ABCMdb

PMID: 15354331

Strom CM, Crossley B, Redman JB, Buller A, Quan F, Peng M, McGinnis M, Sun W
Cystic fibrosis screening: lessons learned from the first 320,000 patients.
Genet Med. 2004 May-Jun;6(3):136-40., [PubMed]

Sentences

No. Mutations Sentence Comment

12 ABCC7 p.Arg117His The ACMG also recommended that a reflex test for the IVS-8 5T variant be performed in the presence of the mild CF mutation R117H.2 As with the introduction of any large scale screening program, the initial 18 months of population-based CF carrier screening revealed the imperfections of such a program. Login to comment 14 ABCC7 p.Ile148Thr Further work by another laboratory established that in CF patients, the I148T caused CF almost exclusively when coupled with a second, much rarer mutation, 3199del6.11-13 This haplotype also includes the IVS-8 9T allele. Login to comment 15 ABCC7 p.Ile148Thr In response to these new data, the ACMG published an advisory recommending that any patient who is discovered to have I148T and 9T should be tested for 3199del6. Login to comment 17 ABCC7 p.Ile148Thr Based on this new information it is possible an unaffected fetus might have been terminated based on a genotype of I148T and another CF mutation. Login to comment 24 ABCC7 p.Ile148Thr 3 testing is that one or both parents carries I148T, is to contact the physician and advise him or her. Login to comment 36 ABCC7 p.Ile148Thr ABCC7 p.Ile148Thr Because current evidence suggests that I148T is not CF causing mutation (see earlier) the 1,136 patients with I148T have been considered "wild type" and excluded from the table. Login to comment 37 ABCC7 p.Arg117His ABCC7 p.Arg117His In addition, patients with R117H are divided into those with and those without the 5T variant because only those individuals with R117H and 5T in the same allele are at risk for having children with classic CF. Login to comment 42 ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Ile148Thr Using the data from Table 1, which omits I148T cases, excludes carriers of the mild mutation R117H without 5T, and also excludes half of the patients with R117H and 5T (because only half would be predicted to have the 5T in cis), there are 10,139 carriers of classic CF. Login to comment 47 ABCC7 p.Gly551Asp ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Ala455Glu ABCC7 p.Trp1282* ABCC7 p.Arg553* ABCC7 p.Arg334Trp ABCC7 p.Arg347Pro ABCC7 p.Asn1303Lys ABCC7 p.Gly542* ABCC7 p.Arg1162* ABCC7 p.Ile148Thr ABCC7 p.Arg560Thr Frequency, all tests Frequency, CF mutations (%) delta F508 7610 1:44 75% R117H/7T or 9T 1030 1:325 NAb R117H/5T 103 1:3,254 0.51c W1282X 529 1:625 5.2 G542X 382 1:909 3.8 G551D 278 1:1,250 2.7 N1303K 201 1:1,668 2.0 3849ϩ10kb CϾT 167 1:2,007 1.6 1717-1 GϾA 102 1:3,286 1.0 R553X 102 1:3,286 1.0 621ϩ1 GϾT 98 1:3,420 0.97 2789ϩ5 GϾA 82 1:4,087 0.80 3120ϩ1 GϾA 73 1:4,591 0.72 R1162X 54 1:6,207 0.53 R334W 54 1:6,207 0.53 685E 52 1:6,446 0.51 R560T 52 1:6,446 0.51 Delta I507 51 1:6,572 0.50 711ϩ1 GϾT 40 1:8,380 0.39 1898ϩ1 GϾA 37 1:9,059 0.36 3659 del C 36 1:9,311 0.36 A455E 34 1:9,858 0.33 R347P 33 1:10,158 0.32 2184 del A 14 1:23,943 0.14 1078 del T 6 1:55,867 0.06 a I148T has been eliminated from these data. Login to comment 48 ABCC7 p.Arg117His b R117H without 5T is not considered a classic CF mutation (see text). Login to comment 49 ABCC7 p.Arg117His c Only half of these patients were used for calculations due to the prediction that 50% of the 5T alleles will be in trans to the R117H (see text). Login to comment 54 ABCC7 p.Ile148Thr We detected 1,136 patients with I148T in this series. Login to comment 55 ABCC7 p.Ile148Thr ABCC7 p.Ile148Thr After the publication of the association of the haplotype I148T/ IVS-8 9T/3199del6 with CF,13 we began analyzing the IVS-8 status for all patients found to have I148T. Login to comment 56 ABCC7 p.Ile148Thr Of 544 heterozygous patients for I148T, only 86 (16%) lacked the 9T allele. Login to comment 57 ABCC7 p.Ile148Thr ABCC7 p.Ile148Thr Because most patients with I148T will have the 9T allele and the number of patients in the initial published study13 was only 9, we believe that all patients found to have I148T should be offered 3199del6 testing regardless of their IVS-8 genotype. Login to comment 58 ABCC7 p.Ile148Thr Approximately 1% of more than 400 patients with I148T were found to have 3199del6 (data submitted elsewhere). Login to comment 59 ABCC7 p.Ile148Thr In our series of 335,204 tests, 1,136 patients