ABCMdb

PMID: 18344710

Madore AM, Prevost C, Dorfman R, Taylor C, Durie P, Zielenski J, Laprise C
Distribution of CFTR mutations in Saguenay- Lac-Saint-Jean: proposal of a panel of mutations for population screening.
Genet Med. 2008 Mar;10(3):201-6., [PubMed]

Sentences

No. Mutations Sentence Comment

4 ABCC7 p.Ala455Glu Results: Significant differences in allelic frequencies of common mutations (as ‚F508, 621 ϩ 1GϾT and A455E), and in percentage of covered allele with three or six mutations, were found in Saguenay-Lac-Saint-Jean compared to other regions. Login to comment 12 ABCC7 p.Met1101Lys CF is a multisystemic disorder caused by mutations in the CF transmembrane conductance regulator (CFTR) gene.10 It affects both the respiratory and the digestive systems, and can also induce infertility in men.11 A variable genetic correlation was observed between CFTR mutations and pulmonary function,12 pancreatic insufficiency,13 and congenital bilateral absence of the vas deferens.14 This subject is reviewed at length in a recent review by Dorfman and Zielenski.15 Since it was cloned in 1989, over 1,500 CFTR mutations have been documented.16,17 Some of them, such as ‚F508, are commonly distributed, whereas others are found in specific populations or ethnic groups, such as the M1101K in Hutterites.18,19 The protein encoded by the CFTR gene is expressed in the apical membrane of exocrine epithelial cells, and is a cyclic adenosine monophosphate (cAMP)-induced chloride channel that can also regulate other ion channels.10,20 For CF neonatal screening, many programs throughout the world have adopted a two-tier combination of trypsinogen and DNA analysis with either ‚F508 allele alone or a panel of CF-causing mutations.21 In the same way, multimutation plat- From the 1 Universite´ Laval, Que´bec, Canada; 2 Universite´ de Montre´al Community Genomic Medicine Center, Saguenay, Canada; 3 Universite´ du Que´bec a` Chicoutimi, Saguenay, Canada; 4 Service de conseil ge´ne´tique, Centre de sante´ et de services sociaux de Chicoutimi, Saguenay, Canada; and 5 Hospital for Sick Children, Toronto, Canada. Login to comment 41 ABCC7 p.Ala455Glu ABCC7 p.Tyr1092* Three mutations are prevalent in the SLSJ population (‚F508, 621 ϩ 1GϾT, and A455E); according to data provided by the genetic counseling services and the Chicoutimi CF clinic, three other mutations are present in at least three different families (711 ϩ 1GϾT, 3199del6, and Y1092X). Login to comment 46 ABCC7 p.Ala455Glu Similarly, the A455E mutation frequency is two to three times higher in the SLSJ population compared with the other Francophone population studied (P ϭ 0.004) and eight times higher than in the Anglophone and multiethnic population of Montreal (P ϭ 0.013). Login to comment 48 ABCC7 p.Gly551Asp ABCC7 p.Ala455Glu ABCC7 p.Trp1282* ABCC7 p.Arg553* ABCC7 p.Arg334Trp ABCC7 p.Arg347Pro ABCC7 p.Asn1303Lys ABCC7 p.Gly542* ABCC7 p.Leu206Trp ABCC7 p.Val520Phe ABCC7 p.Gly85Glu ABCC7 p.Ser549Asn ABCC7 p.Arg1158* ABCC7 p.Arg1066Cys ABCC7 p.Tyr1092* ABCC7 p.Arg117Cys ABCC7 p.Ile1027Thr ABCC7 p.Ser489* ABCC7 p.Tyr109Cys ABCC7 