ABCMdb

PMID: 24357848

Zvereff VV, Faruki H, Edwards M, Friedman KJ
Cystic fibrosis carrier screening in a North American population.
Genet Med. 2014 Jul;16(7):539-46. doi: 10.1038/gim.2013.188. Epub 2013 Dec 19., [PubMed]

Sentences

No. Mutations Sentence Comment

34 ABCC7 p.Arg352Gln ABCC7 p.Arg117Cys ABCC7 p.Gly480Cys ABCC7 p.Ser364Pro The 69-mutation panel was a combined panel that included variants approved by the Food and Drug Administration with 10 additional variants (R117C, R352Q, S364P, 3120G>A, 2869insG, G480C, 405+3A>C, 1812-1G>A, 444delA, and F311del) added on the basis of their published frequencies and relevancy to CF. Login to comment 44 ABCC7 p.Arg347His ABCC7 p.Val520Phe ABCC7 p.Ser549Arg ABCC7 p.Ser549Asn RESULTS The 32-mutation panel is composed of the 23 variants from the ACMG/ACOG screening panel combined with 9 additional mutations, namely, 3876delA, R347H, S549N, 3905insT, 1078delT, V520F, 394delTT, S549R, and 2183AA>G. Login to comment 47 ABCC7 p.Ser549Arg Even the 1078delT mutation that was removed from the ACMG/ ACOG screening panel achieved 0.1% prevalence.8 Only the S549R variant was observed at a lower frequency (0.07%). Login to comment 54 ABCC7 p.Arg117His The R117H variant was the second most common variant identified by both panels (Tables 1 and 2). Login to comment 55 ABCC7 p.Arg117His Among 5,198 carriers of the R117H variant detected by the 32-mutation panel, two copies of 5T alleles were detected in only 23 cases (0.44%). Login to comment 57 ABCC7 p.Arg117His The 5T status of the R117H variant could not be determined in 468 cases (9%) for carriers of 5T/7T or 5T/9T alleles. Login to comment 58 ABCC7 p.Arg117His The 69-mutation panel identified two cases with two copies of the 5T allele (0.73%) among 274 R117H carriers, whereas the majority of carriers (89.41%) did not carry a 5T allele (Table 4). Login to comment 59 ABCC7 p.Arg117His In 27 occurrences (9.86%) the 5T background of the R117H variant could not be identified. Login to comment 60 ABCC7 p.Leu206Trp ABCC7 p.Asp1152His The variants D1152H (4.0%) and L206W (2.4%), each associated with a variable CF phenotype, were the most common variants not present on the ACMG/ACOG 23-mutation panel. Login to comment 63 ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Ala455Glu ABCC7 p.Ala455Glu ABCC7 p.Trp1282* ABCC7 p.Trp1282* ABCC7 p.Arg553* ABCC7 p.Arg553* ABCC7 p.Arg334Trp ABCC7 p.Arg334Trp ABCC7 p.Arg347Pro ABCC7 p.Arg347Pro ABCC7 p.Arg347His ABCC7 p.Arg347His ABCC7 p.Asn1303Lys ABCC7 p.Asn1303Lys ABCC7 p.Gly542* ABCC7 p.Gly542* ABCC7 p.Arg1162* ABCC7 p.Arg1162* ABCC7 p.Arg352Gln ABCC7 p.Leu206Trp ABCC7 p.Gln493* ABCC7 p.Val520Phe ABCC7 p.Ser549Arg ABCC7 p.Ser549Arg ABCC7 p.Gly85Glu ABCC7 p.Gly85Glu ABCC7 p.Ser549Asn ABCC7 p.Ser549Asn ABCC7 p.Tyr122* ABCC7 p.Arg560Thr ABCC7 p.Arg560Thr ABCC7 