ABCMdb

PMID: 22581207

Krulisova V, Balascakova M, Skalicka V, Piskackova T, Holubova A, Paderova J, Krenkova P, Dvorakova L, Zemkova D, Kracmar P, Chovancova B, Vavrova V, Stambergova A, Votava F, Macek M Jr
Prospective and parallel assessments of cystic fibrosis newborn screening protocols in the Czech Republic: IRT/DNA/IRT versus IRT/PAP and IRT/PAP/DNA.
Eur J Pediatr. 2012 Aug;171(8):1223-9. Epub 2012 May 12., [PubMed]

Sentences

No. Mutations Sentence Comment

74 ABCC7 p.Arg117His [1521_1523delCTT]+[350G>A;1210-12T[7]] genotype (legacy name: F508del/R117H-IVS-8 T(7)) had negative sweat test results. Login to comment 75 ABCC7 p.Arg117His The R117H-T7 complex allele is usually considered a CFTR-related disorder mutation [5,24] and when found in compound heterozygosity with a CF-causing mutation, it results in variable phenotypes ranging from mild form of CF, obstructive azoospermia, or to no disease at all [5]. Login to comment 77 ABCC7 p.Arg117His However, the R117H mutation is an integral part of the Elucigene assay and thus could not have been disregarded. Login to comment 78 ABCC7 p.Arg117His The two newborns carrying R117H-T7 allele, were not diagnosed with CF. Login to comment 81 ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Ala455Glu ABCC7 p.Ala455Glu ABCC7 p.Trp1282* 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.Arg1162* ABCC7 p.Ser1251Asn ABCC7 p.Ser1251Asn ABCC7 p.Leu206Trp ABCC7 p.Leu206Trp ABCC7 p.Val520Phe ABCC7 p.Val520Phe ABCC7 p.Ser549Arg ABCC7 p.Ser549Asn ABCC7 p.Ser549Asn ABCC7 p.Tyr122* ABCC7 p.Arg560Thr ABCC7 p.Arg560Thr ABCC7 p.Pro67Leu ABCC7 p.Pro67Leu ABCC7 p.Arg1158* ABCC7 p.Met1101Lys ABCC7 p.Met1101Lys ABCC7 p.Arg1066Cys ABCC7 p.Arg1066Cys ABCC7 p.Asp1152His ABCC7 p.Asp1152His ABCC7 p.Arg117Cys ABCC7 p.Arg117Cys ABCC7 p.Gln890* ABCC7 p.Trp846* ABCC7 p.Ile336Lys ABCC7 p.Ile336Lys ABCC7 p.Glu60* ABCC7 p.Glu1104Lys ABCC7 p.Glu1104Lys According to the protocol, this result indicated the sequencing of the Table 1 Parallel comparison of CF NBS protocols IRT/DNAa /IRT IRT/PAP IRT/PAP/DNAa Newborns screened (N) 106,522 106,522 106,522 IRT positives (N; %) 1,158 (1.09) 3,155 (2.96) 3,155 (2.96) PAP positives (N; %) - 260 (0.24) 260 (0.24) Median age (range) at the availability of DNA-testinga results (days) 36 (9-222b ) - 36 (9-222b ) 1 and/or 2 CF mutations detected (N; %) 76 (0.07) - 27 (0.03) Recalled newborns for repeated IRT examination (N; %) 47 (0.04) - - Positive CF NBS (N; %) 123 (0.12) 260 (0.24) 27 (0.03) Positive IRT in newborns recalled for repeated examination (N) 1 - - ST indicated (N; %) 77 (0.07) 260 (0.24) 27 (0.03) ST carried out (N; % of indicated ST) 72c (93.51) 204c (78.46) 24c (88.89) CF carriers (N) 55 - 12 Prevalence of CF carriers 1 in 21 - 1 in 22 Diagnosed CF patients (N) 19 16 15 False positives based on performed ST (N; % of all cases screened) 99d (0.09) 188 (0.18) 9 (0.01) Newborns with equivocal diagnosis [F508del/R117H-IVS-8 T(7) and ST<30 mmol/L; N] 2 - 0 False negatives (N) 2 