ABCMdb

PMID: 15775760

Ruchon AF, Ryan SR, Fetni R, Rozen R, Scott P
Frequency and phenotypic consequences of the 3199del6 CFTR mutation in French Canadians.
Genet Med. 2005 Mar;7(3):210-1., [PubMed]

Sentences

No. Mutations Sentence Comment

53 ABCC7 p.Ile148Thr ABCC7 p.Ile148Thr ABCC7 p.Ile148Thr ABCC7 p.Ile148Thr ABCC7 p.Ile148Thr Frequency and phenotypic consequences of the 3199del6 CFTR mutation in French Canadians To the Editor: The observation of healthy individuals bearing a severe cystic fibrosis (CF) mutation and I148T in trans but not carrying the 3199del6 mutation has suggested that I148T is not a CF-causing mutation.1,2 Moreover, 3199del6-positive CF patients lacking I148T, compound heterozygous with another CF mutation, indicate that 3199del6 is the disease-causing mutation in the complex allele I148T-3199del6.2,3 Here, we report on the 3199del6 testing results in our cohort of I148T-positive individuals, the frequency of this deletion in the French Canadian population, as well as the phenotype of our 3199del6-positive patients. Login to comment 54 ABCC7 p.Ile148Thr The presence of the 3199del6 mutation was determined in a cohort of 32 I148T-positive samples: 27 unrelated CF French Canadian patients, referred for corroboration of CF diagnosis, and 5 carriers (3 French Canadians, 1 Lebanese, and 1 adopted of unknown origin). Login to comment 57 ABCC7 p.Ile148Thr ABCC7 p.Ile148Thr The phase of I148T and 3199del6 was verified in 17 patients and, in all (100%), both variants occurred in cis (I148T- 3199del6complexallele).Ofthepatientsreferredforcarrierstatus determination, the three French Canadians also carried the deletion, whereas the two others, one Lebanese and one of unknown origin, did not. Login to comment 60 ABCC7 p.Ile148Thr ABCC7 p.Ile148Thr ABCC7 p.Ile148Thr This I148T-3199del6 frequency is in contrast to the previously reported I148T frequency of 9.1% in French Canadians.5 Explanations for this frequency discrepancy could be as follows: a sample bias, because we receive patients from all Quebec regions and the previousreportanalyzedonlyFrenchCanadiansfromtheQuebec Cityarea;ormorelikely,thatthe2.2%reflectsthefrequencyofthe real CF-causing mutation, 3199del6, in French Canadians, which inthispopulationcomplexesinciswithI148T,whereas9.1%corresponds to the I148T polymorphism frequency. Login to comment 64 ABCC7 p.Asn1303Lys As expected, a pancreatic insufficiency (PI) phenotype was observed in 21 of 22 patients bearing 3199del6 and another severe CF allele (F508del, I507del, N1303K, or 621ϩ1GϾT). Login to comment 66 ABCC7 p.Ile148Thr In only one patient (F508del/I148T-3199del6) was a pancreatic sufficiency phenotype observed. Login to comment 67 ABCC7 p.Ala455Glu ABCC7 p.Ala455Glu A pancreatic sufficiency phenotype was found in two patients carrying A455E on the second allele, consistent with the previously reported association of A455E with a mild CF phenotype.6 In two patients, a second CF-causing mutation was not identified despite the use of a 35 mutation panel, which included the 25 ACMG recommended mutations. Login to comment 69 ABCC7 p.Ile148Thr Altogether, our observations further demonstrate that the 3199del6 mutation is associated with a classical pancreatic insufficiency CF phenotype, consistent with the suggestion of Buyse et al.7 Previous studies have identified 3199del6 in 1.8%, 0.9%, and 0.6% of I148T heterozygous carriers and determined the frequency of 3199del6 in the general North American population to beϽ0.1%,belowthefrequencythresholdcriteriaforinclusionin the ACMG CF mutation screening panel.1,8,9 In this study, we reporta2.2%frequencyforthe3199del6mutationamongFrench Canadian CF chromosomes. Login to comment 70 ABCC7 p.Ile148Thr ABCC7 p.Ile148Thr As mentioned, only two I148T carriers (one Lebanese and one of unknown origin) tested negative for the 3199del6 mutation in our cohort of 32 unrelated I148T individuals. Login to comment 71 ABCC7 p.Ile148Thr In other words, in our samples, all I148T French Ca- nadianallelesalsohadthe3199del6mutation,probablyreflecting a founder effect, and justifying its inclusion in routine CF testing/ screening in this ethnic group. Login to comment 73 ABCC7 p.Ile148Thr ABCC7 p.Ile148Thr The 2004 ACMG mutation panel revision recommends exclusion of I148T from the CF mutation panel.10 However, in the French Canadian population, I148T testing must be replaced by 3199del6 testing, which can be done using a simple PCR-based heteroduplex assay. Login to comment 74 ABCC7 p.Ile148Thr ABCC7 p.Ile148Thr If I148T testing is continued, then the data presented here strongly support 3199del6 testing for every I148T-positive result. Login to comment 76 ABCC7 p.Ile148Thr Rohlfs EM, Zhou Z, Sugarman EA, Heim RA, Pace RG, Knowles MR et al. The I148T CFTR allele occurs on multiple haplotypes: a complex allele is associated with cystic fibrosis. Login to comment 81 ABCC7 p.Asp1270Asn ABCC7 p.Arg74Trp ABCC7 p.Ile148Thr Are p.I148T, p.R74W and p.D1270N cystic fibrosis causing mutations? Login to comment 88 ABCC7 p.Ala455Glu Phenotype correlation in cystic fibrosis patients compound heterozygous for the A455E mutation. Login to comment 94 ABCC7 p.Ile148Thr Frequency of the cystic fibrosis 3199del6 mutation in individuals heterozygous for I148T. Login to comment 96 ABCC7 p.Ile148Thr Monaghan KG, Highsmith WE, Amos J, Pratt VM, Roa B, Friez M et al. Genotype-phenotype correlation and frequency of the 3199del6 cystic fibrosis mutation among I148T carriers: Results from a collaborative study. Login to comment 104 ABCC7 p.Asn1303Lys ABCC7 p.Ile148Thr ABCC7 p.Ile148Thr ABCC7 p.Ile148Thr ABCC7 p.Ile148Thr ABCC7 p.Ile148Thr ABCC7 p.Ile148Thr ABCC7 p.Ile148Thr ABCC7 p.Ile148Thr ABCC7 p.Ile148Thr ABCC7 p.Ile148Thr To diagnose most of the Table 1 Genotype-phenotype correlation of CF patients bearing the complex allele I148T-3199del6 Genotype No. of patients Age (y) Pancreatic status Sweat test Age at diagnosis Ethnicity F508del/I148T-3199del6 18 3 to 31 PI 88 to 154 Birth to 12y Fr Cdn I507del/I148T-3199del6 1 4 PI 106 2 months Fr Cdn 621ϩ1GϾT/I148T-3199del6 1 PI 105 Fr Cdn N1303K/I148T-3199del6 1 35 PI 18 months Fr Cdn F508del/I148T-3199del6 1 24 PS 142 4 months Fr Cdn A455E/I148T-3199del6 2 23/55 PS 130 16/20 y Fr Cdn I148T-3199del6/Unk. Mut. 1 5 PI 108 3 months Fr Cdn I148T-3199del6/Unk. Mut. 1 Fr Cdn F508del/I148T-3199del6 1 Fr Cdn PI, pancreatic insufficiency; PS, pancreatic sufficiency; Fr Cdn, French Canadian. Login to comment