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1. Functional characterization and phenotypic spectrum of three recurrent disease-causing deep intronic variants of the CFTR gene

Author

Anne Bergougnoux, J.-P. Altieri, C. Raynal, Thierry Bienvenu, Guy Lalau, Michel Koenig, Jessica Varilh, E. Girodon, Magali Taulan-Cadars, Mireille Claustres, M.-P. Audrézet, Alexandra Pommier, Karine Deletang, Florence Houriez, A. Pagin, Claude Férec, 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), CHU Cochin [AP-HP], 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 Hospitalier Régional Universitaire [Lille] (CHRU Lille), Laboratoire de Génétique Moléculaire et d'Histocompatibilité [Brest], Hôpital Morvan [Brest]-Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), 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), IFR3, Université Montpellier 1 (UM1)-Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), 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), and Centre Hospitalier Régional Universitaire de Brest (CHRU Brest)-Hôpital Morvan [Brest]

Subjects
Adult, Male, 0301 basic medicine, Pulmonary and Respiratory Medicine, congenital, hereditary, and neonatal diseases and abnormalities, Adolescent, Cystic Fibrosis, [SDV]Life Sciences [q-bio], Cystic Fibrosis Transmembrane Conductance Regulator, Locus (genetics), Deep intronic variants, Cystic fibrosis, DNA sequencing, Male infertility, CFTR gene, 03 medical and health sciences, 0302 clinical medicine, Recurrence, Genotype, medicine, Humans, Child, 10. No inequality, Pseudo-exon inclusion, Splicing alteration, Genetics, business.industry, Haplotype, Genetic Variation, Infant, respiratory system, medicine.disease, Phenotype, Introns, 3. Good health, 030104 developmental biology, 030228 respiratory system, Child, Preschool, Pediatrics, Perinatology and Child Health, RNA splicing, Female, Large phenotypic spectrum, business
Abstract

International audience; BACKGROUND:The CFTR genotype remains incomplete in 1% of Cystic Fibrosis (CF) cases, because only one or no disease-causing variants is detected after extended analysis. This fraction is probably higher in CFTR-Related Disorders (CFTR-RD). Deep-intronic CFTR variants are putative candidates to fill this gap. However, the recurrence, phenotypic spectrum and full molecular characterization of newly reported variants are unknown.METHODS:Minigenes and analysis of CFTR transcripts in nasal epithelial cells were used to determine the impact on CFTR splicing of intronic variants that we previously identified by next generation sequencing of the whole CFTR locus. Phenotypic data were collected in 19 patients with CF and CFTR-RD, in whom one of the deep intronic variants has been detected.RESULTS:Three deep-intronic variants promoted the inclusion of pseudo-exons (PE) in the CFTR transcript, hindering the synthesis of a functional protein. The c.2989-313A > T variant, detected in four patients with CF or CFTR-RD from three different families, led to the inclusion of a 118 bp PE. The c.3469-1304C > G variant promoted the inclusion of a 214 bp-PE and was identified in five patients with CF from four families. Haplotype analysis confirmed that this variant was associated with one CF chromosome of African origin. The most represented variant in our cohort was the c.3874-4522A > G, detected in 10 patients with various phenotypes, from male infertility to CF with pancreatic insufficiency.CONCLUSION:These three deep intronic CFTR variants are associated with a large phenotypic spectrum, including typical CF. They should be included in CF diagnostic testing and carrier screening strategies.

Published
2019
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2. Truncating Mutations in the Adhesion G Protein-Coupled Receptor G2 Gene ADGRG2 Cause an X-Linked Congenital Bilateral Absence of Vas Deferens

Author

Stanislas Faguer, Aurore Siegfried, Valérie Mitchell, Roger Mieusset, Guy Lalau, Laetitia Monteil, Jean-Marc Rigot, Olivier Patat, V. Gaston, François Marcelli, Nicolas Chassaing, Monique Courtade-Saïdi, A. Pagin, Eric Bieth, Louis Bujan, Unité différenciation épidermique et auto-immunité rhumatoïde (UDEAR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Toulouse [Toulouse], Toxicologie et Génopathies [CHRU Lille], Pôle de Biologie Pathologie Génétique [CHU Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Hôpital Jeanne de Flandres, Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Gamétogenèse et Qualité du Gamète - ULR 4308 (GQG), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Université de Lille, Département de Néphrologie et Transplantation d'organes, Hôpital de Rangueil, CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse], Groupe de recherche en fertilité humaine ( GRFH), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Hôpital Albert Calmette, Hôpital Paule de Viguier, Hôpital Purpan [Toulouse], Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de Néphrologie et Transplantation d'organes [CHU Toulouse], Pôle Urologie - Néphrologie - Dialyse - Transplantations - Brûlés - Chirurgie plastique - Explorations fonctionnelles et physiologiques [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), and Université de Toulouse (UT)-Université de Toulouse (UT)

