ABCMdb

PMID: 22043142

Lilley M, Christian S, Hume S, Scott P, Montgomery M, Semple L, Zuberbuhler P, Tabak J, Bamforth F, Somerville MJ
Newborn screening for cystic fibrosis in Alberta: Two years of experience.
Paediatr Child Health. 2010 Nov;15(9):590-4., [PubMed]

Sentences

No. Mutations Sentence Comment

22 ABCC7 p.Arg117His ABCC7 p.Met1101Lys A relatively high frequency of the R117H mutation and the M1101K mutation was noted. Login to comment 23 ABCC7 p.Met1101Lys The M1101K mutation is common in the Hutterite population. Login to comment 24 ABCC7 p.Arg117His The presence of the R117H mutation has created both counselling and management dilemmas. Login to comment 29 ABCC7 p.Arg117His ABCC7 p.Met1101Lys Les d&#e9;pistages positifs sont suivis d`un test &#e0; la sueur et d`une &#e9;valuation par un sp&#e9;cialiste de la FK. Des 99 408 nouveau-n&#e9;s ayant fait l`objet d`un test de d&#e9;pistage en Alberta pendant les deux premi&#e8;res ann&#e9;es du programme, 221 ont obtenu des r&#e9;sultats positifs au d&#e9;pistage n&#e9;onatal de la FK. Le programme a ensuite permis de rep&#e9;rer et d`amorcer un traitement chez 31 nouveau-n&#e9;s atteints de FK. On a remarqu&#e9; une fr&#e9;quence relativement &#e9;lev&#e9;e des mutations R117H et M1101K. Login to comment 30 ABCC7 p.Met1101Lys La mutation M1101K est courante au sein de la population hutt&#e9;rienne. Login to comment 31 ABCC7 p.Arg117His La pr&#e9;sence de la mutation R117H a cr&#e9;&#e9; &#e0; la fois des dilemmes de counseling et de prise en charge. Login to comment 46 ABCC7 p.Gly551Asp ABCC7 p.Arg117His ABCC7 p.Ala455Glu ABCC7 p.Trp1282* ABCC7 p.Arg553* ABCC7 p.Arg334Trp ABCC7 p.Arg347Pro ABCC7 p.Arg347His ABCC7 p.Asn1303Lys ABCC7 p.Gly542* ABCC7 p.Arg1162* ABCC7 p.Val520Phe ABCC7 p.Ser549Arg ABCC7 p.Gly85Glu ABCC7 p.Ser549Asn ABCC7 p.Tyr122* ABCC7 p.Arg560Thr ABCC7 p.Met1101Lys ABCC7 p.Tyr1092* ABCC7 p.Ser1255* ABCC7 p.Ala559Thr These include the following mutations: delF508, I507del, G542X, G85E, R117H, 621+1G࢐T, 711+1G࢐T, G551D, R334W, R347P, A455E, 1717-1G࢐A, R560T, R553X, N1303K, 1898+1G࢐A, 2184delA, 2789+5G࢐A, 3120+1G࢐A, R1162X, 3659delC, 3849+10kbC࢐T, W1282X, 1078delT, 394delTT, Y122X, R347H, V520F, A559T, S549N, S549R, 1898+5G࢐T, 2183AA࢐G, 2307insA, Y1092X, M1101K, S1255X, 3876delA and 3905insT. Login to comment 47 ABCC7 p.Phe508Cys ABCC7 p.Ile506Val ABCC7 p.Ile507Val If indicated, testing includes reflex analysis for the following variants: 5/7/9T exon 9 splice acceptor tracts, F508C, I507V and I506V. Login to comment 48 ABCC7 p.Arg117His Molecular analysis of parents is recommended when R117H and 5 thymine (5T) are identified to assess phase. Login to comment 52 ABCC7 p.Arg117His Newborns are reported to have an inconclusive screen if they fall into one of the following three categories: an elevated IRT and one mutation; a markedly elevated IRT and no mutations; or an elevated IRT and two mutations, in which the second mutation is R117H without 5T. Login to comment 53 ABCC7 p.Arg117His Newborns with an elevated IRT and two mutations (excluding R117H without 5T) are reported as having probable CF. Login to comment 58 ABCC7 p.Arg117His ABCC7 p.Arg117His Sweat chloride testing is generally performed when infants are between four and six weeks of Immunoreactive Trypsinogen (IRT) measurement Elevated IRT Normal IRT= Negative newborn screen for CF CFTR mutation screening (39 mutation panel) Probable Screen (2 mutations, excluding R117H without 5T) Inconclusive Screen (1 mutation, IRT >99.9% or mut/ R117H) Negative screen (no mutations and IRT is not markedly elevated) Lab Genetic Counsellor contacts physician regarding results Lab Genetic Counsellor contacts physician regarding results Referral to CF Clinic for sweat test and clinical assessment Referral to CF Clinic for sweat test and clinical assessment Sweat Test Positive Clinical diagnosis of CF Sweat Test Borderline/ Negative Further follow-up required Sweat Test Positive Full CFTR sequencing Sweat Test Borderline Repeat sweat test and/or CFTR full