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1. Clinical Phenotype and Genotype of Children with Borderline Sweat Test and Abnormal Nasal Epithelial Chloride Transport

Author

Stéphanie Bui, Thierry Bienvenu, Philippe Reix, Gabriel Bellon, Emanuelle Girodon, E. Deneuville, Isabelle Sermet-Gaudelus, Nathalie Stremmler, Albert Iron, Veronika Skalická, Michel Roussey, F. Huet, Delphine Roussel, Gérard Lenoir, M. Lebourgeois, V. Vavrova, Dorota Sands, Milan Macek, Aleksander Edelman, Jacques Sarles, Anne Munck, and Isabelle Fajac

Subjects
Pulmonary and Respiratory Medicine, medicine.medical_specialty, Pathology, Pancreatic disease, Adolescent, Cystic Fibrosis, Genotype, DNA Mutational Analysis, Cystic Fibrosis Transmembrane Conductance Regulator, Critical Care and Intensive Care Medicine, Cystic fibrosis, Gastroenterology, SWEAT, Chlorides, Predictive Value of Tests, Intensive care, Internal medicine, medicine, Humans, Child, Sweat, Sweat test, biology, medicine.diagnostic_test, business.industry, Respiratory disease, Infant, Reproducibility of Results, medicine.disease, Cystic fibrosis transmembrane conductance regulator, Nasal Mucosa, Phenotype, Case-Control Studies, biology.protein, business, Biomarkers
Abstract

The diagnosis of cystic fibrosis (CF) is based on a characteristic clinical picture in association with a sweat chloride (Cl(-)) concentration greater than 60 mmol/L or the identification of two CF-causing mutations. A challenging problem is the significant number of children for whom no definitive diagnosis is possible because they present with symptoms suggestive of CF, a sweat chloride level in the intermediate range between 30 and 60 mmol/L, and only one or no identified CF-causing mutation.To investigate the function of the cystic fibrosis transmembrane conductance regulator (CFTR) protein in the airways of children with intermediate sweat tests and inconclusive genetic findings in correlation with clinical phenotype and genotype.We developed a composite nasal potential difference (NPD) diagnostic score to discriminate patients with CF from non-CF patients. We tested NPD in 50 children (age, 6 mo to 18 yr) with equivocal diagnoses and correlated the NPD diagnostic score with clinical phenotypes and genotypes.Fifteen of the 50 children had NPD scores in the CF range. Eight of the 15 carried two CFTR mutations compared with only 5 of the 35 children with normal NPD scores (P = 0.01). They were significantly younger at evaluation and had recurrent lower respiratory tract infections, chronic productive coughs, and chronic Staphylococcus aureus colonization significantly more often than the 35 children with normal NPD results.Evaluation of CFTR function in the nasal epithelium of children with inconclusive CF diagnoses can be a useful diagnostic tool and help clinicians to individualize therapeutic strategy.

Published
2010

2. Influence of the Duplication of CFTR Exon 9 and Its Flanking Sequences on Diagnosis of Cystic Fibrosis Mutations

Author

Véronique Ladeveze, Marie-Claude Pasquet, M.-P. Reboul, Ayman El-Seedy, Frédéric Bilan, Alain Kitzis, Tony Dudognon, and Albert Iron

Subjects
Genetics, congenital, hereditary, and neonatal diseases and abnormalities, Cystic Fibrosis, biology, Nucleic acid sequence, Cystic Fibrosis Transmembrane Conductance Regulator, Sequence alignment, Exons, Polymerase Chain Reaction, Molecular biology, DNA sequencing, Cystic fibrosis transmembrane conductance regulator, Pathology and Forensic Medicine, Exon, Consultations in Molecular Diagnostics, Pregnancy, Mutation, Gene duplication, biology.protein, Humans, Molecular Medicine, Female, Human genome, Gene
Abstract

The DNA sequences of seven regions in the human genome were examined for sequence identity with exon 9 of the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which is mutated in cystic fibrosis, and its intronic boundaries. These sequences were 95% to 96% homologous. Based on this nucleotide sequence similarity, PCR primers for CFTR exon 9 can potentially anneal with other homologous sequences in the human genome. Sequence alignment analysis of the CFTR exon 9 homologous sequences revealed that five registered mutations in the Cystic Fibrosis Mutation Database may be due to the undesired annealing of primers to a homologous sequence, resulting in inappropriate PCR amplification. For this reason, we propose that certain pseudomutations may result from the similarity between CFTR exon 9 (and its flanking introns) and related sequences in the human genome. Here we show that two mutations previously described in the CFTR database (c.1392 + 6insC; c.1392 + 12G>A) were inappropriately attributed to two individuals who sought carrier testing. A more detailed study by either direct sequencing or subcloning and sequencing of PCR products using specially designed primers revealed that these apparent mutations were not, in fact, present in CFTR. In addition, we present new PCR conditions that permit specific amplification of CFTR exon 9 and its flanking regions.

