PMID: 17329263

Ratbi I, Legendre M, Niel F, Martin J, Soufir JC, Izard V, Costes B, Costa C, Goossens M, Girodon E
Detection of cystic fibrosis transmembrane conductance regulator (CFTR) gene rearrangements enriches the mutation spectrum in congenital bilateral absence of the vas deferens and impacts on genetic counselling.
Hum Reprod. 2007 May;22(5):1285-91. Epub 2007 Feb 28., [PubMed]
Sentences
No. Mutations Sentence Comment
15 ABCC7 p.Arg117His
X
ABCC7 p.Arg117His 17329263:15:245
status: NEW
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The most frequent are the main CF-associated defect, F508del (21-40% of alleles in CBAVD patients, depending on studies), and two mild defects, the T(5) variant of the polypyrimidin tract of the intron 8 (IVS8) acceptor splice site (19-37%) and R117H (3-14%). Login to comment
49 ABCC7 p.Arg75Gln
X
ABCC7 p.Arg75Gln 17329263:49:216
status: NEW
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Apart from the IVS8(T)5 variant, sequence variations which are reported as neutral because of segregation analysis in CF families or their frequency in the general population (Bombieri et al., 2000) (such as 356G.A (R75Q), 1540A.G (M470V) or 1716G.A) were not considered as disease-causing when found in isolation. Login to comment
50 ABCC7 p.Arg117His
X
ABCC7 p.Arg117His 17329263:50:332
status: NEW
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ABCC7 p.Trp1282*
X
ABCC7 p.Trp1282* 17329263:50:249
status: NEW
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ABCC7 p.Arg74Trp
X
ABCC7 p.Arg74Trp 17329263:50:490
status: NEW
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ABCC7 p.Leu206Trp
X
ABCC7 p.Leu206Trp 17329263:50:313
status: NEW
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ABCC7 p.Asp1152His
X
ABCC7 p.Asp1152His 17329263:50:339
status: NEW
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ABCC7 p.Asp443Tyr
X
ABCC7 p.Asp443Tyr 17329263:50:466
status: NEW
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ABCC7 p.Gly1069Arg
X
ABCC7 p.Gly1069Arg 17329263:50:590
status: NEW
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ABCC7 p.Val1153Glu
X
ABCC7 p.Val1153Glu 17329263:50:598
status: NEW
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ABCC7 p.Gln1352His
X
ABCC7 p.Gln1352His 17329263:50:437
status: NEW
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ABCC7 p.Ala959Val
X
ABCC7 p.Ala959Val 17329263:50:583
status: NEW
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CFTR mutations were detected in 387 out of 444 alleles (87.2%), most of them being previously described in patients with CF of varying severity, CBAVD or other CFTR diseases: 45% of identified alleles consisted of severe CF mutations (e.g. F508del, W1282X, 2183AA.G); 13.8% of mild or variable CF mutations (e.g. L206W, 3272-26A.G, R117H, D1152H); 36.7% of mild CFTR defects which are currently not considered CF-causing (e.g. IVS8(T)5, Q1352H, the complex alleles [D443Y;G576A;R668C] and [R74W;D1270N]) and 4.5% of rare missense mutations whose effect is difficult to predict (e.g. A959V, G1069R, V1153E). Login to comment
53 ABCC7 p.Val562Ile
X
ABCC7 p.Val562Ile 17329263:53:63
status: NEW
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In five out of the 14 patients carrying the (TG)11(T)5 allele, V562I was also identified, probably in cis as documented in two of these cases and in other patients who do not have CBAVD (Girodon et al., unpublished data). Login to comment
62 ABCC7 p.Val938Gly
X
ABCC7 p.Val938Gly 17329263:62:38
status: NEW