sequencing Sweat Test Negative CF carrier, unlikely to have classic CF Figure 1) Alberta cystic fibrosis (CF) newborn screening protocol. Login to comment 75 ABCC7 p.Arg117His During the first two years of the program, 198 newborns had an inconclusive screen including 191 newborns with one mutation, two newborns with markedly elevated IRTs and five newborns with R117H/delF508 genotypes (Table 2). Login to comment 79 ABCC7 p.Arg117His Six newborns had R117H in conjunction with a second CF mutation. Login to comment 81 ABCC7 p.Arg117His Five of the newborns had delF508/R117H without 5T and, therefore, were reported as having an inconclusive screen for CF. Login to comment 84 ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg347His ABCC7 p.Val520Phe ABCC7 p.Ser549Arg ABCC7 p.Ser549Asn ABCC7 p.Tyr122* ABCC7 p.Met1101Lys ABCC7 p.Tyr1092* ABCC7 p.Ser1255* ABCC7 p.Ala559Thr TAbLe 1 Mutation frequency Mutation name Number of times detected (247 total mutations) Frequency, % expected, % (reference) delF508* 156 63.2 68.6 (1) R117H* 36 14.6 0.7 (1) G551D* 11 4.5 2.1 (1) 3849+10kbC࢐T* 6 2.4 0.7 (1) M1101K 5 2.0 Undetermined (1) G542X* 4 1.6 2.4 (1) 1717-1G࢐A* 4 1.6 0.7 (1) 621+1G࢐T* 3 1.2 0.9 (1) 3120+1G࢐A* 3 1.2 1.5 (1) G85E* 2 0.8 0.3 (1) A455E* 2 0.8 0.2 (1) R553X* 2 0.8 0.9 (1) 2789+5G࢐A* 2 0.8 0.3 (1) ƊI507* 1 0.4 0.3 (1) 711+1G࢐T* 1 0.4 0.1 (1) R334W* 1 0.4 0.2 (1) N1303K* 1 0.4 1.3 (1) 1898+1G࢐A* 1 0.4 Undetermined (1) 2184delA* 1 0.4 0.1 (1) 394delTT 1 0.4 Undetermined (1) R347H 1 0.4 0.2 (4) V520F 1 0.4 0.2 (4) S549N 1 0.4 0.1 (1) 2307insA 1 0.4 0.2 (1) R347P* 0 0 0.2 (1) R560T* 0 0 0.2 (1) R1162X* 0 0 0.2 (1) 3659delC* 0 0 0.2 (1) W1282X* 0 0 1.4 (1) 1078delT 0 0 0.03 (2) Y122X 0 0 Undetermined (3) A559T 0 0 0.2 (1) S549R 0 0 Undetermined (1) 1898+5G࢐T 0 0 Undetermined (1) 2183AA࢐G 0 0 0.1 (1) Y1092X 0 0 Undetermined (1) S1255X 0 0 0.2 (1) 3876delA 0 0 Undetermined (4) 3905insT 0 0 0.12 (1) *American College of Medical Genetics-recommended mutations TAbLe 2 Positive cystic fibrosis newborn screen summary Screen result Unaffected Affected Further follow-up required Lost to follow-up Total Probable screen 0 23 0 0 23 Inconclusive screen One mutation 179 8 2 2 191 Markedly elevated IRT 2 0 0 0 2 R117H/F508del 0 0 5 0 5 Total 181 31 7 2 221 Data presented as n. IRT Immunoreactive trypsinogen TAbLe 3 F508del/R117H cases ID number Mutation status Sweat test result(s), &#b5;mol/L Other clinical information 24827 F508del/R117H 28 None 23726 F508del/R117H 36/insufficient/20 Fecal elastase normal 22578 F508del/R117H 10 None 24500 F508del/R117H 34/insufficient None 18527 F508del/R117H 29 None 23317 F508del/R117H+5T 47/62 Affected sibling 5T 5 thymine There were 23 newborns with probable screens. Login to comment 88 ABCC7 p.Val520Phe ABCC7 p.Met1101Lys One baby (4%) was a M1101K homozygote, and one was a compound heterozygote V520F/1898+1G࢐A. Login to comment 94 ABCC7 p.Gly458Val An affected sibling was identified as having F508del/G458V after CFTR full sequencing. Login to comment 109 ABCC7 p.Arg117His The individual frequency of those mutations was as expected, apart from R117H, which was more common in our study population. Login to comment 110 ABCC7 p.Met1101Lys We also reported a 2% mutation frequency for the M1101K mutation. Login to comment 111 ABCC7 p.Met1101Lys The relatively high frequency of M1101K was expected based on the Hutterite population in Alberta. Login to comment 114 ABCC7 p.Arg117His The overall frequency of the R117H mutation in our sample population appears to be higher than previously reported in the literature. Login to comment 115 ABCC7 p.Arg117His The R117H mutation is known to be modified by the length of the polythymine tract in intron 8. Login to comment 117 ABCC7 p.Arg117His Whereas, when R117H is in cis with 7T or 9T, it is believed to act as a mild mutation and is associated primarily with congenital absence of the vas deferens or atypical adult-onset CF. Login to comment 118 ABCC7 p.Arg117His The frequency of R117H in the literature varies from 0.5% to 