0/0 0 0 PVs Abbreviations: BEM, bull`s-eye maculopathy; CRA, chorioretinal atrophy; NA, not applicable; NK, not known; NP, not performed; PV, pathogenic variant; RP, retinitis pigmentosa; STGD, Stargardt disease. aThe presence of flecks at the macula was classified as follows: m indicates flecks confined to the macula; maf9;, sparse flecks extending beyond the arcades; and maf9;af9;, more extensive flecks outside the arcades. Cone and rod function was based on International Society for Clinical Electrophysiology of Vision electrophysiology including rod, standard bright white flash, cone flicker, and photopic electroretinograms. These were graded as follows: 0 indicates unaffected; 1, mild; 2, moderate; 3, moderately severe; and 4, severe. bNovel mutation. Susan M. Downes, MBChB, MD, FRCOphth Emily Packham, DipRCPath Treena Cranston, BSc, DipRCPath Penny Clouston, PhD, FRCPath Anneke Seller, PhD, DipRCPath Andrea H. Ne &#b4;meth, BSc, MBBS, DPhil, FRCP ARCH OPHTHALMOL/VOL 130 (NO. 11), NOV 2012 WWW.ARCHOPHTHALMOL.COM 1489 lopathy is genetically heterogeneous. A total of 10 novel mutations were identified (Table). Login to comment 52 ABCA4 p.Asp576His Table. Results From Direct Sequencing of the ABCA4 Gene in 50 Patients (continued) Subject No. Change 1 Change 2 Phase Segregation Age at Onset, y Phenotype Grade, Macula Flecks/ Cones/Rodsa Additional Variants Conclusion Nucleotide Amino Acid Nucleotide Amino Acid 48 NA NA NA NA NA NA 16 Vitelliform (historical diagnosis of STGD) maf9;af9;/0/1 0 0 PVs 49 5461-10Tb0e;C Disease-associated allele, unknown mechanism 1726Gb0e;C D576H NA NA 50 Pattern dystrophy (historical diagnosis of STGD) maf9;af9;/1/2 0 1 Splice and 1 uncertain 50 NA NA NA NA NA Unaffected sibling 45 Atypical pattern dystrophy (historical diagnosis of STGD) maf9;af9;/0/0 0 0 PVs Abbreviations: BEM, bull`s-eye maculopathy; CRA, chorioretinal atrophy; NA, not applicable; NK, not known; NP, not performed; PV, pathogenic variant; RP, retinitis pigmentosa; STGD, Stargardt disease. aThe presence of flecks at the macula was classified as follows: m indicates flecks confined to the macula; maf9;, sparse flecks extending beyond the arcades; and maf9;af9;, more extensive flecks outside the arcades. Cone and rod function was based on International Society for Clinical Electrophysiology of Vision electrophysiology including rod, standard bright white flash, cone flicker, and photopic electroretinograms. These were graded as follows: 0 indicates unaffected; 1, mild; 2, moderate; 3, moderately severe; and 4, severe. bNovel mutation. Susan M. Downes, MBChB, MD, FRCOphth Emily Packham, DipRCPath Treena Cranston, BSc, DipRCPath Penny Clouston, PhD, FRCPath Anneke Seller, PhD, DipRCPath Andrea H. Ne &#b4;meth, BSc, MBBS, DPhil, FRCP ARCH OPHTHALMOL/VOL 130 (NO. 11), NOV 2012 WWW.ARCHOPHTHALMOL.COM 1489 (c)2012 American Medical Association. All rights reserved. Downloaded From: http://archopht.jamanetwork.com/ by a Semmelweis University Budapest User on 12//2015 . Login to comment