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Patient #2, heterozygous for the mild V938G missense mutation, had a deletion of exons 22 and 23, for which sequencing analysis showed the same breakpoints as those previously described (Audre´zet et al., 2004). Login to comment
63 ABCC7 p.Arg117His
X
ABCC7 p.Arg117His 17329263:63:96
status: NEW
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Patient #3 had already been referred to in Niel et al. (2004): he was apparently homozygous for R117H with IVS8(T)7 in cis and was found to carry a complete deletion of the CFTR gene, inherited from his mother. Login to comment
67 ABCC7 p.Arg117His
X
ABCC7 p.Arg117His 17329263:67:168
status: NEW
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Rearrangements, found in 6.9% of 58 unknown alleles (57 alleles from the first two groups of patients and one allele from the patient who was apparently homozygous for R117H), thus accounted for 0.9% of CBAVD alleles and 1% of the identified alleles. Login to comment
69 ABCC7 p.Arg74Trp
X
ABCC7 p.Arg74Trp 17329263:69:465
status: NEW
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ABCC7 p.Arg74Trp
X
ABCC7 p.Arg74Trp 17329263:69:486
status: NEW
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ABCC7 p.Arg74Trp
X
ABCC7 p.Arg74Trp 17329263:69:503
status: NEW
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ABCC7 p.Leu206Trp
X
ABCC7 p.Leu206Trp 17329263:69:400
status: NEW
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ABCC7 p.Asp1152His
X
ABCC7 p.Asp1152His 17329263:69:412
status: NEW
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ABCC7 p.Arg668Cys
X
ABCC7 p.Arg668Cys 17329263:69:342
status: NEW
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ABCC7 p.Arg668Cys
X
ABCC7 p.Arg668Cys 17329263:69:392
status: NEW
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ABCC7 p.Gly576Ala
X
ABCC7 p.Gly576Ala 17329263:69:377
status: NEW
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ABCC7 p.Asp443Tyr
X
ABCC7 p.Asp443Tyr 17329263:69:355
status: NEW
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ABCC7 p.Val562Ile
X
ABCC7 p.Val562Ile 17329263:69:440
status: NEW
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Frequent cystic fibrosis transmembrane conductance regulator (CFTR) defects found in congenital bilateral absence of the vas deferens (CBAVD) patients (above 1% among the identified alleles) Mutation No. of alleles % of the 390 identified alleles F508dela 119 30.5 IVS8(T)5a,b 107 27.4 (TG)12(T)5 82 (TG)13(T)5 16 (TG)11(T)5b 9 R117Ha 25 6.4 R668C 9 2.3 [D443Y;G576A;R668C] 6 [G576A;R668C] 2 R668C 1 L206W 7 1.8 D1152H 6 1.5 W1282Xa 5 1.3 [V562I;(TG)11(T)5] 5 1.3 [R74W;D1270 N] 4 1.0 [R74W;D1270 N] 3 [R74W;V201M;D1270 N] 1 Q1352H(G . Login to comment
71 ABCC7 p.Val562Ile
X
ABCC7 p.Val562Ile 17329263:71:22
status: NEW
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b Do not include the [V562I;(TG)11(T)5] complex alleles that are indicated below. Login to comment
83 ABCC7 p.Asp443Tyr
X
ABCC7 p.Asp443Tyr 17329263:83:3
status: NEW
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2 [D443Y;G576A;R668C] þ [?] Login to comment
84 ABCC7 p.Gly576Ala
X
ABCC7 p.Gly576Ala 17329263:84:3
status: NEW
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1 [G576A;R668C] þ [?] Login to comment
85 ABCC7 p.Arg668Cys
X
ABCC7 p.Arg668Cys 17329263:85:3
status: NEW
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1 [R668C] þ [?] Login to comment
88 ABCC7 p.Arg170His
X
ABCC7 p.Arg170His 17329263:88:3
status: NEW
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2 [R170H] þ [?] Login to comment
89 ABCC7 p.Val938Gly
X
ABCC7 p.Val938Gly 17329263:89:3
status: NEW
