ABCMdb

PMID: 22892530

Sobczynska-Tomaszewska A, Oltarzewski M, Czerska K, Wertheim-Tysarowska K, Sands D, Walkowiak J, Bal J, Mazurczak T
Newborn screening for cystic fibrosis: Polish 4 years' experience with CFTR sequencing strategy.
Eur J Hum Genet. 2012 Aug 15. doi: 10.1038/ejhg.2012.180., [PubMed]

Sentences

No. Mutations Sentence Comment

8 ABCC7 p.Lys710* The frequency of some mutations (eg, 2184insA, K710X) was assessed in Poland for the first time. Login to comment 15 ABCC7 p.Lys710* Only one mutation, the F508del accounts for B70% of CFTR mutant alleles in Europe but this also differs between populations.12,13 In Polish CF patients the frequency of the F508del mutation is estimated as 53-57%.14,15 According to the a panel of the most frequent mutations in Polish CF patients published in 200916 and our personal experience (unpublished data), mutations such as K710X and 2184insA have a frequency 40.45%. Login to comment 56 ABCC7 p.Thr1053Ile ABCC7 p.Leu467Phe ABCC7 p.Asp537Asn ABCC7 p.Pro731Leu These newborns had the CFTR genotype as follows: [F508del];[D537N], [F508del];[P731L], [F508del];[T1053I] (two unrelated newborns) and [F508del];[L467F]. Login to comment 57 ABCC7 p.Gly551Asp ABCC7 p.Arg117His ABCC7 p.Ala455Glu ABCC7 p.Trp1282* ABCC7 p.Arg553* ABCC7 p.Arg553* ABCC7 p.Arg553* ABCC7 p.Arg334Trp ABCC7 p.Arg334Trp ABCC7 p.Arg334Trp ABCC7 p.Arg347Pro ABCC7 p.Arg347Pro ABCC7 p.Arg347Pro ABCC7 p.Arg347His ABCC7 p.Arg347Leu ABCC7 p.Asn1303Lys ABCC7 p.Asn1303Lys ABCC7 p.Asn1303Lys ABCC7 p.Gly542* ABCC7 p.Gly542* ABCC7 p.Gly542* ABCC7 p.Arg1162* ABCC7 p.Ser1251Asn ABCC7 p.Ile148Thr ABCC7 p.Gly85Glu ABCC7 p.Arg560Thr ABCC7 p.Arg117Leu ABCC7 p.Ser1235Arg ABCC7 p.Gln552* ABCC7 p.Lys710* ABCC7 p.Lys710* ABCC7 p.Glu60* ABCC7 p.Arg560Lys ABCC7 p.Arg553Gly ABCC7 p.Arg117Pro ABCC7 p.Asp537Asn ABCC7 p.Pro731Leu ABCC7 p.Trp1282Cys Mutations D537N and P731L have not been Period of NBS CF Method The most frequent mutations in Polish population under analysis September 2006 - December 2007 Estonia Asper Biotech assay E60X, G85E, 394delTT, R117H, R117P, R117L, I148T, 621G>A, 711+1G>T, 711+5G>A, 1078delT, R334W, R347H, R347P, R347L, IVS8-T, A455E, I507del, F508del, 1717-1G>A, G542X, p.G551D, Q552X, R553X, R553G, R560T, R560K, 1898+1G>A, 1898+1G>T, 1898+1G>C, 2143delT, 2184delA, 2183AA>G, 2789+5G>A, 3120+1G>A, 3199del6, 3272-26A>G, R1162X, 3659delC, 3849+10kbC>T, 3905insT, S1235R, S1251N, W1282X, W1282C, N1303K, CFTRdele2,3 January 2007 - June 2009 Sanger sequencing of exons: 4, 7, 10, 11, 13, 21, fragment of intron 19 F508del, CFTRdele2,3, 3849+10kbC>T, R117H+IVS8-T*, R334W, R347P, 1717-1G>A, G542X, R553X, K710X, 2184insA, 2143delT, 2183AA>G, N1303K July 2009 - currently Sanger sequencing of exons: 7, 10, 11, 13, 17b, 20, 21, fragment of intron 19 F508del, CFTRdele2,3, 3849+10kbC>T, R334W, R347P, 1717-1G>A, G542X, R553X, K710X, 2184insA, 2143delT, 2183AA>G, N1303K, 3272-26A>G**, W1282X** * removed