Published
2009

3. Analysis of the effect of aluminum in drinking water and transferrin C2 allele on Alzheimer's disease

Author

Virginie Rondeau, Benoit Arveiler, François Duchêne, Jean-François Dartigues, Luc Letenneur, Daniel Commenges, Albert Iron, Rondeau, Virginie, Equipe de Biostatistique, Institut National de la Santé et de la Recherche Médicale (INSERM) - Université Bordeaux Segalen - Bordeaux 2 - IFR99 - ISPED, Laboratoire de Génétique Humaine, Développement et Cancer, Université Bordeaux Segalen - Bordeaux 2, Epidémiologie, santé publique et développement, and Université Bordeaux Segalen - Bordeaux 2 - Institut National de la Santé et de la Recherche Médicale (INSERM) - IFR99 - ISPED

Subjects
Male, Risk, Apolipoprotein E, Neurotoxins, Article, Apolipoproteins E, Cohort Studies, Gene Frequency, Alzheimer Disease, [SDV.SPEE] Life Sciences [q-bio]/Public Health and Epidemiology, Humans, Medicine, Genetic Predisposition to Disease, Allele, Allele frequency, Alleles, Aged, Retrospective Studies, Aged, 80 and over, chemistry.chemical_classification, Chi-Square Distribution, Polymorphism, Genetic, business.industry, Transferrin, Case-control study, Environmental Exposure, Environmental exposure, medicine.disease, Logistic Models, Neurology, chemistry, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Case-Control Studies, Immunology, Female, Neurology (clinical), Alzheimer's disease, business, Aluminum
Abstract

Although highly controversial, the hypothesis of a link between aluminum in drinking water and Alzheimer’s disease (AD) has been supported by several epidemiological studies. Transferrin (Tf) is a major transport protein for both iron and aluminum. Moreover, it has been demonstrated that defective binding of iron and aluminum to the transferrin variant C2 could be present in Alzheimer’s disease. Individuals carrying the Tf C2 allele might therefore be at greater risk of developing AD. We investigated whether the transferrin C2 allele (Tf C2) might be responsible for susceptibility to Alzheimer’s disease in a sample of 292 subjects (with 55 AD) aged 75 years and over from south west France, some exposed to high levels of aluminum in tap water (n=181 subjects) and others to low levels of aluminum (n=111 subjects). We also examined the combined genetic effects of Tf C2 and ε4 allele of apolipoprotein E gene (ApoE). Logistic regression analysis showed that neither Tf C2 itself nor its interaction with aluminum or with the ε4 allele of the ApoE were significantly associated with the risk of AD.

Published
2006

4. Rapid and accurate detection of the CFTR gene mutation 1811+1.6kbA>G by real-time fluorescence resonance energy transfer PCR

Author

Albert Iron, Laurent Higueret, M.-P. Reboul, and Nicolas Biteau

Subjects
Genetics, Cystic Fibrosis, Genotype, DNA Mutational Analysis, Cystic Fibrosis Transmembrane Conductance Regulator, Single-nucleotide polymorphism, Cell Biology, Amplicon, Biology, Polymerase Chain Reaction, Molecular biology, Melting curve analysis, Förster resonance energy transfer, Mutation, Mutation (genetic algorithm), Fluorescence Resonance Energy Transfer, Humans, Restriction fragment length polymorphism, Molecular Biology, Genotyping, Polymorphism, Restriction Fragment Length, Fluorescent Dyes
Abstract

The CFTR gene mutation 1811+1.6 kbA>G has been reported as associated with a severe phenotype of cystic fibrosis with pancreatic insufficiency. This mutation has been identified as a rather common one in the South West of France and in the Iberian Peninsula. Because of the precise geographical origin of the subjects and its frequency, the mutation has to be investigated with accuracy. We have developed an original real-time Fluorescence Resonance Energy Transfer (FRET) PCR assay for genotyping the mutation 1811+1.6 kbA>G. It is based on the amplification of a region spanning the mutation with simultaneous detection of the amplicon by hybridization with a bi-probe followed by a melting curve analysis. The results obtained are identical with those resulting from either restriction fragment length polymorphism analysis or sequencing. The distinction between the wild type and the mutation 1811+1.6 kbA>G is easy because the corresponding melting points shows a difference of 6 or 9.5 degrees C depending on the associated SNP A/T located 16 bp downstream. We demonstrated that a FRET assay showed enough sensitivity to discriminate between two nucleotide polymorphisms (SNPs) in the sequence of the sensor. In conclusion, this method is specific, fast, easy to perform, reproducible, inexpensive as it uses only one bi-probe and well adapted to daily practice.

Published
2005

5. Génétique épidémiologique et moléculaire de l’obésité humaine

Author

Albert Iron

Subjects
obesity, genetic epidemiology, molecular genetics, susceptibility genes, lcsh:TP670-699, lcsh:Oils, fats, and waxes, Biochemistry, Food Science
Abstract