p.Arg1158* ABCC7 p.Met1101Lys ABCC7 p.Arg1066Cys ABCC7 p.Tyr1092* ABCC7 p.Ser1255* ABCC7 p.Asp1152His ABCC7 p.Arg117Cys ABCC7 p.Gln890* ABCC7 p.Trp1089* ABCC7 p.Arg75* ABCC7 p.Gly480Cys ABCC7 p.Glu60* ABCC7 p.Ala559Thr This threshold could not be reached Table 1ߒ CFTR allele frequency identified by the CF32 mutation panel Varianta Number of detected alleles Mutation (%) Legacy nomenclature HGVS nomenclature F508delb p.F508del 31,142 68.69 R117Hb p.R117H 5,198 11.46 G542Xb p.G542X 1,162 2.56 G551Db p.G551D 989 2.18 W1282Xb p.W1282X 824 1.82 3120ߙ+ߙ1G>Ab c.2988ߙ+ߙ1G>A 706 1.56 N1303Kb p.N1303K 648 1.43 R553Xb p.R553X 487 1.07 3849ߙ+ߙ10kbC>Tb c.3717ߙ+ߙ12191C>T 436 0.96 621ߙ+ߙ1G>Tb c.489ߙ+ߙ1G>T 410 0.90 1717-1G>Ab c.1585-1G>A 388 0.86 2789ߙ+ߙ5G>Ab c.2657ߙ+ߙ5G>A 382 0.84 I507delb p.I507del 258 0.57 R334Wb p.R334W 257 0.57 R1162Xb p.R1162X 211 0.47 G85Eb p.G85E 199 0.44 1898ߙ+ߙ1G>Ab c.1766ߙ+ߙ1G>A 170 0.37 R347Hc p.R347H 160 0.35 3659delCb c.3528delC 155 0.34 3876delAc c.3744delA 153 0.34 R560Tb p.R560T 132 0.29 S549Nc p.S549N 125 0.28 3905insTc c.3773dupT 121 0.27 R347Pb p.R347P 117 0.26 2184delAb c.2052delA 107 0.24 A455Eb p.A455E 106 0.23 711ߙ+ߙ1G>Tb c.579ߙ+ߙ1G>T 65 0.14 394delTTc c.262_263delTT 56 0.12 V520Fc p.V520F 54 0.12 1078delTc c.948delT 52 0.11 2183AA>Ga,c c.2051_2052delAAinsG 37 0.08 S549Rc p.S549R 31 0.07 Total 45,338 100 a 2183AA>G variant was added to the panel in 2010. b Variants from ACMG/ACOG CF screening panel. c Classified as a CF-causing mutation by the CFTR2 Database. ACMG, American College of Medical Genetics and Genomics; ACOG, American College of Obstetricians and Gynecologists; CF, cystic fibrosis; HGVS, Human Genome Variation Society. Table 2ߒ Continued on next page Table 2ߒ CFTR allele frequency identified by the CF69 mutation panel Varianta Allele frequency Mutation (%) Legacy nomenclature HGVS nomenclature F508delb p.F508del 1,868 60.49 R117Hb p.R117H 274 8.87 D1152Hc p.D1152H 125 4.05 G542Xb p.G542X 98 3.17 L206Wd p.L206W 73 2.36 3120ߙ+ߙ1G>Ab c.2988ߙ+ߙ1G>A 65 2.10 G551Db p.G551D 47 1.52 N1303Kb p.N1303K 42 1.36 W1282Xb p.W1282X 38 1.23 3849ߙ+ߙ10kbC>Tb c.3717ߙ+ߙ12191C>T 28 0.91 3876delAd c.3744delA 28 0.91 F311dele p.F312del 24 0.78 I507delb p.I507del 24 0.78 R553Xb p.R553X 24 0.78 R117Cd p.R117C 22 0.71 621ߙ+ߙ1G>Tb c.489ߙ+ߙ1G>T 21 0.68 1717-1G>Ab c.1585-1G>A 18 0.58 S549Nd p.S549N 18 0.58 R334Wb p.R334W 17 0.55 2789ߙ+ߙ5G>Ab c.2657ߙ+ߙ5G>A 16 0.52 G85Eb p.G85E 14 0.45 3199del6e c.3067_3072delATAGTG 12 0.39 R1066Cd p.R1066C 11 0.36 1898ߙ+ߙ1G>Ab c.1766ߙ+ߙ1G>A 10 0.32 R347Hd p.R347H 10 0.32 R1162 Xb p.R1162X 9 0.29 W1089Xd p.W1089X 9 0.29 2184delAb c.2052delA 8 0.26 2307insAd c.2175dupA 8 0.26 1078delTd c.948delT 7 0.23 R75Xd p.R75X 7 0.23 3120G>Ad c.2988 G>A 6 0.19 3659delCb c.3528delC 6 0.19 Q493Xd p.Q493X 6 0.19 R1158Xd p.R1158X 6 0.19 R560Tb p.R560T 6 0.19 1812-1G>Ad