https://arep.med.harvard.edu/pdf/Reich01.pdf

On the allelic spectrum of human disease.

http://genome.imb-jena.de/publications/download/free/Varon_1998.pdf

Nibrin, a Novel DNA Double-Strand Break Repair Protein, Is Mutated in Nijmegen Breakage Syndrome

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 ancestry-genotype 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 gene's most common allele, DeltaF508 (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, DeltaF508 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 DeltaF508 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 ancestry-genotype 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.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/humu.10041

Cystic fibrosis: a worldwide analysis of CFTR mutations--correlation with incidence data and application to screening.

Haemochromatosis is a genetic disease associated with progressive iron overload, and is common among populations of northern European origin HLA-H is a recently reported candidate gene for this condition Two mutations have been identified, a substitution of cysteine for tyrosine at amino acid 282 (C282Y, nucleotide 845) and of histidine for aspartate at amino acid 63 (H63D, nucleotide 187) Over 90% of UK haemochromatosis patients are homozygous for the C282Y mutation We have examined 5956 chromosomes (2978 people) for the presence of HLA-H C282Y and H63D by PCR followed by restriction enzyme analysis We have found world wide allele frequencies of 19% for C282Y and 81% for H63D The highest frequencies were 10% for C282Y in 90 Irish chromosomes and 304% for H63D in 56 Basque chromosomes C282Y was most frequent in northern European populations and absent from 1042 African chromosomes, 484 Asian chromosomes, and 644 Australasian chromosomes The distribution of the C282Y mutation coincides with that of populations in which haemochromatosis has been reported and is consistent with the theory of a north European origin for the mutation The H63D polymorphism is more widely distributed and its connection with haemochromatosis remains unclear

https://jmg.bmj.com/content/jmedgenet/34/4/275.full.pdf

Global prevalence of putative haemochromatosis mutations.

Cystic fibrosis (CF) is a common genetic disorder in the Caucasian population. The gene was identified in 1989 on the basis of its map location on chromosome 7. The encoded gene product, named cystic fibrosis transmembrane conductance regulator (CFTR), corresponds to a cAMP-regulated chloride channel found almost exclusively in the secretory epithelial cells. Although the major mutation that results in a single amino acid deletion (F508) accounts for 70% of the disease alleles, more than 550 additional mutant alleles of different forms have been detected. Many of these mutations can be divided into five general classes in terms of their demonstrated or presumed molecular consequences. In addition, a good correlation has been found between CFTR genotype and one of the clinical variables--pancreatic function status. An unexpected finding, however, is the documentation of CFTR mutations in patients with atypical CF disease presentations, including congenital absence of vas deferens and several pulmonary diseases. Thus, the implication of CFTR mutation is more profound than CF alone.

Cystic fibrosis: genotypic and phenotypic variations

delta F508 is the most frequent cystic fibrosis (CF) mutation and accounts for approximately 70% of CF chromosomes worldwide. Three highly polymorphic microsatellite markers have been used to study the origin and evolution of delta F508 chromosomes in Europe. Haplotype data demonstrate that delta F508 occurred more than 52,000 years ago, in a population genetically distinct from any present European group, and spread throughout Europe in chronologically distinct expansions, which are responsible for the different frequencies of delta F508 in Europe.

S. Garnerone

Papers

The origin of the major cystic fibrosis mutation (ΔF508) in European populations