ABCMdb

PMID: 23276700

Krenkova P, Piskackova T, Holubova A, Balascakova M, Krulisova V, Camajova J, Turnovec M, Libik M, Norambuena P, Stambergova A, Dvorakova L, Skalicka V, Bartosova J, Kucerova T, Fila L, Zemkova D, Vavrova V, Koudova M, Macek M, Krebsova A, Macek M Jr
Distribution of CFTR mutations in the Czech population: positive impact of integrated clinical and laboratory expertise, detection of novel/de novo alleles and relevance for related/derived populations.
J Cyst Fibros. 2013 Sep;12(5):532-7. doi: 10.1016/j.jcf.2012.12.002. Epub 2012 Dec 29., [PubMed]

Sentences

No. Mutations Sentence Comment

46 ABCC7 p.Trp57Gly ABCC7 p.Glu292Lys ABCC7 p.Gly27Arg ABCC7 p.Arg709Gln [874GNA]+[2126GNA] E292K/R709Q Ex7/Ex13 4 0.33 22. c.1585-1GNA 1717-1GNA*# In10 4 0.33 23. c.3454 GNC D1152H*# Ex18 4 0.33 24. c.3484CNT R1162X*# Ex19 4 0.33 25. c.4242+1GNT 4374+1GNT In23 4 0.33 26. c.1000CNT R334W*# Ex7 3 0.25 27. c.1767-?_2619+?del CFTRdele13,14a Ex13-Ex14a 3 0.25 28. c.3468+2_3468+3insT 3600+2insT In18 3 0.25 29. c.3469-?_3717+?dup CFTRdup19 Ex19 3 0.25 30. c.3964-78_4242+577del CFTRdele22,23# Ex22-Ex23 3 0.25 31. c.53+1GNT 185+1GNT In1 2 0.17 32. c.54-1161_164+1603del2875 CFTRdele2 Ex2 2 0.17 33. c.169TNG W57G Ex3 2 0.17 34. c.254GNA G85E*# Ex3 2 0.17 35. c.274GNT E92X# Ex4 2 0.17 36. c.328GNC D110H# Ex4 2 0.17 37. c.579+3ANG 711+3ANG# In5 2 0.17 38. c.3528delC 3659delC*# Ex19 2 0.17 39. c.4127_4131delTGGAT 4259del5 Ex22 2 0.17 40. c.1-?_1584+?del CFTRdele1,10 Ex1-Ex10 1 0.08 41. c.115CNT Q39X# Ex1 1 0.08 42. c.79GNC G27R Ex2 1 0.08 43. Login to comment 48 ABCC7 p.Arg170His ABCC7 p.Tyr301Cys ABCC7 p.Ser42Phe ABCC7 p.Gly178Glu ABCC7 p.Tyr563His ABCC7 p.Gln372* [125CNT]+[223CNT] S42F/R75X# Ex2/Ex3 1 0.08 44. c.164+1GNA 296+1GNA In2 1 0.08 45. c.274GNA E92K# Ex4 1 0.08 46. c.349CNT R117C*# Ex4 1 0.08 47. c.509GNA R170H Ex5 1 0.08 48. c.533GNA G178E Ex5 1 0.08 49. c.579+1GNT 711+1GNT*# In5 1 0.08 50. c.902ANG Y301C Ex7 1 0.08 51. c.1040GNA R347H*# Ex7 1 0.08 52. c.1114CNT Q372X Ex7 1 0.08 53. c.1117-1GNA 1249-1GNA In7 1 0.08 54. c.1209+1GNA 1341+1GNA# In8 1 0.08 55. c.1519_1521delATC I507del*# Ex10 1 0.08 56. c.1654CNT Q552X# Ex11 1 0.08 57. c.1673TNC L558S# Ex11 1 0.08 58. c.1679+1GNC 1811+1GNC In11 1 0.08 59. c.1687TNC Y563H Ex12 1 0.08 60. c.1753GNT E585X# Ex12 1 0.08 61. c.1766+1GNC 1898+1GNC In12 1 0.08 62. c.2044delA 2176delA Ex13 1 0.08 63. c.2051_2052delAAinsG 2183delAANG# Ex13 1 0.08 64. c.2052delA 2184delA*# Ex13 1 0.08 3. Login to comment 49 ABCC7 p.Gly551Asp ABCC7 p.Asn1303Lys ABCC7 p.Gly542* Results Altogether we found 91 different CFTR mutations (Table 1), with only seven being present at a frequency N1%: F508del (67.42%), CFTRdele2,3(21kb) (5.75%), G551D (2.92%), N1303K (2.42%), G542X (2.0%), 3849+10kbCNT (1.67%) and 1898+1GNA (1.42%) (using the legacy/traditional nomenclature). Login to comment 51 ABCC7 p.Ser1456Asn In addition, 20 novel mutations (Table 1) and a novel variant (S1456N) were discovered. Login to comment 54 ABCC7 p.Asn1303Lys ABCC7 p.Val754Met In addition, we observed the previously described V754M mutation in trans to N1303K in an unaffected mother (sweat test: 40 mmol/l). Login to comment 55 ABCC7 p.Asn1303Lys ABCC7 p.Val754Met ABCC7 