L’obésité est une pathologie majeure pour plusieurs raisons qu’il est difficile de hiérarchiser. D’abord parce qu’elle est commune, concernant aujourd’hui près d’un individu sur trois dans les pays industrialisés. Ensuite, parce qu’elle est grave en raison des complications nombreuses et sévères, parmi lesquelles on peut citer des cardiopathies, le diabète, l’HTA, des cancers, etc. Enfin, parce que répondant à la définition de maladie multifactorielle résultant de l’interaction entre des facteurs héréditaires et des facteurs environnementaux, sa connaissance a beaucoup progressé ces dernières années, notamment grâce à l’apport de la génétique moléculaire. À l’échelon individuel et d’une manière simple, on peut définir l’obésité comme résultant d’un excès de tissu adipeux qui va se traduire par un poids élevé par rapport à ce qu’on peut considérer comme étant un poids idéal donné par la formule de Lorentz : Poids idéal (kg) = Taille (cm) – 100 – [Taille (cm) – 150]/4 (homme) ou 2,5 (femme) Sous l’angle épidémiologique, c’est-à-dire à l’échelle des populations, l’obésité sera définie à partir de critères de nature anthropologique utilisés aussi en clinique pour typer le patient obèse. On peut prendre en compte le rapport du tour de hanche sur le tour de taille (qui permet de définir une obésité de type androïde ou gynoïde selon que ce rapport est supérieur ou inférieur à 0,85) ou la mesure de l’adiposité évaluée par l’appréciation des plis cutanés (en particulier le pli tricipital) ou surtout l’indice de corpulence qui est le critère majeur des épidémiologistes pour l’étude de l’obésité chez l’adulte. Cet indice est la référence pour la définition de l’obésité chez l’adulte ; il est aussi appelé indice de masse corporelle (IMC) ou indice de Quetelet ; il exprime le rapport du poids (en kg) au carré de la taille (en m). Il a été choisi par l’OMS en 1998 pour établir la classification de l’obésité adulte [1]. Entre 18,5 et 25, le poids du sujet est normal, souhaitable avec un risque standard. Au-delà de 25, on définit d’abord une zone de surpoids puis trois degrés de sévérité et de complications croissantes.

Published
2000

6. Spectrum of CFTR mutations in cystic fibrosis and in congenital absence of the vas deferens in France

Author

Francoise Chevalier, C. Verlingue, Isabelle Creveaux, Thierry Bienvenu, Jean-Claude Chomel, Eric Bieth, M.-C. Malinge, Michèle Chery, Perrine Malzac, Albert Iron, Mireille Claustres, C. Guittard, Emanuelle Girodon, Christine Clavel, Nicole Monnier, Claude Férec, Jean-Paul Bonnefont, Martine Blayau, Hervé Mittre, Cécile Cazeneuve, Delphine Feldmann, Viviane Dumur, Marie des Georges, Guy Lalau, and Dominique Bozon

Subjects
Adult, Male, medicine.medical_specialty, Cystic Fibrosis, Genotype, Mutation, Missense, Cystic Fibrosis Transmembrane Conductance Regulator, Biology, medicine.disease_cause, Gastroenterology, Cystic fibrosis, Vas Deferens, Gene Frequency, Internal medicine, Genetics, medicine, Humans, Allele, Frameshift Mutation, Gene, Alleles, Infertility, Male, Genetics (clinical), Mutation, Polymorphism, Genetic, Vas deferens, Middle Aged, medicine.disease, Congenital absence of the vas deferens, Mutagenesis, Insertional, medicine.anatomical_structure, Mutation testing, France, Chromosome Deletion
Abstract

We have collated the results of cystic fibrosis (CF) mutation analysis conducted in 19 laboratories in France. We have analyzed 7, 420 CF alleles, demonstrating a total of 310 different mutations including 24 not reported previously, accounting for 93.56% of CF genes. The most common were F508del (67.18%; range 61-80), G542X (2.86%; range 1-6.7%), N1303K (2.10%; range 0.75-4.6%), and 1717-1G>A (1.31%; range 0-2.8%). Only 11 mutations had relative frequencies >0. 4%, 140 mutations were found on a small number of CF alleles (from 29 to two), and 154 were unique. These data show a clear geographical and/or ethnic variation in the distribution of the most common CF mutations. This spectrum of CF mutations, the largest ever reported in one country, has generated 481 different genotypes. We also investigated a cohort of 800 French men with congenital bilateral absence of the vas deferens (CBAVD) and identified a total of 137 different CFTR mutations. Screening for the most common CF defects in addition to assessment for IVS8-5T allowed us to detect two mutations in 47.63% and one in 24.63% of CBAVD patients. In a subset of 327 CBAVD men who were more extensively investigated through the scanning of coding/flanking sequences, 516 of 654 (78. 90%) alleles were identified, with 15.90% and 70.95% of patients carrying one or two mutations, respectively, and only 13.15% without any detectable CFTR abnormality. The distribution of genotypes, classified according to the expected effect of their mutations on CFTR protein, clearly differed between both populations. CF patients had two severe mutations (87.77%) or one severe and one mild/variable mutation (11.33%), whereas CBAVD men had either a severe and a mild/variable (87.89%) or two mild/variable (11.57%) mutations.