c.1680-1G>A 5 0.16 2055del9>Ad c.1923_1931del9insA 5 0.16 406-1G>Ad c.274-1G>A 5 0.16 A559Td p.A559T 5 0.16 R347Pb p.R347P 5 0.16 S1255Xd p.S1255X 5 0.16 1677delTAd c.1545_1546delTA 4 0.13 711ߙ+ߙ1G>Tb c.579ߙ+ߙ1G>T 4 0.13 E60Xd p.E60X 4 0.13 R352Qd p.R352Q 4 0.13 Y1092Xd p.Y1092X 4 0.13 2183AA>Gd c.2051_2052delAAinsG 3 0.10 3791delCd c.3659delC 3 0.10 3905insTd c.3773dupT 3 0.10 by 10 variants: the 2143delT, A455E, S549R, Y122X, and M1101K mutations, typically observed in Caucasians; 935delA, 2869insG, and Q890X in Hispanics; and 405+3A>C and G480C in the African-American population. Login to comment 65 ABCC7 p.Lys710* ABCC7 p.Ser1196* ABCC7 p.Ser364Pro ABCC7 p.Gly330* These were 1898+5G>T, 444delA, G330X, S364P, K710X, and S1196X. Login to comment 66 ABCC7 p.Ala455Glu The low frequency of the A455E mutation (0.07%) from the ACMG/ACOG panel may be explained by patient preselection through the use of the 32-mutation panel, or random drift. Login to comment 79 ABCC7 p.Ser1255* ABCC7 p.Arg75* ABCC7 p.Gly480Cys ABCC7 p.Ala559Thr Six of these variants were specific to African Americans (R75X, G480C, A559T, 2307insA, 3791delC, and S1255X). Login to comment 80 ABCC7 p.Arg117His ABCC7 p.Ala455Glu ABCC7 p.Val520Phe ABCC7 p.Ser549Arg ABCC7 p.Tyr122* ABCC7 p.Met1101Lys ABCC7 p.Lys710* ABCC7 p.Gln890* ABCC7 p.Gly480Cys ABCC7 p.Ser1196* ABCC7 p.Gly178Arg ABCC7 p.Gly330* The Table 3ߒ Frequency of 5T/7T/9T genotypes as a result of R117H reflex testing Poly-T alleles Number of detected alleles (%) CF32 panel CF69 panel 5T/5T 23 (0.44) 2 (0.73) 5T/7T 430 (8.27) 26 (9.49) 5T/9T 38 (0.73) 1 (0.37) 7T/7T 4,103 (78.93) 219 (79.92) 7T/9T 604 (11.61) 26 (9.49) 9T/9T 1 (0.02) 0 Total 5,198 (100) 274 (100) 394delTTd c.262_263delTT 3 0.10 G178Rd p.G178R 3 0.10 V520Fd p.V520F 3 0.10 2143delTd c.2012delT 2 0.06 935delAe c.803delA 2 0.06 A455Eb p.A455E 2 0.06 Q890Xd p.Q890X 2 0.06 S549Rd p.S549R 2 0.06 2869insGd c.2737insG 1 0.03 405ߙ+ߙ3A>Ce c.273ߙ+ߙ3A>C 1 0.03 G480Ce p.G480C 1 0.03 M1101Kd p.M1101K 1 0.03 Y122Xd p.Y122X 1 0.03 Total 3,088 100 a 1898ߙ+ߙ5G>Te , 444delA, G330X, S364Pe , K710X, and S1196X mutations were not detected in the target population. Login to comment 86 ABCC7 p.Leu206Trp ABCC7 p.Asp1152His Two variants, L206W and D1152H, accounted for 19.1% of the mutant alleles detected in this ethnic group. Login to comment 99 ABCC7 p.Leu206Trp ABCC7 p.Ser549Asn ABCC7 p.Asp1152His ABCC7 p.Arg117Cys Several alleles not found on the ACMG/ACOG panel were found at relatively high frequency (Table 2), including D1152H (4.0%), L206W (2.4%), c.3744delA (0.9%), F311del (0.8%), R117C (0.7%), and S549N (0.6%). Login to comment 107 ABCC7 p.Arg352Gln ABCC7 p.Ser549Asn ABCC7 p.Arg1158* ABCC7 p.Trp1089* These variants are 3876delA, S549N, 406-1G>A, 3199del6, W1089X, R1158X, R352Q, and 2183AA>G, and they account for 8.1% of