from DNA analysis since July 2009 , **added into DNA analysis since July 2009 Figure 1 NBS CF in Poland. Login to comment 65 ABCC7 p.Asp537Asn ABCC7 p.Pro731Leu The D537N variant in exon 11 was designated as possibly pathogenic and P731L as possibly tolerated. Login to comment 66 ABCC7 p.Thr1053Ile ABCC7 p.Leu467Phe Of note, in the case of some other changes, the results were unclear - for example, in the case of already known mutations published in the CFTR Mutation Database: T1053I (according to Align-GVGD: 'less likely to be pathogenic`, score C0, PolyPhen: 'possible damaging`, score 0.816 and SIFT: 'deleterious`, score 0.01), similarly for L467F (Align-GVGD: 'less likely`, class C0, PolyPhen: 'probably damaging`, score 0.994 and SIFT: 'deleterious`, score 0.03). Login to comment 67 ABCC7 p.Val1240Gly ABCC7 p.Val1240Gly The evaluation of the most frequent CFTR mutations in the Polish population in examined gene regions showed that three additional mutations reached our adopted cutoff (0.45% of frequency): 3600þ 2insT, 1898þ 1G4C and V1240G (Table 3). Login to comment 69 ABCC7 p.Leu997Phe ABCC7 p.Leu997Phe ABCC7 p.Glu92Lys ABCC7 p.Glu92Lys ABCC7 p.Gln207* ABCC7 p.Gln207* Based on this assumption, the previously published data of the frequency of this mutation in the Polish population (57%,15), the data from the Polish Cystic Fibrosis Patients Registry3 (56-62%) and the results of the clinical follow-up Table 1 Characteristic of the cases omitted in the screening for CF programme owing to IRT values o99.4 percentile Newborn Patients` genotype after first stage CFTR analysisa Sweat test (pilocarpine ionthoforesis (mmol/l)) Clinical history Patients` genotype after extended CFTR analysis (performed on physician`s request; sequencing of entire coding region) 1 [2183AA4G ];[ ¼ ] 116; 139 Recurrent diarrhoea, pneumonia, liver dysfunction [2183AA4G];[E92K] 2 [F508del];[ ¼ ] 80; 127; 136 Chronic diarrhoea, failure to thrive, pneumonia [F508del];[4218insT] 3 [ ¼ ];[ ¼ ] 118;140 Pneumonia, liver dysfunction [Q207X];[ ¼ ] 4 [ ¼ ];[ ¼ ] 56 Diarrhoea, pneumonia [L997F];[1210-12T[5] þ 1210-13G4T]b Abbreviations: CF, cystic fibrosis; IRT, immunoreactive trypsin; NBS CF, newborn screening for CF; ¼ , no mutation identified. Login to comment 72 ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp ABCC7 p.Trp1282* ABCC7 p.Trp1282* ABCC7 p.Arg553* ABCC7 p.Arg553* ABCC7 p.Arg553* ABCC7 p.Arg553* ABCC7 p.Arg553* ABCC7 p.Arg553* ABCC7 p.Arg334Trp ABCC7 p.Arg334Trp ABCC7 p.Arg347Pro ABCC7 p.Arg347Pro ABCC7 p.Asn1303Lys ABCC7 p.Asn1303Lys ABCC7 p.Asn1303Lys ABCC7 p.Asn1303Lys ABCC7 p.Gly542* ABCC7 p.Gly542* ABCC7 p.Lys710* ABCC7 p.Lys710* ABCC7 p.Val1240Gly ABCC7 p.Val1240Gly ABCC7 p.Asn1303Leu ABCC7 p.Asn1303Leu Table 2 Genotypes of CF newborns with mutations not included into common commercial kits applied in Poland and European countries* Genotype Number of cases [F508del]; [1767-8T4A*] 