Published
2000

7. CFTR p.Arg117His associated with CBAVD and other CFTR-related disorders

Author

Christel, Thauvin-Robinet, Anne, Munck, Frédéric, Huet, Alix, de Becdelièvre, Clément, Jimenez, Guy, Lalau, Elodie, Gautier, Jacques, Rollet, Jean, Flori, Raphaëlle, Nové-Josserand, Jean-Claude, Soufir, Alain, Haloun, Dominique, Hubert, Elise, Houssin, Gil, Bellis, Gilles, Rault, Albert, David, Laurent, Janny, Raphaël, Chiron, Nathalie, Rives, Dominique, Hairion, Patrick, Collignon, Antoine, Valeri, Gilles, Karsenty, Annick, Rossi, Marie-Pierre, Audrézet, Claude, Férec, Julie, Leclerc, Marie des, Georges, Mireille, Claustres, Thierry, Bienvenu, Bénédicte, Gérard, Pierre, Boisseau, Faïza, Cabet-Bey, David, Cheillan, Delphine, Feldmann, Christine, Clavel, Eric, Bieth, Albert, Iron, Brigitte, Simon-Bouy, Vincent, Izard, Julie, Steffann, Stéphane, Viville, Catherine, Costa, Véronique, Drouineaud, Patricia, Fauque, Christine, Binquet, Claire, Bonithon-Kopp, Mike A, Morris, Laurence, Faivre, Michel, Goossens, Michel, Roussey, Emmanuelle, Girodon, L, Weiss, Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Service de pédiatrie (CHU de Dijon), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institut des Maladies Neurodégénératives [Bordeaux] (IMN), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Centre de Biologie Pathologie, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre d'Investigation Clinique 1432 (Dijon) - Epidemiologie Clinique/Essais Cliniques (CIC-EC), Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre hospitalier universitaire de Nantes (CHU Nantes), CIC Cochin Pasteur (CIC 1417), Institut National de la Santé et de la Recherche Médicale (INSERM)-Groupe hospitalier Broca-Université Paris Descartes - Paris 5 (UPD5)-Hôtel-Dieu-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut national d'études démographiques (INED), Centre de Ressources et de Compétences de la Mucoviscidose (CRCM), Centre de Perharidy-Cellule de Coordination du Réseau Mucoviscidose (CECOREM), MLab, Dauphine Recherches en Management (DRM), Université Paris Dauphine-PSL, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Dauphine-PSL, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), Génétique, Reproduction et Développement (GReD), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Gamétogenèse et Qualité du Gamète - ULR 4308 (GQG), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Université de Lille, Département de génétique médicale [Hôpital de la Timone - APHM], Institut National de la Santé et de la Recherche Médicale (INSERM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU), CHRU de Brest, service de chirurgie urologique et de la transplantation reinale (CHU - BREST - Urologie), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Chirurgie urologique et transplantation rénale [Hôpital de la Conception - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille, Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques (LGMR), Université Montpellier 1 (UM1)-IFR3, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Biochimie et biologie moléculaire, Hôpital Cochin [AP-HP], Service d'hématologie et immunologie, Université Paris Diderot - Paris 7 (UPD7)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Service de génétique médicale [CHU Nantes], Service d'Endocrinologie Moléculaire et Maladies rares, Hospices Civils de Lyon (HCL), Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Biochimie et de Biologie Moléculaire [CHU Trousseau], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Plasticité de l'épithélium respiratoire dans les conditions normales et pathologiques - UMR-S 903 (PERPMP), SFR CAP Santé (Champagne-Ardenne Picardie Santé), Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Centre Hospitalier Universitaire de Reims (CHU Reims)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Reims Champagne-Ardenne (URCA), CHU Toulouse [Toulouse], Laboratoire de Génétique Humaine, Développement et Cancer, Université Bordeaux Segalen - Bordeaux 2, Centre Hospitalier de Versailles André Mignot (CHV), Université Paris Descartes - Paris 5 (UPD5), Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Laboratoire de Biologie de la reproduction CECOS - [CHU de Dijon], Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Génétique des Anomalies du Développement (GAD), Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC, Service de Pédiatrie, Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Institut Mondor de recherche biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôtel-Dieu-Université Paris Descartes - Paris 5 (UPD5)-Groupe hospitalier Broca-Institut National de la Santé et de la Recherche Médicale (INSERM), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), EFS-Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Université de Reims Champagne-Ardenne (URCA)-Centre Hospitalier Universitaire de Reims (CHU Reims)-Institut National de la Santé et de la Recherche Médicale (INSERM)-SFR CAP Santé (Champagne-Ardenne Picardie Santé), Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université de Reims Champagne-Ardenne (URCA)-Université de Reims Champagne-Ardenne (URCA), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Cochin [AP-HP]-Hôtel-Dieu-Université Paris Descartes - Paris 5 (UPD5)-Groupe hospitalier Broca-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Université Paris Dauphine-PSL-Centre National de la Recherche Scientifique (CNRS)-Université Paris Dauphine-PSL, Génétique, Reproduction et Développement - Clermont Auvergne (GReD), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA)-Centre National de la Recherche Scientifique (CNRS), Gamétogenèse et Qualité du Gamète (GQG), Normandie Université (NU)-Normandie Université (NU)-Université de Lille, Droit et Santé-Université de Lille, Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Hôpital de la Conception [CHU - APHM] (LA CONCEPTION ), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer (JPArc - U1172 Inserm), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université Lille 2 - Faculté de Médecine, CHU Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris]-Université Paris Diderot - Paris 7 (UPD7), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), Service de biochimie [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Trousseau [APHP], and Centre Hospitalier de Versailles (CHV)

