Cystic fibrosis: A worldwide analysis ofCFTR mutations?correlation with incidence data and application to screening

Abstract

Although there have been numerous reports from around the world of mutations in the gene of chromosome 7 known as CFTR (cystic fibrosis transmembrane conductance regulator), little attention has been given to integrating these mutant alleles into a global understanding of the population molecular genetics associated with cystic fibrosis (CF). We determined the distribution of CFTR mutations in as many regions throughout the world as possible in an effort designed to: 1) increase our understanding of ancestrygenotype relationships, 2) compare mutational arrays with disease incidence, and 3) gain insight for decisions regarding screening program enhancement through CFTR multi-mutational analyses. Information on all mutations that have been published since the identification and cloning of the CFTR genes most common allele, DF508 (or F508del), was reviewed and integrated into a centralized database. The data were then sorted and regional CFTR arrays were determined using mutations that appeared in a given region with a frequency of 0.5% or greater. Final analyses were based on 72,431 CF chromosomes, using data compiled from over 100 original papers, and over 80 regions from around the world, including all nations where CF has been studied using analytical molecular genetics. Initial results confirmed wide mutational heterogeneity throughout the world; however, characterization of the most common mutations across most populations was possible. We also examined CF incidence, DF508 frequency, and regional mutational heterogeneity in a subset of populations. Data for these analyses were filtered for reliability and methodological strength before being incorporated into the final analysis. Statistical assessment of these variables revealed that there is a significant positive correlation between DF508 frequency and the CF incidence levels of regional populations. Regional analyses were also performed to search for trends in the distribution of CFTR mutations across migrant and related populations; this led to clarification of ancestrygenotype patterns that can be used to design CFTR multi-mutation panels for CF screening programs. From comprehensive assessment of these data, we offer recommendations that multiple CFTR alleles should eventually be included to increase the sensitivity of newborn screening programs employing two-tier testing with trypsinogen and DNA analysis. Hum Mutat 19:575606, 2002.

Newborn screening for cystic fibrosis: Polish 4 years’ experience with CFTR sequencing strategy

“…This particulary important within the first years of a screening programme, when clinical follow-ups are continued. The incidence of the CF in Poland calculated on the number of F508del homozygotes and the previously reported F508del allele frequency 15 would be 1/4394. The incidence of disease estimated directly on basis of the NBS CF programme results is 1 per 5248-5486.…”

“…For each positive IRT result (499.4 percentile) direct CFTR gene analysis was performed by sequencing of selected regions. The complete analysis using this diagnostic panel allowed us to identify (1) nearly 80% of the mutated alleles in Poland and (2) mutations in one or both alleles in nearly 95% of screened CF patients (according to frequency data published by Bobadilla et al 15 ). Blood trypsin values above the threshold were found in 7532 neonates.…”

“…We assumed that during the period of the NBS CF programme, we detected all F508del homozygotes (90/221 cases, 41%). Based on this assumption, the previously published data of the frequency of this mutation in the Polish population (57%, 15 ), the data from the Polish Cystic Fibrosis Patients Registry 3 (56-62%) and the results of the clinical follow-up Newborn screening for CF in Poland A Sobczyńska-Tomaszewska et al ending in December 2011, we calculated the CF incidence in our country as 1/4394 and carrier frequency as 1/33. The incidence and carrier frequency are lower (1/5249:5486 and 1/36:37, respectively) when results from NBS CF are taken into account.…”

“…12,13 In Polish CF patients the frequency of the F508del mutation is estimated as 53-57%. 14,15 According to the a panel of the most frequent mutations in Polish CF patients published in 2009 16 and our personal experience (unpublished data), mutations such as K710X and 2184insA have a frequency 40.45%. As these sequence variants, are not included in commercial assays (eg, InnoLipa Innogenetics, CF assay Abbott, Tepnel Diagnostics Elucigene), we decided to apply the direct sequencing of selected CFTR gene regions as part of the genetic protocol of NBS CF, in order to avoid the poor effectiveness of the IRT/DNA protocol using commercial kits.…”

Spectrum of CFTR gene mutations in Ecuadorian cystic fibrosis patients: the second report of the p.H609R mutation

“…2002) and in Israel, 1% of frequency (World Health Organization, 2006). Prevalence of the mutations p.N1303K and p. R1162X in this study are similar to other countries.…”