Geographic distribution and regional origin of 272 cystic fibrosis mutations in European populations

Abstract

The geographic distribution of 272 cystic fibrosis (CF) mutations has been studied by assessing the origin of 27,177 CF chromosomes from 29 European countries and three countries from the North of Africa. The most common mutations are delta F308 (66.8%), G542X (2.6%), N1303K (1.6%), G551D (1.5%) and W1282X (1.0%). The delta F508 mutation has the highest frequency in Denmark (87.2%) and the lowest in Algeria (26.3%). Mutation G542X is common in the Mediterranean countries, with a mean frequency of 6.1%. N1303K is found in most of the western and Mediterranean countries and has the highest frequency in Tunisia (17.2%). The wide distribution of these mutations suggests an ancient origin. G551D is common in north-west and central Europe, but is uncommon in other parts of Europe. W1282X has the highest frequency in Israel (36.2%), being also common in most Mediterranean countries and north Africa. Seventeen mutation have frequencies between 0.1 and 0.9%, 1717-1G-->A (0.83%), R553X (0.75%), R1162X (0.51%), 621 + 1G-->T (0.54%) and 2183AA-->G (0.36%), being the most common ones. Some mutations reach relatively high frequencies in some extended geographic regions, such as mutation 394delTT in northern Europe (1.1-28.8%), R117H in northwestern Europe (1.3-3.0%), R553X in central Europe (1.1-24.4%), 1717-1G-->A in Belgium and France (1.1-5.3%), and 2183AA-->G in Italy and Greece (3.2%). Other mutations are only common in small regions: T338I (Sardinia), 711 + 1G-->T (Tunisia), R1162X (Algeria and north of Italy), 1609delCA (east of Spain), 1811 + 1.6kbA-->G (southeastern Spain), R1066C (Portugal), S549R (Algeria), R334W (Crete), 621 + 1G-->T (Central Greece), 3849 + 10kbC-->T (Israel), 2789 + 5G-->A (south of Greece), 451 + 1G--A (Israel), R347P (south of Bulgaria), 1677delTA (south of Bulgaria and Turkey), G85E (south of Greece), R347H (Turkey), 3905insT (Switzerland), 1078delT (Brittany), 1898 + 1G-->A (Wales), A455E (The Netherlands), delta I507 (Brittany), 3659delC (Sweden) and R560T (northern Ireland). Most of these mutations must have an origin and diffusion in the specific European population subgroup. Overall 55 mutations are common in one or several countries or regions of Europe and 217 mutations are rare with relative frequencies of lower than 1% in any of these regions and countries. This information might facilitate mutation analysis of CF in the different regions of Europe.

CFTR mutation distribution among U.S. Hispanic and African American individuals: Evaluation in cystic fibrosis patient and carrier screening populations

“…In the current study, 42 different mutations were identified among the Hispanic individuals (patients and carriers) tested and the most common mutations included those previously reported to be common among Hispanics, 3876delA, 32 W1089X, 17 as well as mutations considered frequent in African Americans (3120ϩ1GϾA) 19 and panethnic (e.g., G542X, ⌬I507) populations. 33 Although regional variation in overall detection rates may occur, these data provide general guidance when developing a panethnic mutation panel and information useful for genetic counseling purposes. By directly comparing CFTR mutation distribution between CF chromosomes identified via affected patients and carrier screening, we have made a number of interesting observations.…”

“…D1270N has been identified in individuals with cystic fibrosis 24,33,35,36 as well as in men with congenital absence of the vas deferens. 24,37 Similar discrepancies in mutation frequency between carrier and patient populations are now well known for the R117H 15 and I148T 38,39 sequence changes, each of which has a cis-acting modifier influencing phenotype (5T 21 and 3199del6, 40 respectively).…”

CFTR allelic heterogeneity in Brazil: historical and geographical perspectives and implications for screening and counseling for cystic fibrosis in this country

“…This can be showed when we compare the occurrence of the eight most frequent mutations in Italy (which consists of B70% of all mutations in this country) with those of other populations (Table 3). 14,53,54 Faucz et al 19 found nine mutations with a frequency higher than 1% (p.F508del: 45.5%; p.G542X: 6.3%; p.N1303K: 4.5%; p.G85E, p.R334W and p.R1162X: total of 3.6%; c.2183AA4G and p.W1282X: 2.7%; and p.R553X: 1.8%) in CF patients from PR and SC (south of Brazil). These nine mutations represented 74.1% of the CFTR alleles and 16 others were identified by this group.…”

“…13 The frequency of the p.F508del mutation differs between populations, ranging from 26% in Algeria and Venezuela to 47% in one Brazilian study and 87% in Denmark; other mutations also vary widely depending on the ethnic composition of the studied groups. [14][15][16][17] Because geographic differences in the frequency of CFTR mutations affect the false-negative rates that arise when CFTR mutation analysis is used for diagnosis and carrier testing, such data should be made available for each different region and ethnic group of a specific country. We previously reported mutation heterogeneity in Brazilian CF patients by direct analysis of the p.F508del mutation and other common sequence alterations (p.G542X, p.N1303 K, p.G551D and p.R553X).…”

Updated assessment of cystic fibrosis mutation frequencies in non-Hispanic Caucasians

“…6 -9 One of these reported frequencies only for European or African countries. 8 Another could have been used, 9 but a proportion of its data was already included in an earlier, collaborative study 6 and appeared to be biased toward underestimating the frequency of delF508. The two remaining data sources were suitable for use in analysis.…”