Subjects
Infertility, Male, medicine.medical_specialty, Heterozygote, Cystic Fibrosis, Offspring, [SDV]Life Sciences [q-bio], Cystic Fibrosis Transmembrane Conductance Regulator, Gene mutation, Compound heterozygosity, Asymptomatic, Cystic fibrosis, 03 medical and health sciences, 0302 clinical medicine, Vas Deferens, Male Urogenital Diseases, Mutation Rate, Internal medicine, Prenatal Diagnosis, Genotype, Genetics, medicine, Humans, Family history, Child, Sweat, Genetics (clinical), Infertility, Male, 030304 developmental biology, 0303 health sciences, business.industry, Infant, Newborn, Infant, medicine.disease, 3. Good health, Phenotype, 030228 respiratory system, Child, Preschool, Immunology, Mutation, Female, medicine.symptom, business
Abstract

International audience; BACKGROUND:The high frequency of the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) gene mutation p.Arg117His in patients with congenital bilateral absence of the vas deferens (CBAVD) and in newborns screened for CF has created a dilemma.METHODS:Phenotypic and genotypic data were retrospectively collected in 179 non-newborn French individuals carrying p.Arg117His and a second CFTR mutation referred for symptoms or family history, by all French molecular genetics laboratories, referring physicians, CF care centres and infertility clinics.RESULTS:97% of the patients had the intronic T7 normal variant in cis with p.Arg117His. 89% patients were male, with CBAVD being the reason for referral in 76%. In 166/179 patients with available detailed clinical features, final diagnoses were: four late-onset marked pulmonary disease, 83 isolated CBAVD, 67 other CFTR-related phenotypes, including 44 CBAVD with pulmonary and/or pancreatic symptoms and 12 asymptomatic cases. Respiratory symptoms were observed in 30% of the patients, but the overall phenotype was mild. No correlation was observed between sweat chloride concentrations and disease severity. Five couples at risk of CF offspring were identified and four benefited from prenatal or preimplantation genetic diagnoses (PND or PGD). Eight children were born, including four who were compound heterozygous for p.Arg117His and one with a severe CF mutation.CONCLUSIONS:Patients with CBAVD carrying p.Arg117His and a severe CF mutation should benefit from a clinical evaluation and follow-up. Depending on the CBAVD patients' genotype, a CFTR analysis should be considered in their partners in order to identify CF carrier couples and offer PND or PGD

Published
2013

8. p.Ser1235Arg should no longer be considered as a Cystic Fibrosis mutation: results from a large collaborative study: p.Ser1235Arg is not associated with CF disease

Author

Emmanuelle Girodon, Julie Leclerc, Faïza Cabet-Bey, Thierry Bienvenu, Albert Iron, Marie des Georges, Martine Blayau, Guy Lalau, Hervé Mittre, Delphine Feldmann, Mireille Claustres, Catherine Costa, Céline René, Damien Paulet, C. Guittard, Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques (LGMR), Université Montpellier 1 (UM1)-IFR3, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), INSERM U955, équipe 11, Service de Biochimie [Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Centre de Biologie Pathologie, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service d'Endocrinologie Moléculaire et Maladies rares, Hospices Civils de Lyon (HCL), Service de biochimie et de génétique moléculaire [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de génétique clinique [Rennes], Université de Rennes (UR)-CHU Pontchaillou [Rennes]-hôpital Sud, Service de génétique médicale, Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Service de biochimie [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes]-hôpital Sud, Service de Biochimie et de Biologie Moléculaire [CHU Trousseau], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)

Subjects
Male, Models, Molecular, medicine.medical_specialty, Heterozygote, diagnosis, Genetic counseling, Population, Molecular Sequence Data, Mutation, Missense, Cystic Fibrosis Transmembrane Conductance Regulator, Prenatal diagnosis, Biology, Compound heterozygosity, Arginine, Cystic fibrosis, Gastroenterology, Article, cystic fibrosis, 03 medical and health sciences, Vas Deferens, Male Urogenital Diseases, Pregnancy, Internal medicine, Prenatal Diagnosis, Genetics, medicine, Serine, Missense mutation, Humans, Amino Acid Sequence, education, Genetics (clinical), 030304 developmental biology, 0303 health sciences, education.field_of_study, Molecular Epidemiology, genetic counseling, 030305 genetics & heredity, medicine.disease, Cystic fibrosis transmembrane conductance regulator, 3. Good health, Urogenital Abnormalities, Mutation (genetic algorithm), biology.protein, Female, mutation
Abstract

International audience; Among the 1700 mutations reported in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, a missense mutation, p.Ser1235Arg, initially reported in a CF patient with a second mutation (p.Gly628Arg) on the same allele, is a relatively frequent finding. To clarify its clinical significance, we collected data from 104 subjects heterozygous for the mutation p.Ser1235Arg from the French CF network, addressed for various indications including classical CF, atypical phenotypes or carrier screening in subjects with or without a family history. Among them, twenty-six patients (five having CF, ten CBAVD -Congenital Absence of the Vas Deferens- and eleven with CF-like symptoms) and fourteen healthy subjects were compound heterozygous for a second CFTR mutation. An exhaustive CFTR gene analysis identified a second mutation in cis of p.Ser1235Arg in all CF patients and in 81.8% CBAVD patients. Moreover, epidemiological data from more than 2100 individuals found a higher frequency of p.Ser1235Arg in the general population than in CF or CBAVD patients. These data, added to the fact that in silico analysis and functional assays suggest a benign nature of this substitution gives several lines of evidence against an association of p.Ser1235Arg with CF or CBAVD.