Subjects
Male, 0301 basic medicine, DNA Mutational Analysis, MESH: Exome / genetics, Cystic Fibrosis Transmembrane Conductance Regulator, Obstructive azoospermia, Bioinformatics, Receptors, G-Protein-Coupled, Pathogenesis, Vas Deferens, 0302 clinical medicine, Male Urogenital Diseases, Genes, X-Linked, Genetics(clinical), Exome, MESH: DNA Mutational Analysis, Genetics (clinical), 030219 obstetrics & reproductive medicine, Vas deferens, MESH: Genes, X-Linked / genetics, Cystic fibrosis transmembrane conductance regulator, Pedigree, medicine.anatomical_structure, Female, Infertility, medicine.medical_specialty, MESH: Pedigree, Genetic counseling, Biology, 03 medical and health sciences, Report, Internal medicine, Genetics, medicine, Humans, MESH: Vas Deferens / abnormalities, MESH: Humans, MESH: Receptors, G-Protein-Coupled / genetics, MESH: Male Urogenital Diseases / genetics, [SDV.BDLR]Life Sciences [q-bio]/Reproductive Biology, MESH: Gene Deletion, medicine.disease, MESH: Cystic Fibrosis Transmembrane Conductance Regulator / genetics, MESH: Male, 030104 developmental biology, Endocrinology, biology.protein, MESH: Female, Gene Deletion
Abstract

International audience; In 80% of infertile men with obstructive azoospermia caused by a congenital bilateral absence of the vas deferens (CBAVD), mutations are identified in the cystic fibrosis transmembrane conductance regulator gene (CFTR). For the remaining 20%, the origin of the CBAVD is unknown. A large cohort of azoospermic men with CBAVD was retrospectively reassessed with more stringent selection criteria based on consistent clinical data, complete description of semen and reproductive excurrent ducts, extensive CFTR testing, and kidney ultrasound examination. To maximize the phenotypic prioritization, men with CBAVD and with unilateral renal agenesis were considered ineligible for the present study. We performed whole-exome sequencing on 12 CFTR-negative men with CBAVD and targeted sequencing on 14 additional individuals. We identified three protein-truncating hemizygous mutations, c.1545dupT (p.Glu516Ter), c.2845delT (p.Cys949AlafsTer81), and c.2002_2006delinsAGA (p.Leu668ArgfsTer21), in ADGRG2, encoding the epididymal- and efferent-ducts-specific adhesion G protein-coupled receptor G2, in four subjects, including two related individuals with X-linked transmission of their infertility. Previous studies have demonstrated that Adgrg2-knockout male mice develop obstructive infertility. Our study confirms the crucial role of ADGRG2 in human male fertility and brings new insight into congenital obstructive azoospermia pathogenesis. In men with CBAVD who are CFTR-negative, ADGRG2 testing could allow for appropriate genetic counseling with regard to the X-linked transmission of the molecular defect.

Published
2016
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3. CFTR -France, a national relational patient database for sharing genetic and phenotypic data associated with rare CFTR variants

Author

Ingrid Duguépéroux, Emmanuelle Girodon, C. Thèze, David Baux, Marie-Pierre Audrézet, M.-P. Reboul, V. Gaston, Eric Bieth, Thierry Bienvenu, Marie des Georges, Lydie Lemonnier, C. Bareil, Mireille Claustres, C. Raynal, Guy Lalau, Marie-Claire Malinge, Souphatta Sasorith, Vincent Thoreau, Chadia Mekki, Pascale Fanen, Anne Bergougnoux, Patricia Fergelot, Alain Kitzis, Claude Férec, A. Pagin, Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques (LGMR), IFR3, Université Montpellier 1 (UM1)-Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), 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), Biochimie et biologie moléculaire, Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), 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 Biologie Pathologie, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service Génétique Médicale [CHU Poitiers], Centre hospitalier universitaire de Poitiers (CHU Poitiers), Service de génétique médicale [Toulouse], CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Département de Biochimie et Génétique [Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Association Vaincre La Mucoviscidose, Laboratoire de Genetique, UPEC (Universite' Paris Est Creteil), Laboratoire de Genetique, 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)-IFR10, Université Montpellier 1 (UM1)-IFR3, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), 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), and Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)

Subjects
0301 basic medicine, congenital, hereditary, and neonatal diseases and abnormalities, Cystic Fibrosis, Genetic counseling, In silico, [SDV]Life Sciences [q-bio], Cystic Fibrosis Transmembrane Conductance Regulator, Genetic Counseling, Context (language use), Biology, Preimplantation genetic diagnosis, Compound heterozygosity, Bioinformatics, Cystic fibrosis, MESH: CFTR-RD, cystic fibrosis, cystic fibrosis transmembrane regulator, locus-specific mutation database, 03 medical and health sciences, Databases, Genetic, Genetics, medicine, Humans, Allele, Alleles, Genetics (clinical), Infant, Newborn, medicine.disease, Phenotype, 3. Good health, 030104 developmental biology, Mutation, France
Abstract