1 [F508del];[2184insA*] 6 [F508del];[E33X*] 1 [F508del];[F1286C*] 1 [F508del];[G314R*] 1 [F508del];[K710X*] 1 [F508del];[W1282R*] 1 [F508del];[1898 þ 1G4C*] 1 [F508del];[3600 þ 2insT*] 1 [F508del];[F1052V*] 1 [F508del];[V1240G*] 1 [F508del];[T582I*] 1 [2143delT];[R1102X*] 1 [2143delT];[2721del11*] 1 [3272-26A4G];[K967S*] 1 [CFTRdele2,3];[Y1092X*] 1 [K710X*];[K710X*] 1 [L732X*];[3600 þ 2insT*] 1 [N1303K];[2184insA*] 1 [N1303L];[T1036I*] 1 [R553X];[3182ins8*] 1 [2143delT];[V1240G*] 1 [R553X];[Trp356X*] 1 [L997F*];[1210-12T[5];1210-13G4T] 1 Total 29 Table 3 Frequency of CFTR mutations in Polish CF patients from newborns screening programme CFTR mutations Frequency according to Bobadilla et al15 Frequency according to NBS CF results (all ¼ 442 CF alleles) Name Position % % F508del Exon11 57.1 62.4 3849 þ 10kbC4T Intron 22 2.7 3.0 G542X Exon 12 2.6 1.6 1717-1G4A Intron 11 2.4 1.4 R553X Exon 12 1.9 2.5 CFTRdele2,3 Exons 2 and 3 1.8 6.2 N1303K Exon 24 1.8 2.1 2143delT Exon 14 No data 2.8 2184insA Exon 14 No data 1.8 2183AA4G Exon 14 No data 1.6 W1282X Exon 23 0.7 1.5 R334W Exon 8 No data 0.7 R347P Exon 8 No data 0.5 G551D Exon 12 0.5 0.0 K710X Exon 14 No data 0.7 3272-26A4G Intron 19 No data 0.7 3600 þ 2insT Intron 21 No data 0.5 1898 þ 1G4C Intron 13 No data 0.5 V1240G Exon 23 No data 0.5 Othersa - No data 10.0 Abbreviations: CF, cystic fibrosis; NBS CF, newborn screening for CF. Login to comment 98 ABCC7 p.Lys710* Data from the Polish registry were used to designate the CFTR gene mutations and to prepare a 'Polish assay` with mutations such as K710X and 2184insA. Login to comment 101 ABCC7 p.Val1240Gly These variants, together with V1240G (two alleles, frequency40.45%) may therefore be candidates for a first line NBS CF molecular test panel in future. Login to comment 106 ABCC7 p.Asp537Asn ABCC7 p.Pro731Leu In example, the detection of a sporadic missense variants (eg, D537N, P731L), still do not provide a clear answer to the biological and clinical significance of the defect. Login to comment 107 ABCC7 p.Asp537Asn ABCC7 p.Pro731Leu The D537N variant was designated as possibly pathogenic by bioinformatic analysis, whereas the P731L was designated as 'tolerated`. Login to comment 113 ABCC7 p.Thr1053Ile ABCC7 p.Leu467Phe For example, the diagnosis of CF has not been confirmed following the identification of the T1053I and L467F mutations. Login to comment 116 ABCC7 p.Ile148Thr For example, the I148T variant no longer has the qualification of a pathogenic mutation but is still included in the commercial kits (eg, InnoLipa, Innogenetics).33 Prudence is therefore always essential in molecular genetics. Login to comment 117 ABCC7 p.Ile148Thr For example, the I148T variant no longer has the qualification of a pathogenic mutation but is still included in the commercial kits (eg, InnoLipa, Innogenetics).33 Prudence is therefore always essential in molecular genetics. Login to comment