Published
2010

9. Measurement of nasal potential difference in young children with an equivocal sweat test following newborn screening for cystic fibrosis

Author

Emmanuelle Girodon, E. Deneuville, Anne Munck, Michel Renouil, Marcel Guillot, Frédéric Huet, Isabelle Fajac, Marie des Georges, Albert Iron, Christel Thauvin-Robinet, Michel Roussey, Isabelle Sermet-Gaudelus, Delphine Roussel, Rola Abou-Taam, Stéphanie Bui, Gérard Lenoir, Aleksander Edelman, Cystic Fibrosis Center - hôpital Necker, Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Expression des gènes des phosphorylations oxydatives mitochondriales. Maintenance de l'ADN MT, Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pontchaillou [Rennes], Institut de biologie et chimie des protéines [Lyon] (IBCP), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Hôpital Robert Debré, CRCM, Université Paris7, Assistance Publique - Hôpitaux de Paris, Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques (LGMR), Université Montpellier 1 (UM1)-IFR3, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre de biophysique moléculaire (CBM), Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Franche-Comté Électronique Mécanique, Thermique et Optique - Sciences et Technologies (UMR 6174) (FEMTO-ST), Université de Technologie de Belfort-Montbeliard (UTBM)-Ecole Nationale Supérieure de Mécanique et des Microtechniques (ENSMM)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Centre National de la Recherche Scientifique (CNRS), Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Université de Franche-Comté (UFC)-Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Supérieure de Mécanique et des Microtechniques (ENSMM)-Université de Technologie de Belfort-Montbeliard (UTBM)

Subjects
Pulmonary and Respiratory Medicine, medicine.medical_specialty, Pediatrics, Composite score, Cystic Fibrosis, [SDV]Life Sciences [q-bio], Cystic Fibrosis Transmembrane Conductance Regulator, Cystic fibrosis, Gastroenterology, Membrane Potentials, 03 medical and health sciences, 0302 clinical medicine, Neonatal Screening, Chlorides, 030225 pediatrics, Internal medicine, Genotype, medicine, Humans, Trypsin, Genetic Testing, Sweat, Sweat test, Genetic testing, Newborn screening, medicine.diagnostic_test, business.industry, Infant, Newborn, Infant, medicine.disease, Prognosis, 3. Good health, Nasal Mucosa, 030228 respiratory system, Potential difference, Lung disease, Child, Preschool, business, Follow-Up Studies
Abstract

International audience; BACKGROUND:A challenging problem arising from cystic fibrosis (CF) newborn screening is the significant number of infants with hypertrypsinaemia (HIRT) with sweat chloride levels in the intermediate range and only one or no identified CF-causing mutations.OBJECTIVES:To investigate the diagnostic value for CF of assessing CF transmembrane conductance regulator (CFTR) protein function by measuring nasal potential difference in children with HIRT.METHODS:A specially designed protocol was used to assess nasal potential difference (NPD) in 23 young children with HIRT (3 months-4 years) with inconclusive neonatal screening. Results were analysed with a composite score including CFTR-dependent sodium and chloride secretion. Results were correlated with genotype after extensive genetic screening and with clinical phenotype at follow-up 3 years later.RESULTS:NPD was interpretable for 21 children with HIRT: 13 had NPD composite scores in the CF range. All 13 were finally found to carry two CFTR mutations. At follow-up, nine had developed a chronic pulmonary disease consistent with a CF diagnosis. The sweat test could be repeated in nine children, and six had sweat chloride values >or=60 mmol/l. Of the eight children with normal NPD scores, only two had two CFTR mutations, both wide-spectrum mutations. None had developed a CF-like lung disease at follow-up. The sweat test could be reassessed in five of these eight children and all had sweat chloride values

Published
2010

10. Renal impairment in children with cystic fibrosis

Author

Jérôme Harambat, Annick Andrieux, Stéphanie Bui, Albert Iron, Michael Fayon, Fabienne Nacka, and Brigitte Llanas

Subjects
Pulmonary and Respiratory Medicine, Male, medicine.medical_specialty, Adolescent, Cystic Fibrosis, Renal function, urologic and male genital diseases, Gastroenterology, Cystic fibrosis, Liver disease, Urolithiasis, Antibiotics, Internal medicine, medicine, Odds Ratio, Prevalence, Albuminuria, Humans, Hypercalciuria, Pediatrics, Perinatology, and Child Health, Longitudinal Studies, Renal Insufficiency, Nephrotoxicity, Child, Retrospective Studies, Hyperoxaluria, business.industry, Infant, Newborn, Infant, Odds ratio, Kidney disease, medicine.disease, female genital diseases and pregnancy complications, Endocrinology, Child, Preschool, Pediatrics, Perinatology and Child Health, Microalbuminuria, Female, France, medicine.symptom, business, Glomerular Filtration Rate
Abstract

Background Due to the improvement in life expectancy in cystic fibrosis (CF), co-morbidities such as renal function impairment may be more frequent. Aim To determine the prevalence of renal disease in children with CF and to identify associated risk factors. Methods A single-center retrospective study analyzing the genetic, clinical and therapeutic characteristics of 112 children. The estimated glomerular filtration rate (GFR), microalbuminuria and lithiasic risk factors were assessed. Results The median calculated GFR (Schwartz) was 123, 161 and 155ml/min/1.73m 2 in children aged 1, 6 and 15years, respectively. The cumulative dose of aminoglycosides was not correlated to GFR. Microalbuminuria was present in 22/38 patients. Hyperoxaluria was observed in 58/83 patients and was associated with a severe genotype, pancreas insufficiency and liver disease. Hypercalciuria, hyperuricuria and hypocitraturia were identified in 16/87, 15/83 and 57/76 patients, respectively. Conclusion Renal impairment in CF has various presentations. There appears to be low levels of renal impairment in children with CF. However, the risk of oxalocalcic urolithiasis is enhanced, and GFR may be underestimated by the Schwartz formula. Further studies using measured GFR techniques are thus warranted.