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1 [V938G] þ [?] Login to comment
90 ABCC7 p.Ala959Val
X
ABCC7 p.Ala959Val 17329263:90:5
status: NEW
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1 1 [A959V] þ [?] Login to comment
91 ABCC7 p.Gly1069Arg
X
ABCC7 p.Gly1069Arg 17329263:91:3
status: NEW
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1 [G1069R] þ [?] Login to comment
92 ABCC7 p.Val1153Glu
X
ABCC7 p.Val1153Glu 17329263:92:3
status: NEW
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1 [V1153E] þ [?] Login to comment
93 ABCC7 p.Arg117His
X
ABCC7 p.Arg117His 17329263:93:32
status: NEW
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ABCC7 p.Arg334Trp
X
ABCC7 p.Arg334Trp 17329263:93:338
status: NEW
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ABCC7 p.Asp1152His
X
ABCC7 p.Asp1152His 17329263:93:147
status: NEW
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ABCC7 p.Met952Ile
X
ABCC7 p.Met952Ile 17329263:93:137
status: NEW
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ABCC7 p.Gly622Asp
X
ABCC7 p.Gly622Asp 17329263:93:368
status: NEW
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ABCC7 p.Leu997Phe
X
ABCC7 p.Leu997Phe 17329263:93:231
status: NEW
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ABCC7 p.Val232Asp
X
ABCC7 p.Val232Asp 17329263:93:308
status: NEW
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ABCC7 p.Ser977Phe
X
ABCC7 p.Ser977Phe 17329263:93:267
status: NEW
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ABCC7 p.Tyr1032Cys
X
ABCC7 p.Tyr1032Cys 17329263:93:194
status: NEW
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ABCC7 p.Glu1473*
X
ABCC7 p.Glu1473* 17329263:93:277
status: NEW
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1 Two CFTR mutations 15 0-15 0 [R117H] þ [(TG)13(T)5] 1 [R117H] þ [(TG)12(T)5] 1 [R117H] þ [(TG)11(T)5] 1 [R117H] þ [M952I] 1 [D1152H] þ [(TG)12(T)5] 2 [D1152H] þ [Y1032C] 1 [(TG)11(T)5;V562I] þ [L997F] 1 [(TG)11(T)5;V562I] þ [S977F] 1 [E1473X] þ [(TG)13(T)5] 1 [V232D] þ [(TG)12(T)5] 1 [R334W] þ [(TG)12(T)5] 1 [G622D] þ [(TG)12(T)5] 1 [3272-26A . Login to comment
95 ABCC7 p.Arg117His
X
ABCC7 p.Arg117His 17329263:95:52
status: NEW
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ABCC7 p.Arg117His
X
ABCC7 p.Arg117His 17329263:95:67
status: NEW
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ABCC7 p.Arg74Trp
X
ABCC7 p.Arg74Trp 17329263:95:104
status: NEW
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ABCC7 p.Arg74Trp
X
ABCC7 p.Arg74Trp 17329263:95:126
status: NEW
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ABCC7 p.Asp110His
X
ABCC7 p.Asp110His 17329263:95:79
status: NEW
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ABCC7 p.Asp110His
X
ABCC7 p.Asp110His 17329263:95:94
status: NEW
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ABCC7 p.Ile556Val
X
ABCC7 p.Ile556Val 17329263:95:12
status: NEW
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C)] þ [I556V] 1 Apparent homozygosity 3 0-3 1 [R117H] þ [R117H] 1 1 [D110H] þ [D110H] 1 [R74W;D1270 N] þ [R74W;D1270 N] 1 Total 61 57-75 4 F508del, 2221dupA, as well as variants at the IVS8(TG)m(T)n polymorphic site. Login to comment
113 ABCC7 p.Arg117His
X
ABCC7 p.Arg117His 17329263:113:327
status: NEW
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ABCC7 p.Val938Gly
X
ABCC7 p.Val938Gly 17329263:113:250
status: NEW
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Phenotype and genotype data of patients carrying CFTR rearrangements Patient Current age (years) Origin Allele 1 Allele2 Reference Simple name Extent 1 45 Syria (TG)12(T)5 CFTRdele17a_18 8.6 kb deletion Lerer et al. (1999) 2 33 France/Southern Italy V938G CFTRdele22_23 1.5 kb deletion Audre´zet et al. (2004) 3 47 France R117H CFTRdele1_24 3 Mb deletion This study and Niel et al. (2004) 4 34 Morocco (TG)12(T)5 CFTRdup11_13 Unknown (4.9-35.2 kb duplication) This study Figure 1. Login to comment
