Studies of RFLP closely linked to the cystic fibrosis locus throughout Europe lead to new considerations in populations genetics

Serre, Jean‐Louis; Simon‐Bouy, Brigitte; Mornet, Étienne; Jaume-Roig, B; Balassopoulou, Angeliki; Schwartz, Marianne; Taillandier, A.; Boué, J; Boué, A

doi:10.1007/bf00195818

Cited by 86 publications

(83 citation statements)

References 17 publications

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“…10 For example, while the common DF508 mutation is found in 70% of cystic fibrosis probands, hundreds of rarer mutations have also been identified. 10,42 There is no strong experimental or theoretical reason why genes associated with complex genetic disorders involving multiple genes should utilize a different mutational spectrum than genes for single-hit disorders. [10][11][12][13]24 We suggest, then, that both CVCD association and allelic heterogeneity (RVCD) contribute to the association of the DRD4 gene and ADHD (Figure 3).…”

Section: Discussionmentioning

confidence: 99%

High prevalence of rare dopamine receptor D4 alleles in children diagnosed with attention-deficit hyperactivity disorder

et al. 2003

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Associations have been reported of the 7-repeat (7R) allele of the human dopamine receptor D4 (DRD4) gene with both the personality trait of novelty seeking and attention-deficit/ hyperactivity disorder (ADHD). The increased prevalence of the 7R allele in ADHD probands is consistent with the common variant-common disorder hypothesis, which proposes that the high frequency of many complex genetic disorders is related to common DNA variants. Recently, based on the unusual DNA sequence organization and strong linkage disequilibrium surrounding the DRD4 7R allele, we proposed that this allele originated as a rare mutational event, which nevertheless increased to high prevalence in human populations by positive selection. We have now determined, by DNA resequencing of 250 DRD4 alleles obtained from 132 ADHD probands, that most ADHD 7R alleles are of the conserved haplotype found in our previous 600 allele worldwide DNA sample. Interestingly, however, half of the 24 haplotypes uncovered in ADHD probands were novel (not one of the 56 haplotypes found in our prior population studies). Over 10 percent of the ADHD probands had these novel haplotypes, most of which were 7R allele derived. The probability that this high incidence of novel alleles occurred by chance in our ADHD sample is much less than 0.0001. These results suggest that allelic heterogeneity at the DRD4 locus may also contribute to the observed association with ADHD.

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Section: Discussionmentioning

confidence: 99%

High prevalence of rare dopamine receptor D4 alleles in children diagnosed with attention-deficit hyperactivity disorder

et al. 2003

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“…There is a considerable range of estimates obtained for the two different methods. This is not inconsistent with estimates of the age of ∆F 508 which vary from 100 to over 2000 generations (Serre et al 1990;Collins & Morton, 1998;Morral et al 1994). There is, however, a problem in the interpretation of the parameter t. The physical distance between MET and D7S8 is 1.67 Mb compared to a sex-averaged genetic distance of just 0.8 cM (Collins et al 1996).…”

Section: Cystic Fibrosismentioning

confidence: 68%

Fine scale association mapping of disease loci using simplex families

Morris¹,

Whittaker²

2000

Annals of Human Genetics

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summaryWe present a new method for the fine scale mapping of disease loci based on samples of simplex families, each containing an affected child. The method is based on a generalisation of a single locus allele transmission model to multiple marker loci. The model is developed under the assumption of a single ancestral mutation and allows for the calculation of posterior probabilities that each allele at a particular marker was present on the founder chromosome. We illustrate the method using simulated family data for cystic fibrosis and Huntingtons disease, for which the locations of mutations in the disease genes are now known. For both diseases, our new method provides good estimates of the location of the mutations.

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“…Over the last few years, such data (2,3 ) have become the basis for recommendations regarding mutation screening (1,4 ). The most common CF mutation is F508del (two-thirds of all CF mutations) with an incidence decreasing from northwest Europe to southeast Europe (5)(6)(7)(8)(9)(10). Although in a worldwide context most CFTR mutations do not have a frequency Ͼ0.1%, some may still be common in various ethnic, religious, or geographically isolated groups (1,2,(11)(12)(13).…”

confidence: 99%

“…Cystic fibrosis (CF) 5 is a common autosomal recessive genetic disorder caused by various mutations in the CFTR gene [cystic fibrosis transmembrane conductance regulator (ATP-binding cassette sub-family C, member 7)], 6 for which approximately 1500 sequence alterations are presently known (1,2 ). As expected and demonstrated in previous mutational analyses, the frequencies of specific mutations vary widely across ethnic groups.…”

confidence: 99%

A Novel Approach to CFTR Mutation Testing by Pyrosequencing-Based Assay Panels Adapted to Ethnicities

Bickmann¹,

Kamin

Wiebel

et al. 2009

Clinical Chemistry

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Background: Cystic fibrosis (CF) is a common autosomal recessive genetic disorder caused by a variety of sequence alterations in the CFTR gene [cystic fibrosis transmembrane conductance regulator (ATP-binding cassette sub-family C, member 7)]. Because the relative prevalence of mutations strongly depends on the ethnic background, first-level testing of CF as defined by recent consensus recommendations ought to be adaptable to the ethnicity of patients. Methods: We therefore developed and implemented a diagnostic approach to first-level testing for CF based on published mutation frequencies and Pyrosequencing (PSQ) technology that we complemented with standard procedures of mutation detection at the second level. Results: The current test system of PSQ assays for 46 target CF mutations [including CFTRdele2,3 (21 kb) and 1342-6 (T)n (5T/7T/9T)] permits recombinations of single assays to optimize sensitivities for certain ethnicities. By easy expansion of the original mutation panel, the first-level test sensitivities with other ethnic groups would be increased, provided that the mutation frequencies are known. The test was validated with our local, ethnically mixed, but mainly German population (155 patients). The mutation-detection rate for the 92 patients whose CF was confirmed by the sweat test was 89.0% for the patients of German descent (73 of the 92 patients) and 73.7% for the patients of any other origin (19 of the 92 patients). Ethnicity-adapted testing panels for our foreign CF patients would increase the sensitivities for the respective groups by approximately 5%. Conclusions: PSQ-based genotyping is a reliable, convenient, highly flexible, and inexpensive alternative to conventional methods for first-level testing of CFTR, facilitating flexible adaptation of the analyzed mutation panel to any local ethnic group.

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Studies of RFLP closely linked to the cystic fibrosis locus throughout Europe lead to new considerations in populations genetics

Cited by 86 publications

References 17 publications

High prevalence of rare dopamine receptor D4 alleles in children diagnosed with attention-deficit hyperactivity disorder

High prevalence of rare dopamine receptor D4 alleles in children diagnosed with attention-deficit hyperactivity disorder

Fine scale association mapping of disease loci using simplex families

A Novel Approach to CFTR Mutation Testing by Pyrosequencing-Based Assay Panels Adapted to Ethnicities

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