Published
2009

11. CFTR Mutations in Turkish and North African Cystic Fibrosis Patients in Europe: Implications for Screening

Author

Anne Munck, Martina C. Cornel, Albert Iron, Hartmut Grasemann, Harry G.M. Heijerman, Leo P. ten Kate, Antje Schuster, Phillis Lakeman, Johan J.P. Gille, J.E. Dankert-Roelse, Human genetics, and EMGO - Quality of care

Subjects
Adult, Male, Parents, congenital, hereditary, and neonatal diseases and abnormalities, medicine.medical_specialty, Pediatrics, Adolescent, Cystic Fibrosis, Turkey, Turkish, DNA Mutational Analysis, Genetic Carrier Screening, Cystic Fibrosis Transmembrane Conductance Regulator, Test sensitivity, Consanguinity, Sensitivity and Specificity, Cystic fibrosis, Neonatal Screening, Africa, Northern, Gene Frequency, Surveys and Questionnaires, Internal medicine, medicine, Humans, Genetic Testing, Allele, Child, Allele frequency, Alleles, Genetics (clinical), business.industry, Homozygote, Infant, Newborn, Emigration and Immigration, medicine.disease, language.human_language, Europe, Mutation, language, Female, North african, business
Abstract

To obtain more insight into the variability of the CFTR mutations found in immigrant cystic fibrosis (CF) patients who are living in Europe now, and to estimate the test sensitivity of different frequently used methods of DNA analysis to detect CF carriers or patients among these Turkish or North African immigrants.A survey among 373 European CF centers asking which CFTR mutations had been found in Turkish and North African CF patients.31 and 26 different mutations were reported in Turkish and North African patients, identifying 64.2% (113/176) and 87.4% (118/135) alleles, respectively (p0.001). The mean sensitivity (detection rate) of three most common CFTR mutation panels to detect these mutations differed between Turkish and North African people, 44.9% (79/176) versus 69.6% (94/135) (p0.001), and can be increased to 57.4% (101/176) and 79.3% (107/135) (p0.001), respectively, by expanding these panels with 13 mutations which have been found on two or more alleles.35.8% and 12.6%, respectively, of CF alleles in Turkish and North African patients living in Europe now had not been identified. Among these populations, the test sensitivity of common CFTR mutation panels is insufficient for use in screening programs in Europe, even after expansion with frequent Turkish and North African mutations. This raises questions about whether and how to implement CF carrier and neonatal screening in a multiethnic society.

Published
2008

12. Isolated idiopathic chronic pancreatitis associated with a compound heterozygosity for two mutations of the CFTR gene

Author

Marie-Pierre, Reboul, David, Laharie, Michel, Amouretti, Didier, Lacombe, and Albert, Iron

Subjects
Adult, Male, Heterozygote, Pancreatitis, Chronic Disease, Mutation, Cystic Fibrosis Transmembrane Conductance Regulator, Humans, Pedigree
Abstract

We report the case of a patient suffering from idiopathic chronic pancreatitis (ICP) and compound heterozygous for mutations G542X and S1235R of the cystic fibrosis transmembrane regulator (CFTR) gene. The patient had normal sweat test and no other clinical sign usually linked with a typical or moderate pathology (bronchiectasis, nasal polyposis, congenital absence of the vas deferens) of the CFTR gene. G542X is a severe mutation, which is usually found in classical cystic fibrosis when associated with other severe mutations. S1235R is a quite rare abnormality recently reported as being potentially pathogenic when combined in trans with a second CF mutation. Our case is quite similar to the only other six patients in the literature in whom only the pancreas is affected and who bear a rare mutation with moderate effect. The history and the clinical features of our patient indicate an unambiguous isolated ICP in which the presence of the S1235R mutation--in trans with regard to G542X--is likely responsible for the ICP phenotype. This case could throw light on some of the as yet poorly known abnormalities of the CFTR gene in the ICP phenotype.