p.Glu292Lys ABCC7 p.Glu292Lys ABCC7 p.Arg709Gln ABCC7 p.Arg709Gln Her first CF child bears a R709Q-E292K/ N1303K in trans, while sequencing of exon 7, 13 and 21 during prenatal diagnosis of her second child, who is unaffected, revealed the R709Q-E292K/V754M genotype. Login to comment 56 ABCC7 p.Ser1455* The S1455X mutation was observed in compound heterozygosity with the F508del in a male patient who was clinically diagnosed at age 7 years, in which "repeated bronchitis" led to sweat testing (mean concentration 70 mmol/l). Login to comment 57 ABCC7 p.Ser1455* ABCC7 p.Ser1456Asn ABCC7 p.Ser1456Asn Interestingly, the patient's asymptomatic father bears mutation S1455X in trans to a novel variant S1456N and the patient's apparently healthy brother has the maternal-F508del/S1456N genotype. Login to comment 62 ABCC7 p.Met1101Arg ABCC7 p.Met952Ile ABCC7 p.Ser1118Phe ABCC7 p.Gln1476* ABCC7 p.Leu1335Pro ABCC7 p.Leu1335Phe ABCC7 p.Glu1104Lys ABCC7 p.Gly1047Arg ABCC7 p.Glu1046* ABCC7 p.Arg1066Gly ABCC7 p.Ile1366Asn ABCC7 p.Leu1324Pro There are over 10 million inhabitants in the country, which according to population genetic analyses, is a representative of the CE ethnic composition [3], with significant overlaps with Table 1 (continued) Mutations/HGVS nomenclature/ Mutations/traditional nomenclature, legacy name/ Legacy exon/intron No. of alleles % 65. c.2290CNT R764X# Ex13 1 0.08 66. c.2490+1GNA 2622+1GNA# In13 1 0.08 67. c.2538GNA W846X*# Ex14a 1 0.08 68. c.2551CNT R851X# Ex14a 1 0.08 69. c.2589_2599delAATTTGGTGCT 2721del11 Ex14a 1 0.08 70. c.2705delG 2837delG Ex15 1 0.08 71. c.2789delG 2921delG Ex15 1 0.08 72. c.2803_2813delCTACCACTGGT 2935del11 Ex15 1 0.08 73. c.2856GNC M952I Ex15 1 0.08 74. c.2991GNC L997F# Ex17a 1 0.08 75. c.3106delA 3238delA Ex17a 1 0.08 76. c.3136GNT E1046X Ex17a 1 0.08 77. c.3139GNC G1047R Ex17a 1 0.08 78. c.3196CNT R1066C*# Ex17b 1 0.08 79. c.3196CNG R1066G Ex17b 1 0.08 80. c.3302TNG M1101R Ex17b 1 0.08 81. c.3310GNA E1104K Ex17b 1 0.08 82. c.3353CNT S1118F Ex17b 1 0.08 83. c.3472CNT R1158X*# Ex19 1 0.08 84. c.3587CNG S1196X# Ex19 1 0.08 85. c.3708delT 3840delT Ex19 1 0.08 86. c.3937CNT Q1313X# Ex21 1 0.08 87. c.3971TNC L1324P Ex22 1 0.08 88. c.4003CNT L1335F Ex22 1 0.08 89. c.4004TNC L1335P Ex22 1 0.08 90. c.4097TNA I1366N Ex22 1 0.08 91. c.4426CNT Q1476X Ex24 1 0.08 92. Login to comment 63 ABCC7 p.Asp1152His ABCC7 p.Leu997Phe Unknown 6 0.50 Total 1200 100.00 Legend: Within the traditional nomenclature column: "*" mutations included in the Elucigene CF-EU2v1ࡊ assay; "# " genotype-phenotype correlations of detected mutations are described in the CFTR2 database [21] with e.g. D1152H, L997F having "varying consequences"&#a8;; "?" Login to comment 71 ABCC7 p.Gly551Asp However, the G551D mutation is more common within the "core Hallstatt culture territory" [17] that comprises the current CZ, DE, AT and AT- Tyrol [18, Table 2]. Login to comment 72 ABCC7 p.Gly551Asp Therefore, a "Celtic" origin of G551D is likely and is supported by its common origin and extrapolated "age" [19]. Login to comment 73 ABCC7 p.Gly542* Similarly, we presume that the "Mediterranean" mutation G542X [8] is, according to historical patterns of CE colonization [17], the most