p.Gln1313* Altogether, the six mutations represent 95.89% of the CFTR allele of CF patients in the SLSJ population, whereas the proportions are 86.85, 85.27, and Table 2 Cystic fibrosis mutations present in the four populations studied Mutationa Allelic frequency (number of alleles [%]) Populationb 1 2 3 4 „F508 106 (62.35) 55 (72.37) 398 (72.36) 67 (57.78) 621 ؉ 1G>T 42 (24.71) 6 (7.89) 30 (5.45) 1 (0.85) A455E 12 (7.06) 2 (2.63) 14 (2.55) 1 (0.85) 3199del6 1 (0.59) 1 (1.32) 7 (1.27) 1 (0.85) 711 ؉ 1G>T 1 (0.59) 1 (1.32) 15 (2.73) 1 (0.85) Y1092X 1 (0.59) 1 (1.32) 5 (0.91) 0 R117C 2 (1.18) 0 0 0 ‚I507 1 (0.59) 2 (2.63) 10 (1.82) 0 L206W 1 (0.59) 1 (1.32) 9 (1.64) 0 R1158X 1 (0.59) 0 0 0 S489X 1 (0.59) 0 1 (0.18) 0 R553X 0 2 (2.63) 2 (0.36) 0 R334W 0 1 (1.32) 2 (0.36) 0 G542X 0 0 10 (1.82) 0 G85E 0 0 6 (1.09) 5 (4.24) N1303K 0 0 5 (0.91) 1 (0.85) IVS8-5T 0 0 4 (0.73) 0 W1282X 0 0 3 (0.55) 7 (5.93) R347P 0 0 1 (0.18) 2 (1.69) V520F 0 0 1 (0.18) 0 I1027T 0 0 1 (0.18) 0 R1066C/IVS 0 0 1 (0.18) 0 Q1313X 0 0 1 (0.18) 0 1898ϩ3GϾA 0 0 1 (0.18) 0 2183AAϾG 0 0 1 (0.18) 0 2951insA 0 0 1 (0.18) 0 G551D 0 0 0 2 (1.69) 1525-iG-A 0 0 0 2 (1.69) Y109C 0 0 0 1 (0.85) S549N 0 0 0 1 (0.85) 3154del1G 0 0 0 1 (0.85) UNKNOWN 1 (0.59) 4 (5.26) 20 (3.82) 25 (21.19) Number of alleles genotypedc 170 (100) 76 (100) 550 (100) 118 (100) a The six mutations included in the panels proposed are in bold. Login to comment 59 ABCC7 p.Ala455Glu The three most common alleles in the SLSJ population are the ‚F508, 621 ϩ 1GϾT and A455E mutations. Login to comment 60 ABCC7 p.Ala455Glu The frequency of the ‚F508 mutation is lower in the SLSJ population than in the other Francophones population (P ϭ 0.011) but the frequency of the 621 ϩ 1GϾT and A455E mutation is greater in this region than in any other region described here (P Ͻ 10-12 and P ϭ 0.004 for the Francophone populations, and P Ͻ 10-7 and P ϭ 0.013 for the Anglophone and multiethnic population, respectively). Login to comment 65 ABCC7 p.Ala455Glu In the study of Rozen et al.,33 the authors also observed that the frequency for ‚F508 mutation was lower in SLSJ region (58.0%) than in the other regions of the PQ (71%) (P ϭ 0.047), and that subjects from the SLSJ region also have a higher 621 ϩ 1GϾT (23.2%) frequency than those of the remaining regions of the PQ (12.84%) (P ϭ 10-5 ).21,33 Four of our six most frequent mutations (‚F508, 621 ϩ 1GϾT, A455E, and 711 ϩ 1GϾT) are present in the ACMG- ACOG panel of 23 mutations, representing a detection rate of 94.71% in the SLSJ population. Login to comment 66 ABCC7 p.Ala455Glu However, according to our results, a multimutation panel for carrier screening in the SLSJ region could include only the three principal mutations (‚F508, 621 ϩ 1GϾT, and A455E), covering a total of 94.12% of the CFTR alleles present in the SLSJ region (Fig. 3). Login to comment 67 ABCC7 p.Tyr1092* Another possibility is to include the three additional mutations that are at least present in three different families (711 ϩ 1GϾT, 3199del6, and Y1092X), reaching a detection rate of the CFTR alleles of 95.89% (Fig. 3). Login to comment