124 ABCC7 p.Arg117His
X
ABCC7 p.Arg117His 17329263:124:151
status: NEW
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A complete CFTR gene deletion was found in one patient who had previously been referred to in Niel et al. (2004) and who was apparently homozygous for R117H. Login to comment
142 ABCC7 p.Val562Ile
X
ABCC7 p.Val562Ile 17329263:142:200
status: NEW
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(TG)11(T)5 penetrance reaching only 11% (Groman et al., 2004), we systematically investigated the whole CFTR gene to look for other cis mutations in the 14 patients carrying this variant and we found V562I in five of them. Login to comment
143 ABCC7 p.Trp1282*
X
ABCC7 p.Trp1282* 17329263:143:79
status: NEW
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ABCC7 p.Leu997Phe
X
ABCC7 p.Leu997Phe 17329263:143:62
status: NEW
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ABCC7 p.Ser977Phe
X
ABCC7 p.Ser977Phe 17329263:143:69
status: NEW
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Three of the five carried a mutation on the other chromosome: L997F, S977F and W1282X. Login to comment
144 ABCC7 p.Trp1282*
X
ABCC7 p.Trp1282* 17329263:144:155
status: NEW
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ABCC7 p.Val562Ile
X
ABCC7 p.Val562Ile 17329263:144:9
status: NEW
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ABCC7 p.Val562Ile
X
ABCC7 p.Val562Ile 17329263:144:186
status: NEW
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Although V562I has been considered a severe CF mutation, a series of arguments question its severe deleterious effect: its presence in trans of the severe W1282X mutation, the case of a V562I homozygous CF patient who carried in cis the frameshift 2347delG (Girodon et al., unpublished data), and the fact that residue V562 is not conserved in other proteins containing the ATP-binding cassette motif. Login to comment
145 ABCC7 p.Val562Ile
X
ABCC7 p.Val562Ile 17329263:145:25
status: NEW
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We suggest reconsidering V562I as a mild and CBAVD-associated mutation. Login to comment
146 ABCC7 p.Arg117His
X
ABCC7 p.Arg117His 17329263:146:120
status: NEW
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CBAVD genotypes were varied, the most frequent combined F508del either with the IVS8(T)5 variant (28.0% of 222) or with R117H (6.3%). Login to comment
149 ABCC7 p.Leu206Trp
X
ABCC7 p.Leu206Trp 17329263:149:117
status: NEW
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ABCC7 p.Asp1152His
X
ABCC7 p.Asp1152His 17329263:149:124
status: NEW
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Some genotypes had already been described in patients with moderate or late CF, such as those combining F508del with L206W, D1152H, 3272-26A.G or 2789 þ 5G.A. Login to comment
152 ABCC7 p.Arg117His
X
ABCC7 p.Arg117His 17329263:152:68
status: NEW
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ABCC7 p.Arg74Trp
X
ABCC7 p.Arg74Trp 17329263:152:151
status: NEW
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ABCC7 p.Leu997Phe
X
ABCC7 p.Leu997Phe 17329263:152:123
status: NEW
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Moreover, genotypes combining two mild alleles were found, such as [R117H] þ [(TG)13(T)5], [(TG)11(T)5;V562I] þ [L997F] or homozygosity for [R74W;D1270N]. Login to comment