Comparison of the CFTR mutation spectrum in three cohorts of patients of Celtic origin from Brittany (France) and Ireland

Abstract

This study aims to compare the spectrum of the mutations identified in the gene responsible for cystic fibrosis in three cohorts of patients of Celtic origin from Brittany and Ireland. It included 389 patients from Brittany, 631 from Dublin and 139 from Cork. The CFTR gene analysis relied on the detection of the most common mutations, followed by a complete gene scanning using DGGE or D-HPLC. High mutation detection rates were obtained in each cohort: 99.6%, 96.8%, and 96.0% respectively. A high frequency of the c.1652_1655 del3 mutation (F508del: 74.8% to 81.3%) and of the "Celtic" mutation (c.1784G>A (G551D): 3.7% to 9.7%) was observed in each population. Apart from this, the mutation spectrums differed. In Brittany, the most common abnormalities were: c.1078delT (3.6%), c.4041C>G (N1303K: 1.4%), c.2670G>A (W846X(2): 1.0%) and c.1717-1G>A (1.0%), whereas in the cohort of Dublin, the main mutations were: c.482G>A (R117H: 3.0%), c.1811G>C (R560T: 2.4%) and c.621+1G>T (1.7%). Finally, in the Cork area, only the c.482G>A mutation (R117H) reached a frequency of 1%. Two previously-unreported mutations were identified in the Dublin cohort: c.2623-2A>G and c.3446T>G (M1105R). This collaborative study highlights the similarities of the CFTR alleles in the Breton and Irish populations, but also the disparities that exist between these populations, despite their common origin. Each population has its own history, with its mixture of founder effects and genetic drifts, which are at the origin of the current mutation distribution. The molecular study of the CFTR gene provides new tools for retracing European populations' histories.

Should diffuse bronchiectasis still be considered a CFTR-related disorder?

“…If available, the range of minor allele frequencies (MAF) found in different studies in the general population (dbSNP) or patients with CF [10,11] was presented (Table 1). …”

“…Based on the CFTR-France database [16] and the Cystic Fibrosis Mutation database (Toronto, CA, www.genet.sickkids.on.ca/app), 0 (n 1 ) P P a n = variable, dbSNP database. b n 1 = 100, our laboratory cohort; n 2 = 27177, [10]; n 3 = 778, [11]. these variants were classified in four categories: severe mutations (CF; only detected in patients with DB), mild mutations (M), unclassified variants (UV) and rare polymorphisms (P) (Fig.…”

Assessing the Disease-Liability of Mutations in CFTR

“…The G551D ( p.Gly551Asp) arose in the Celtic population more recently and is still prevalent in Ireland and Brittany (Scotet et al 2003b), and the N1303K ( p.Asn1303Lys) is also rather frequent in populations from the center of Europe (Osborne et al 1992). Besides these rather common mutations, which are largely distributed in the Caucasian population, there are also some founder effects of mutated alleles observed as, for example, in the Reunion Island, where the Y122X ( p.Tyr122X) mutation displays a frequency of 24% (Duguépéroux et al 2004), or the 394delTT ( p.Leu88IlefsX22) referred to as a Nordic mutation found in countries bordering the Baltic sea (Schwartz et al 1994).…”

Preliminary study of haplotypes linked to the rare cystic fibrosis E1104X mutation

“…The E1104X mutation was later described in Germany by Reiss in 1993 (21), in France (4,23,24), and in US (10).…”