prevalent in the Danube basin, i.e. in SK, HU, AT and DE. Login to comment 76 ABCC7 p.Ser1455* We have not included the male with the S1455X/F508del in our cohort, since he only suffers from "isolated elevated sweat chloride concentrations" [20] and does not meet the diagnostic criteria for CF [10]. Login to comment 77 ABCC7 p.Arg117His Similarly, all cases with the R117H-IVS8 T(7) in cis, which did not meet the diagnostic criteria were also excluded from this study. Login to comment 78 ABCC7 p.Val754Met Although the V754M mutation "is still under evaluation" in the CFTR2 database [21], we concluded that its pathogenic potential is limited. Login to comment 80 ABCC7 p.Met952Ile ABCC7 p.Glu92Lys The previously reported pathological L1-mediated retrotranspositional event [23] was detected in one patient who was compound heterozygous for the E92K/M952I mutations. Login to comment 81 ABCC7 p.Met952Ile It is likely that the pathogenetic impact of the "CFTR-related disorder associated" mutation M952I [22] was augmented by the Alu1- related molecular alternation of the CFTR, leading to a "classical" presentation of CF in this case. Login to comment 83 ABCC7 p.Glu292Lys ABCC7 p.Arg709Gln ABCC7 p.Arg709Gln In addition, previously unknown complex allele [25] comprising R709Q-E292K in cis in four unrelated families was discovered, with the R709Q being reported in AT [26]. Login to comment 85 ABCC7 p.Ser945Leu ABCC7 p.Ile336Lys The Elucigene CF-EU2v1ࡊ assay was shown to achieve sufficient mutation detection rates for multi-tier CF NBS (i.e. more than 85%), although the I336K and S945L, with frequency over 0.5% (Table 1), should also be included in the Czech national screening panel [1]. Login to comment 89 ABCC7 p.Gly551Asp ABCC7 p.Trp1282* ABCC7 p.Arg553* ABCC7 p.Arg347Pro ABCC7 p.Asn1303Lys ABCC7 p.Gly542* ABCC7 p.Ser945Leu ABCC7 p.Ile336Lys Mutations/HGVS nomenclature/ Mutations/traditional nomenclature, legacy name/ Czech Republic 2012 (this study) (N=1200) Slovakia 2010 (N=856) Eastern Hungary 2011 (N=80) Germany Bavaria 2002 (N=250) Austria Tyrol 1997 (N=126) Austria NorthEast, North- North 2002 (N=118) Poland (N=1726) c.1521_1523delCTT F508del 67.42 66.80 70.00 74.00 74,60 70.30 57.0 c.54-5940_273+10250del21 kb CFTRdele2,3/21kb 5.75 2.26 5.00 1.2* 2.6# NA 1.80 c.1652GNA G551D 2.91 b0.50 0.00 6.40 1.60 2.50 0.50 c.3909CNG N1303K 2.42 2.03 5.00 2.40 0.00 NA 1.80 c.1624GNT G542X 2.00 4.06 3.75 3.20 2.40 5.10 2.60 c.3718-2477CNT 3849+10kbCNT 1.67 4.28 0.00 NA 0.00 3.40 2.70 c.1766+1GNA 1898+1GNA 1.42 b0.50 0.00 NA 0.00 NA NA c.1040GNC R347P 0.92 1.10 1.25 0.80 1.60 2.50 NA c.2012delT 2143delT 0.92 1.10 0.00 NA 0.00 NA NA c.3140-26ANG 3272-26ANG 0.67 b0.50 0.00 NA 0.00 NA NA c.3846GNA W1282X 0.58 b0.50 0.00 NA 0.00 NA 0.70 c.1007TNA I336K 0.58 0.00 0.00 NA 0.00 NA NA c.1657CNT R553X 0.50 0.90 0.00 1.20 0.00 NA 1.90 c.2657+5GNA 2789+5GNA 0.50 0.00 0.00 NA 2.40 NA NA c.2834CNT S945L 0.50 0.00 0.00 NA 0.00 NA NA c.2052_2053insA 2184insA 0.42 1.58 5.00 NA 0.00 NA NA Legend: data for Slovakia [12], Eastern Hungary [14], Germany-Bavaria [13], Austria-Tyrol [18], Austria North East and North West [13], Poland and *[8], and # [16]. 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