Published
2003

14. Relationships between cholesterol, apolipoprotein E polymorphism and dementia: A cross-sectional analysis from the PAQUID study

Author

Luc Letenneur, Albert Iron, Mojgan Bonarek, B. Dubroca, Pascale Barberger-Gateau, Jean-François Dartigues, and Valérie Deschamps

Subjects
Male, Apolipoprotein E, medicine.medical_specialty, Epidemiology, Cross-sectional study, chemistry.chemical_compound, Apolipoproteins E, Internal medicine, Genotype, medicine, Humans, Dementia, Prospective Studies, Apolipoprotein e polymorphism, Alleles, Aged, Aged, 80 and over, business.industry, Cholesterol, Cholesterol, HDL, Case-control study, Serum cholesterol level, medicine.disease, Cross-Sectional Studies, Endocrinology, chemistry, Case-Control Studies, Female, lipids (amino acids, peptides, and proteins), Neurology (clinical), business
Abstract

This study assesses the cross-sectional relationship between serum cholesterol level and dementia, controlling for apolipoprotein E (apoE) genotype, in a nested case-control study of 334 elderly French subjects aged 73 and over who participated in the PAQUID study (37 demented subjects and 297 nondemented controls). A diagnosis of dementia was established by two-step screening: (1) psychometric testing and DSM-III-R criteria and (2) neurologist’s confirmation. Cholesterol, its fractions and apoE genotype were determined from a blood sample. Elevated high-density lipoprotein cholesterol was associated with a significantly decreased risk of dementia, independent of apoE status and other potential confounding variables, suggesting that cholesterol fractions could be involved in both Alzheimer’s disease and vascular dementia.

15. Neonatal CF screening (2003–2008) in the Aquitaine region in France: high probability of a second CFTR gene mutation in heterozygotes with subnormal sweat tests

Author

Stéphanie Bui, M.-P. Reboul, Albert Iron, P. Fergelot, Didier Lacombe, and Michael Fayon

Subjects
High probability, SWEAT, Genetics, Pulmonary and Respiratory Medicine, Pediatrics, Perinatology and Child Health, Mutation (genetic algorithm), medicine, Heterozygote advantage, Pediatrics, Perinatology, and Child Health, Biology, medicine.disease, Cystic fibrosis, Cftr gene
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16. Comprehensive analysis of the French NBS cohort: Excellent mutation detection rate despite high allelic heterogeneity

Author

Eric Bieth, Thierry Bienvenu, Anne Munck, Michel Roussey, M. des Georges, M.-P. Audrézet, Guy Lalau, E. Girodon, Albert Iron, Alain Kitzis, E. Houssin, M.-C. Malinge, and David Cheillan

Subjects
Pulmonary and Respiratory Medicine, Genetics, business.industry, Pediatrics, Perinatology and Child Health, Cohort, Medicine, Allelic heterogeneity, Mutation detection, Pediatrics, Perinatology, and Child Health, business, medicine.disease, Cystic fibrosis
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17. Incidence of the CFTR exon 9 and its flanking sequence duplication on the mutation diagnosis in CF patients

Author

Ayman El-Seedy, Alain Kitzis, Albert Iron, T. Dudognon, Marie-Claude Pasquet, F. Bilan, and Véronique Ladeveze

Subjects
Pulmonary and Respiratory Medicine, Genetics, business.industry, Incidence (epidemiology), medicine.disease, Molecular biology, Cystic fibrosis, behavioral disciplines and activities, Exon, Pediatrics, Perinatology and Child Health, Gene duplication, Mutation (genetic algorithm), medicine, Pediatrics, Perinatology, and Child Health, business, health care economics and organizations, psychological phenomena and processes, Sequence (medicine)
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18. CFTR genotypes in patients with normal or borderline sweat chloride levels<FN ID="fn1">Communicated by Xavier Estivill</FN><FN ID="fn2">Online Citation: Human Mutation, Mutation in Brief #654 (2003) Online http://www.interscience.wiley.com/humanmutation/pdf/mutation/654.pdf</FN>

Author

Delphine Feldmann, Remy Couderc, Marie-Pierre Audrezet, Claude Ferec, Thierry Bienvenu, Marie Desgeorges, Mireille Claustres, Hervé Mittre, Martine Blayau, Dominique Bozon, Marie-Claire Malinge, Nicole Monnier, Jean-Paul Bonnefont, Albert Iron, Eric Bieth, Viviane Dumur, Christine Clavel, Cécile Cazeneuve, and Emmanuelle Girodon

Subjects
CYSTIC fibrosis, PANCREATIC diseases, CHROMOSOMES, GENETIC disorders, GENETIC mutation
Abstract

In recent years, some patients bearing “atypical” forms of cystic fibrosis (CF) with normal sweat chloride concentrations have been described. To identify the spectrum of mutant combinations causing such atypical CF, we collected the results of CFTR (ABCC7) mutation analysis from 15 laboratories. Thirty patients with one or more typical symptoms of the disease associated with normal or borderline sweat chloride levels and bearing two CFTR mutations were selected. Phenotypes and genotypes of these 30 patients are described. A total of 18 different CFTR mutations were observed in the 60 chromosomes analysed. F508del was present in 31.6 % of the mutated chromosomes and 3849+10kbC>T in 13.3 %. R117H, D1152H, L206W, 3272-26A>G, S1235R, G149R, R1070W, S945L, and the poly-T tract variation commonly called IVS8-5T were also observed. The relative frequency of CFTR mutations clearly differed from that observed in typical CF patients or in CBAVD patients with the same ethnic origin. A mild genotype with one or two mild or variable mutations was observed in all the patients. These findings improve our understanding of the distribution of CFTR alleles in CF with normal or borderline sweat chloride concentrations and will facilitate the development of more sensitive CFTR mutation screening. © 2003 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Published
2003
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