0.7% of CF mutations (3,7-9). Login to comment 119 ABCC7 p.Arg117His In our population of screen-positive newborns, the frequency of R117H was 36 of 247 mutations (14.6%). Login to comment 120 ABCC7 p.Arg117His In six of 36 cases, a second CFTR mutation was detected and in 30 of 36 cases, the baby carried only the R117H mutation, with or without 5T. Login to comment 121 ABCC7 p.Arg117His Other newborn screening programs also report a high frequency of R117H in newborns with two CFTR mutations. Login to comment 122 ABCC7 p.Arg117His The frequency of an R117H mutation in newborns with two CFTR mutations ranges from 7.2% in France, to 8% in Massachusetts (USA), to 26.7% in Wisconsin (USA) (2,10,11). Login to comment 124 ABCC7 p.Trp1204* ABCC7 p.Asp110His Due to milder TAbLe 4 Cystic fibrosis transmembrane regulator full screen results for inconclusive cases with borderline and elevated sweat chloride results ID Sweat chloride, bc;mol/L IRT, bc;g/L 1st mutation 2nd mutation Mutation description (reference) 14920 67/72 194 F508del D110H Associated with mild or atypical CF (5) 14490 105 271 F508del W1204X Rare but associated with classic CF (6) 15810 95 162 1717G࢐A Exon 2-3 del Associated with classic CF (7) 17167 110 178 F508del Not sequenced N/A 15905 40 94 3849+10kb 2789+1G࢐A Not previously reported. Login to comment 125 ABCC7 p.Arg117His ABCC7 p.Leu206Trp ABCC7 p.Gly458Val ABCC7 p.Arg352Trp Predicted splice site mutation 14780 35 69 F508del R352W Rare, no clinical data published 17316 53/35 74 F508del L206W Variable, ranging from classic CF to isolated CBAVD (8) 16053 26/62 72 F508del 5T Associated with atypical CF and CBAVD (9) 21739 N/A 98 F508del G458V Associated with classic CF (17) 16229 31/32 62 F508del - N/A 16369 38/48 79 711+G࢐T - N/A 12468 NSQ/30 103 F508del - N/A 5T 5 thymine; CBAVD Congenital bilateral absence of the vas deferens; CF Cystic fibrosis; IRT Immunoreactive trypsinogen; N/A Not available; NSQ Not sufficient quantity or absent phenotype, individuals with the R117H mutation may be underdiagnosed and the mutation frequency may be under-represented. Login to comment 126 ABCC7 p.Arg117His Newborns with a genotype involving a known disease-causing mutation and R117H create counselling and management dilemmas. Login to comment 127 ABCC7 p.Arg117His We identified five newborns with a F508del/R117H genotype in the absence of 5T. Login to comment 131 ABCC7 p.Arg117His Congenital bilateral absence of the vas deferens is also associated with the combination of a severe mutation and R117H. Login to comment 133 ABCC7 p.Arg117His Currently, there is no consensus on how to manage children with a F508del/R117H genotype. Login to comment 136 ABCC7 p.Arg117His There has been debate in the literature regarding the inclusion of R117H in newborn screen. Login to comment 141 ABCC7 p.Trp1204* We identified a second mutation in seven of 10 newborns, including two mutations that are associated with classic childhood onset CF (W1204X and Exon 2-3 deletion). Login to comment 142 ABCC7 p.Leu206Trp ABCC7 p.Asp110His Three mutations (D110H, L206W and 5T) were identified that are associated with a mild or variable phenotype. Login to comment 143 ABCC7 p.Arg352Trp Two mutations (2789+1 G࢐A and R352W) were also identified for which no published information on clinical phenotype was available. Login to comment 172 ABCC7 p.Met1101Lys Zielenski J, Fujiwara TM, Markiewicz D, et al. Identification of the M1101K mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene and complete detection of cystic fibrosis mutations in the Hutterite population. Login to comment 189 ABCC7 p.Arg117His ABCC7 p.Arg117Cys Massie RJ, Poplawski N, Wilcken B, Goldblatt J, Byrnes C, Robertson C. Intron-8 polythymidine sequence in Australasian individuals with CF mutations R117H and R117C. Login to comment 196 ABCC7 p.Arg117His Scotet V, Audrezet MP, Roussey M, et al. Immunoreactive trypsin/ DNA newborn screening for cystic fibrosis: Should the R117H variant be included in CFTR mutation panels? Login to comment