had I148T, predicting that approximately 11 patients would be expected to have 3199del6. Login to comment 62 ABCC7 p.Arg117His These are all postnatal samples and no efforts to determine the phase of 5T and R117H were made. Login to comment 64 ABCC7 p.Arg117His One sample obtained from a CF center had the genotype delta F508/R117H without 5T. Login to comment 66 ABCC7 p.Arg117His There was also a male patient homozygous for R117H without 5T who was azoospermic and infertile but had bilateral presence of vas deferens. Login to comment 68 ABCC7 p.Arg117His Two of these patients have isolated pancreatitis without significant pulmonary disease and have the genotype delta F508/R117H (with an IVS-8 genotype of 9T/5T) and delta F508/2849ϩ10kb C3T respectively. Login to comment 71 ABCC7 p.Arg117His It is possible that the 2789ϩ5GϾA mutation is a mild CF mutation, causing sinusitis comparable to R117H causing CBAVD. Login to comment 74 ABCC7 p.Arg117His ABCC7 p.Ile148Thr Excluding patients with I148T and R117H without 5T, in our series of 335,204 patients, only 4 patients were discovered to have 2 CF mutations who did not previously have the diagnosis of CF, yielding a "false positive" rate of 0.0012% for 2 CF mutations. Login to comment 80 ABCC7 p.Ile148Thr In all, 5 prenatal diagnoses were performed identifying one parent as heterozygous for I148T. Login to comment 81 ABCC7 p.Arg117His ABCC7 p.Ile148Thr ABCC7 p.Ile148Thr One mother was a compound heterozygote for delta F508 and R117H (without 5T), the father was heterozygous for I148T, and the fetal genotype was delta F508/I148T. Login to comment 82 ABCC7 p.Ile148Thr This couple received counseling regarding the significance of I148T and elected to continue the pregnancy. Login to comment 84 ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg117His of patients ⌬F508 ⌬F508 116 ⌬F508 Classic CF mutationa 55 ⌬F508 R117H 38 R117H R117H 4 R117H Classic CF mutation 6 Classic CF mutation Classic CF mutation 20 a All ACMG panel mutations except R117H (without 5T) and ⌬F508. Login to comment 85 ABCC7 p.Arg117His R117H in cis to 5T is considered a classic CF mutation. Login to comment 86 ABCC7 p.Arg117His ABCC7 p.Ile148Thr Table 3 Patients with 2 CF mutations and unexpected phenotypes Genotype Gender Age Symptoms ⌬F508/R117H Female 22 years no respiratory symptoms (5T/9T) 3 episodes of pancreatitis ⌬F508/3849 ϩ 10kb CϾT Female Adult chronic pancreatitis 2789ϩ5 GϾA/2789ϩ5 GϾAa Female 29 years chronic sinusitis ⌬F508/2789ϩ5 GϾA Female 40 years recurrent sinusitits requiring surgery a Both parents confirmed to be carriers of 2789ϩ5 GϾA. I148T and the other for delta F508 had potentially affected genotypes and no pregnancy losses occurred. Login to comment 104 ABCC7 p.Arg117His Clinical significance of 5T The ACMG statement recommends that the 5T allele be analyzed as a reflex in the presence of the R117H, a usually mild CF mutation. Login to comment 105 ABCC7 p.Arg117His The presence of a 5T allele causes aberrant splicing and reduces the amount of functional CFTR mRNA from the gene containing it.16-18 The ACMG recommendation is based on 2 factors: an effort to screen only for patients at risk for offspring with classic CF and the fact the R117H mutation, when on a chromosome that does not contain a 5T allele, usually does not cause classic CF in combination with a classic CF mutation. Login to comment 106 ABCC7 p.Arg117His Compound heterozygous males for R117H and a classical CF mutation are often infertile due to congenital bilateral absence of the vas deferens (CBAVD). Login to comment 108 ABCC7 p.Arg117His However, when an allele contains R117H and a 5T, this allele can cause classic CF when inherited with a classic CF mutation. Login to comment 118 ABCC7 p.Arg117His homozygous wild type Both parents CF carriers 90 17 45 28 Echogenic bowel 100 1 5 94 Abnormal sonogram (not echogenic bowel) 5 0 1 4 Family history of CF (Parents not tested) 20 0 3 17 Population screening (Prenatal performed for other indications) 88 0 4 84 One parent carrier 57 0 31a 26 One parent carrier other parent 5T 33 0 19 14 One or both parents 5T 32 0 0 0 Miscellaneous 3 0 1 2 Indication unavailable 17 0 1 16 a 1 patient was compound heterozygous for R117H/delta F 508 and negative for 5T. Login to comment 131 ABCC7 p.Ile148Thr The single genotype/phenotype error regarding I148T was recognized quickly and interpretative reporting comments adjusted accordingly. Login to comment