the mutations detected in the Hispanic population. Login to comment 115 ABCC7 p.Ser1255* ABCC7 p.Arg75* ABCC7 p.Gly480Cys ABCC7 p.Ala559Thr The extended panel detected 21.7% more mutations (P < 0.01) using six additional race-specific (R75X, G480C, A559T, 2307insA, S1255X, and 3791delC) and seven panethnic variants (see Supplementary Table S2 online). Login to comment 117 ABCC7 p.Arg352Gln ABCC7 p.Trp1089* Four ethnicity-specific variants (R352Q, 406-1G>A, 3199del6, and W1089X) and 12 panethnic variants were detected. Login to comment 118 ABCC7 p.Leu206Trp ABCC7 p.Asp1152His Two variants, D1152H and L206W, account for 19.1% of all mutations identified in the Hispanic group and deserve special attention. Login to comment 121 ABCC7 p.Leu206Trp ABCC7 p.Asp1152His ABCC7 p.Asp1152His ABCC7 p.Asp1152His Strom et al.7 advocate against adding these variants to CF panels, stating that detection of D1152H and L206W during carrier screening may increase the rate of pregnancy termination among parents who fear having a child with classic CF, not to mention inflating the mutation detection rate among Hispanic Americans.7 It is acknowledged now in the literature that the D1152H variant belongs to both the CF-causing and CFTR-related disorder groups,19-21 and, in conjunction with an established CF-causing mutation, it could still manifest as typical CF.19,22 Burgel et al.23 studied 42 patients with D1152H mutations and reported that the variant, in conjunction with a CF-causing mutation, can cause significant pulmonary disease, albeit with longer survival. Login to comment 122 ABCC7 p.Asp1152His One of the authors of this article observedsimilarresults(K.J.F.,unpublisheddata).Sosnayetal.24 did not find enough evidence for the D1152H variant to meet clinical and functional criteria consistent with disease and hence categorized the variant as indeterminate. Login to comment 124 ABCC7 p.Asp1152His Even without the D1152H variant, the use of the 69-mutation panel will improve the detection rate for the Hispanic population by 22.2% (P < 0.04). Login to comment 125 ABCC7 p.Leu206Trp The same disagreement exists with regard to the L206W variant. Login to comment 126 ABCC7 p.Leu206Trp Clain et al.25 analyzed 36 clinical cases of CF patients who were compound heterozygous for L206W and a severe CF mutation. Login to comment 128 ABCC7 p.Leu206Trp Using clinical and functional studies, the group demonstrated that L206W is a disease-causing mutation with variable phenotype ranging from CF with pancreatic insufficiency to congenital bilateral absence of the vas deferens. Login to comment 129 ABCC7 p.Leu206Trp Data from the CFTR2 project indicated that the L206W variant was observed in 82 CF patients worldwide and should be considered a disease-causing mutation.26 As such, we support this conclusion. Login to comment