ABCMdb

PMID: 23523379

Rechitsky S, Verlinsky O, Kuliev A
PGD for cystic fibrosis patients and couples at risk of an additional genetic disorder combined with 24-chromosome aneuploidy testing.
Reprod Biomed Online. 2013 May;26(5):420-30. doi: 10.1016/j.rbmo.2013.01.006. Epub 2013 Jan 29., [PubMed]

Sentences

No. Mutations Sentence Comment

41 ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Leu206Trp ABCC7 p.Leu206Trp ABCC7 p.Gly85Glu ABCC7 p.Gly85Glu ABCC7 p.Arg75Gln ABCC7 p.Arg75Gln ABCC7 p.Ala120Thr ABCC7 p.Ala120Thr ABCC7 p.Arg117Cys ABCC7 p.Arg117Cys ABCC7 p.Arg75* ABCC7 p.Ala349Val ABCC7 p.Ala349Val ABCC7 p.Thr360Lys ABCC7 p.Gln359Lys Mutation Region Legacy name cDNA name Protein name # of Patient Number of cycles Number of transfers Number of embryos transferred Pregnancy Birth 125G/C c.-8G>C NA Promoter 1 2 2 2 1 (1) 0 E60X c.178G>T p.Glu60X Exon 3 1 1 1 1 0 0 G85E c.254G>A p.Gly85Glu Exon 3 1 1 1 2 1 1 R75Q c.224G>A p.Arg75Gln Exon 3 1 1 1 1 1 1 R75X c.223C>T p.Arg75X Exon 3 1 1 1 2 1 2 A120T c.358G>A p.Ala120Thr Exon 4 1 1 1 1 0 0 R117C c.349C>T p.Arg117Cys Exon 4 2 6 3 5 1 1 R117H c.350G>A p.Arg117His Exon 4 14 22 19 38 8 6 621+1G-T c.489 &#b1; 1G>T - Intron 4 4 7 4 6 2 1 852del22 c.720_741 p.Gly241GlufsX13 Exon 6 1 1 0 0 0 0 L206W c.617T>G p.Leu206Trp Exon 6 1 2 1 2 0 0 A349V c.1046C>T p.Ala349Val Exon 8 1 2 2 4 2 4 1078delT c.948delT p.Phe316LeufsX12 Exon 8 1 1 1 1 1 0 1154ins-TC c.1022_1023insTC p.Phe342HisfsX28 Exon 8 1 2 1 2 0 0 Q359K/T360K c. Login to comment 42 ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp ABCC7 p.Trp1282* ABCC7 p.Arg553* ABCC7 p.Gly551Ser ABCC7 p.Gly551Ser ABCC7 p.Arg347Pro ABCC7 p.Arg347Pro ABCC7 p.Asn1303Lys ABCC7 p.Asn1303Lys ABCC7 p.Gly542* ABCC7 p.Arg1162* ABCC7 p.Arg560Thr ABCC7 p.Arg560Thr ABCC7 p.Thr338Ile ABCC7 p.Thr338Ile ABCC7 p.Ser1235Arg ABCC7 p.Ser1235Arg ABCC7 p.Tyr1092* ABCC7 p.Asp1152His ABCC7 p.Asp1152His ABCC7 p.Phe1052Val ABCC7 p.Phe1052Val ABCC7 p.Gly622Asp ABCC7 p.Gly622Asp ABCC7 p.Leu997Phe ABCC7 p.Leu997Phe ABCC7 p.Ile1027Thr ABCC7 p.Ile1027Thr ABCC7 p.Thr360Lys ABCC7 p.Gln493Arg ABCC7 p.Gln493Arg ABCC7 p.Gln359Lys ABCC7 p.Ala1136Thr ABCC7 p.Ala1136Thr ABCC7 p.Ile556Val ABCC7 p.Ile556Val ABCC7 p.Gln1352His ABCC7 p.Gln1352His ABCC7 p.Ser737Phe ABCC7 p.Ser737Phe ABCC7 p.Met1028Arg ABCC7 p.Met1028Arg ABCC7 p.Asn703Ser ABCC7 p.Asn703Ser [1075C>A; 1079C>A] p.[Gln359Lys; Thr360Lys] Exon 8 1 1 1 4 1 1 R297Q c.890G>A p.Arg297Gln Exon 8 1 1 1 2 0 0 R347P c.1040G>C p.Arg347Pro Exon 8 3 5 2 4 1 1 T338I c.1013C>T p.Thr338Ile Exon 8 1 1 1 2 1 1 DF508 c.1521_1523delCTT p.Phe508del Exon 11 130 195 172 345 88 (4) 92 DI507 c.1519_1521delATC p.Ile507del Exon 11 1 5 5 11 2 1 Q493R c.1478A>G p.Gln493Arg Exon 11 5 5 2 2 2 2 1717-1G-A c.1585-1G>A - Intron 11 6 10 9 18 6 8 G542X c.1624G>T p.Gly542X Exon 12 14 17 15 34 10 10 G551S c.1651G>A p.Gly551Ser Exon 12 1 1 1 2 1 1 G551D c.1652G>A p.Gly551Asp Exon 12 12 22 19 33 7 8 I556V c.1666A>G p.Ile556Val Exon 12 1 2 2 4 1 1 R553X c.1657C>T p.Arg553X Exon 12 3 4 2 4 0 0 R560T c.1679G>C p.Arg560Thr Exon 12 1 1 1 2 1 2 1898+1G-A c.1766 &#b1; 1G>A - Intron 13 1 1 1 2 1 1 2184delA c.2052delA p.Lys684AsnfsX38 Exon 14 1 1 0 0 0 0 G622D c.1865G>A p.Gly622Asp Exon 14 1 1 1 3 0 0 N703S c.2108A>G p.Asn703Ser Exon 14 1 2 2 3 2 2 S737F c.2210C>T p.Ser737Phe Exon 14 1 1 0 0 0 0 2622+1G-A c.2490 &#b1; 1G>A - Intron 14 1 5 5 13 1 1 2752-26A-G c.2620-26A>G - Intron 15 1 2 2 4 0 0 2789+5G-A