5 6 Total of CF patients detected (N) 21e Median age (range) at diagnosis (days) 36 (9-57)e CF prevalence 1 in 5,072e Sensitivity (TP/TP+FN) 0.9048 0.7619 0.7142 Specificity (TN/TN+FP) 0.9991 0.9982 0.9999 PPV (TP/TP+FP) 0.1610 0.0784 0.625 N number, % of all cases screened, TP true positives, FN false negatives, TN true negatives, FP false positives, PPV positive predictive value, ST sweat test a CF-causing mutations covered by Elucigene assays ("legacy" nomenclature) with the CF-EU1Tm accounting for: p.Arg347Pro (R347P), c.2657+ 5G>A (2789+5G>A), c.2988+1G>A (3120+1G>A), c.579+1G>T (711+1G>T), p.Arg334Trp (R334W), p.Ile507del (I507del), p.Phe508del (F508del), c.3718-2477C>T (3849+10kbC>T), p.Phe316LeufsX12 (1078delT), p.Trp1282X (W1282X), p.Arg560Thr (R560T), p.Arg553X (R553X), p.Gly551Asp (G551D), p.Met1101Lys (M1101K), p.Gly542X (G542X), p.Leu1258PhefsX7 (3905insT), p.Ser1251Asn (S1251N), c.1585-1G>A (1717-1G>A), p.Arg117His (R117H), p.Asn1303Lys (N1303K), p.Gly85Glu (G85E), c.1766+1G>A (1898+1G>A), p.Lys684AsnfsX38 (2184delA), p.Asp1152His (D1152H), c.54-5940_273+10250del (CFTRdele2,3), p.Pro67Leu (P67L), p.Glu60X (E60X), p.Lys1177SerfsX15 (3659delC), c.489+1G>T (621+1G>T), p.Ala455Glu (A455E), p.Arg1162X (R1162X), p.Leu671X (2143delT), c.1210-12T[n] (IVS8-T(n) variant), including additional mutations in the CF-EU2Tm : p.Gln890X (Q890X), p.Tyr515X (1677delTA), p.Val520Phe (V520F), c.3140-26A>G (3272-26A>G), p.Leu88IlefsX22 (394delTT), p.Arg1066Cys (R1066C), p.Ile105SerfsX2 (444delA), p.Tyr1092X (C>A) (Y1092X(C>A)), p.Arg117Cys (R117C), p.Ser549Asn (S549N), p.Ser549ArgT>G (S549R T>G), p.Tyr122X (Y122X), p.Arg1158X (R1158X), p.Leu206Trp (L206W), c.1680-886A>G (1811+1.6kbA>G), p.Arg347His (R347H), p.Val739TyrfsX16 (2347delG) and p.Trp846X (W846X) b failed DNA isolation from DBS, including repetition of DNA-testing c deceased patient or non-compliance with referrals (five CF carriers in IRT/DNA/IRT, 56 newborns in IRT/PAP, three CF carriers in IRT/PAP/DNA) d comprising newborns with repeated IRT (47 newborns) e aggregate data from all protocols entire CFTR coding region in both newborns, and led to the identification of p.Ile336Lys (I336K) and p.Glu1104Lys (E1104K) mutations. Login to comment 88 ABCC7 p.Gln552* [Gln552X] + [Leu1376SerfsX8] (Q552X/4259del5) was missed by the utilized commercial assay. Login to comment 109 ABCC7 p.Gly542* ABCC7 p.Glu1104Lys Table 2 False negatives due to mean PAP concentrations below the cut-off IRT (ng/mL) PAP (ng/mL) CFTR Genotypea Sweat chloride concentration (mmol/L) Patient 1 174 0.93 F508del/ F508del 109.6 Patient 2 337 0.49 F508del/ F508del 98.7 Patient 3 203 0.42 F508del/ F508del 103.7 Patient 4 115 0.67 F508del/ I507del 93.2 Patient 5b 87.8 1.43 G542X/ E1104K 74.5 a legacy nomenclature b pancreatic sufficient patient (fecal Elastase-1 level was 507 μg/g) IRT/PAP and IRT/PAP/DNA protocols Five CF patients were false negative within the IRT/PAP protocol due to low PAP concentrations (Table 2). Login to comment