c.2657 &#b1; 5G>A - Intron 16 3 5 4 8 0 0 3120G-A c.2988G>A - Exon 18 2 2 1 2 1 0 3067-72del c.3067_3072del p.Ile1023_Val1024del Exon 19 1 1 1 1 0 0 I1027T c.3080T>C p.Ile1027Thr Exon 19 1 1 1 1 0 0 L997F c.2991G>C p.Leu997Phe Exon 19 1 2 2 4 1 (1) 0 M1028R c.3083T>G p.Met1028Arg Exon 19 1 1 1 2 1 2 F1052V c.3154T>G p.Phe1052Val Exon 20 1 1 0 0 0 0 Y1092X c.3276C>A p.Tyr1092X Exon 20 1 2 1 2 1 1 A1136T c.3406G>A p.Ala1136Thr Exon 21 1 2 1 2 1 0 D1152H c.3454G>C p.Asp1152His Exon 21 3 7 7 15 1 1 3659 del C c.3528delC p.Lys1177SerfsX15 Exon 22 2 4 3 7 3 3 R1162X c.3484C>T p.Arg1162X Exon 22 1 3 2 5 2 2 S1235R c.3705T>G p.Ser1235Arg Exon 22 2 3 3 5 2 1 3849+10kbC>T c.3717 &#b1; 12191C>T - Intron 22 2 4 4 5 0 0 W1282X c.3846G>A p.Trp1282X Exon 23 15 20 20 42 11 11 N1303K c.3909C>G p.Asn1303Lys Exon 24 9 12 11 24 4 5 Q1352H c.4056G>C p.Gln1352His Exon 25 1 1 1 1 1 1 Total 265 404 345 685 172 (6a ) 175 Values are n unless otherwise stated. Login to comment 53 ABCC7 p.Gly551Asp ABCC7 p.Arg117His ABCC7 p.Trp1282* ABCC7 p.Asn1303Lys ABCC7 p.Gly542* Almost half of these (195/404 cycles) were performed for DF508 mutation, one-quarter (103/404 cycles)forsixotherfrequentmutations(W1282X,R117H,G551D, G542X, N1303K, 1717-1G>A), and only a few for each of the remaining 45 CFTR mutations (Table 2). Login to comment 54 ABCC7 p.Trp1282* As shown in Table 3, close to a half of these PGD cycles (180/404) were performed for 122 couples with the same mutation in both parents, including one with both partners carrying 1-3120G>A, two with both partners carrying W1282X, and 119 with both partners carrying the DF508 mutation. Login to comment 56 ABCC7 p.Gly551Asp ABCC7 p.Arg117His ABCC7 p.Trp1282* ABCC7 p.Arg553* ABCC7 p.Asn1303Lys ABCC7 p.Gly542* ABCC7 p.Arg1162* ABCC7 p.Ile148Thr ABCC7 p.Arg560Thr ABCC7 p.Ala120Thr ABCC7 p.Ala349Val ABCC7 p.Gly550* (CA)n EXON 4 (GATT)n Intron 4 Poly T tract Intron 10 R117H G--A R75XH C--T A120T G--A I148T T--C A349V C--T 1259 Ins A 621+1 G--T EXON 3 EXON 7 EXON 8 Delta I 507 EXON 10 Delta F 508 EXON 11 1717-1 G--A G542X G--T G550X G--T G551D G--A R553X C--T R560T G--C EXON 19 EXON 20 EXON 21 R1162X C--T W1282X G--A N1303K C--G IVS 1 Mutations in CFTR gene (PGD PERFORMED FOR 52 MUTATIONS) IVS 6 a IVS 8 (CA)n (CA)n IVS 17b (TA)n (CA)n D7S486 D7S522 D7S633 D7S677 D7S2847 D7S655 115,89 116.07 117.01 117.13 117.19 117.20 118.6 118.81 Mb IVS8-1 IVS8-2 Figure 1 Mutations (above) and linked markers (below) in CFTR that were used in multiplex PCR. Login to comment 60 ABCC7 p.Trp1282* of mutations in a couple Patients Cycles Transfers Embryos transferred Pregnancies Babies born 1 122: 119 with DF508, 2 with W1282X; 1 with 3120G>A 180 159 317 81 (50.9) (4a ) 84 2 118 180 150 296 74 (49.3) 78 3 25 (18 male + 7 female) 44 36 72 17 (47.2) (2a ) 13 (3 from affected mothers; 10 from affected fathers) Total 265 404 345 685 172 (49.9) (6a ) 175 (50.7) Values are n or n (%) unless otherwise stated. a Ongoing pregnancies. Login to comment 67 ABCC7 p.Arg117His PGD for this case seemed to be the only choice, as the male partner was double heterozygous for DF508 and R117H and the female partner was a carrier of the DF508 mutation. Login to comment 75 ABCC7 p.Asp1152His (Upper panel) Pedigree showing that both of the parents are carriers of different CFTR mutations: the mother is a carrier of D1152H and the father is a carrier or V1282X. Login to comment 81 ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Gly542* Because the female partner was double heterozygous, involving two different mutations (R117H and G542X), and the male partner was a carrier of R117H mutation, PGD was based on blastomere biopsy. Login to comment 88 ABCC7 p.Gly542* Two unaffected embryos (nos. 6 and 7) were transferred, resulting in an unaffected pregnancy and birth of a healthy baby girl, confirmed to be a carrier of the maternal G542X mutation. Login to comment 92 ABCC7 p.Arg117His ABCC7 p.Arg117His 1.1 1.2 PGD PGD MARKERS ORDER D7S486 D7S522 D7S633 D7S677 INTRON 1 INTRON 6 INTRON 8-1 CFTR D7S847 1 2 3 4 5 9 10 11 Oocyte # Predicted Genotype: Sequential Polar Body Analysis 117 135 150 131 212 100 126 F508 161 122 131 148 125 217 104 124 N 149 117 137 150 135 208 104 124 R117h 161 124 131 150 131 212 100 139 F508 161 117 135 150 131 212 100 126 F508 161 122 131 148 125 217 104 124 N 149 117 135 150 131 212 100 126 F508 161 122 131 148 125 217 104 124 N 149 122 131 148 125 217 104 124 N 149 117 135 150 131 212 100 126 F508 161 122 131 148 125 217 104 124 N 149 122 131 148 125 217 104 124 N 149 117 135 150 131 212 100 126 F508 161 117 135 150 131 212 100 126 F508 161 117 135 150 131 212 100 126 F508 161 122 131 148 125 217 104 124 N 149 122 131 148 125 217 104 124 N 149 122 131 148 125 217 104 124 N 149 117 135 150 131 212 100 126 F508 161 117 135 150 131 212 100 126 F508 161 117 135 150 131 212 100 126 F508 161 122 131 148 125 217 104 124 N 149 122 131 148 125 217 104 124 N 149 122 131 148 125 217 104 124 N 149 PB1 PB2 AFFECTED AFFECTED NORMAL NORMAL AFFECTED NORMAL NORMAL AFFECTED ET ET 2.1 2.2 R117H/N R117H/N 117 135 150 131 212 100 126 F508 161 Figure 3 PGD for a double-heterozygous CF-affected male patient by sequential polar body analysis. Login to comment 93 ABCC7 p.Arg117His (Upper panel) Pedigree showing that the paternal partner is a double-heterozygous CF-affected patient, with two different CFTR mutations, DF508 and R117H, while the maternal partner is a carrier of DF508. Login to comment 95 ABCC7 p.Arg117His Two embryos resulting from oocytes 3 and 4 were transferred (ET), resulting in an unaffected twin pregnancy and birth of two healthy baby girls carrying the paternal R117H mutation. Login to comment 109 ABCC7 p.Arg117His ABCC7 p.Gly542* (Upper panel) Pedigree, showing that the maternal partner is a double-heterozygous CF-affected patient, with two different CFTR mutations, R117H and G542X, while the paternal partner is a carrier of the 1717 mutation. Login to comment 142 ABCC7 p.Asn703Ser (Upper panel) Pedigree showing that both partners are carriers of SMN1, while the father is also a carrier of DF508 and the mother is also a carrier of the N703S CFTR mutation. Login to comment 144 ABCC7 p.Asn703Ser 1) appeared to be free of both SMN1 and N703S mutations, while others were with either a CFTR or SMN1 mutation. Login to comment 151 ABCC7 p.Asn703Ser As seen from this cycle, both partners are carriers of SMN1, while father is also a carrier of DF508 and mother also the carrier of the N703S CFTR mutation. So sequential PB1 and PB2 testing was performed first to detect oocytes free of CFTR and SMN1 mutations, with further testing of the resulting embryos by 24-chromosome aneuploidy. Login to comment 153 ABCC7 p.Asn703Ser 1) appeared to be free of both SMN1 and N703S mutations, while others were with either a CFTR or SMN1 mutation. Login to comment