International audience; Most of the 2,000 variants identified in the CFTR (cystic fibrosis transmembrane regulator) gene are rare or private. Their interpretation is hampered by the lack of available data and resources, making patient care and genetic counseling challenging. We developed a patient-based database dedicated to the annotations of rare CFTR variants in the context of their cis- and trans-allelic combinations. Based on almost 30 years of experience of CFTR testing, CFTR-France (https://cftr.iurc.montp.inserm.fr/cftr) currently compiles 16,819 variant records from 4,615 individuals with cystic fibrosis (CF) or CFTR-RD (related disorders), fetuses with ultrasound bowel anomalies, newborns awaiting clinical diagnosis, and asymptomatic compound heterozygotes. For each of the 736 different variants reported in the database, patient characteristics and genetic information (other variations in cis or in trans) have been thoroughly checked by a dedicated curator. Combining updated clinical, epidemiological, in silico, or in vitro functional data helps to the interpretation of unclassified and the reassessment of misclassified variants. This comprehensive CFTR database is now an invaluable tool for diagnostic laboratories gathering information on rare variants, especially in the context of genetic counseling, prenatal and preimplantation genetic diagnosis. CFTR-France is thus highly complementary to the international database CFTR2 focused so far on the most common CF-causing alleles.

Published
2017
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4. Applicability and Efficiency of NGS in Routine Diagnosis: In-Depth Performance Analysis of a Complete Workflow for CFTR Mutation Analysis

Author

Martin Figeac, Maryse Truant, Franck Broly, Guy Lalau, Christelle Willoquaux, Aurore Devos, and A. Pagin

Subjects
0301 basic medicine, Cystic Fibrosis, Molecular biology, DNA Mutational Analysis, Gene Identification and Analysis, lcsh:Medicine, Cystic Fibrosis Transmembrane Conductance Regulator, Artificial Gene Amplification and Extension, Polymerase Chain Reaction, Workflow, Database and Informatics Methods, 0302 clinical medicine, Sequencing techniques, Coding region, DNA sequencing, lcsh:Science, Genetics, Multidisciplinary, biology, medicine.diagnostic_test, Genomics, Cystic fibrosis transmembrane conductance regulator, 030220 oncology & carcinogenesis, Transcriptome Analysis, Sequence Analysis, Research Article, Next-Generation Sequencing, Sequence analysis, Bioinformatics, 03 medical and health sciences, Multiplex polymerase chain reaction, medicine, Humans, Genetic Testing, Allele, Mutation Detection, Alleles, Genetic testing, Biology and life sciences, lcsh:R, Dideoxy DNA sequencing, Computational Biology, Sequence Analysis, DNA, Genome Analysis, Research and analysis methods, 030104 developmental biology, Molecular biology techniques, Genetic Loci, biology.protein, lcsh:Q, Sequence Alignment
Abstract

BACKGROUND:Actually, about 2000 sequence variations have been documented in the CFTR gene requiring extensive and multi-step genetic testing in the diagnosis of cystic fibrosis and CFTR-related disorders. We present a two phases study, with validation and performance monitoring, of a single experiment methodology based on multiplex PCR and high throughput sequencing that allows detection of all variants, including large rearrangements, affecting the coding regions plus three deep intronic loci. METHODS:A total of 340 samples, including 257 patients and 83 previously characterized control samples, were sequenced in 17 MiSeq runs and analyzed with two bioinformatic pipelines in routine diagnostic conditions. We obtained 100% coverage for all the target regions in every tested sample. RESULTS:We correctly identified all the 87 known variants in the control samples and successfully confirmed the 62 variants identified among the patients without observing false positive results. Large rearrangements were identified in 18/18 control samples. Only 17 patient samples showed false positive signals (6.6%), 12 of which showed a borderline result for a single amplicon. We also demonstrated the ability of the assay to detect allele specific dropout of amplicons when a sequence variation occurs at a primer binding site thus limiting the risk for false negative results. CONCLUSIONS:We described here the first NGS workflow for CFTR routine analysis that demonstrated equivalent diagnostic performances compared to Sanger sequencing and multiplex ligation-dependent probe amplification. This study illustrates the advantages of NGS in term of scalability, workload reduction and cost-effectiveness in combination with an improvement of the overall data quality due to the simultaneous detection of SNVs and large rearrangements.

Published
2015

5. WS15.2 Massive parallel sequencing of the CFTR gene: a collaborative validation in diagnostic practice highlights strengths and limitations

Author

M.-P. Audrézet, M.-P. Reboul, A. Pagin, Claude Férec, V. Gaston, Guy Lalau, C. Raynal, P. Maurin, E. Girodon, Anne Bergougnoux, O. Said, Eric Bieth, and Thierry Bienvenu

Subjects
Pulmonary and Respiratory Medicine, Genetics, Massive parallel sequencing, Pediatrics, Perinatology and Child Health, medicine, Biology, medicine.disease, Cystic fibrosis, Cftr gene
Published
2017
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6. WS15.1 CysMA, a new tool for the interpretation of rare CFTR missense variants

Author

Eric Bieth, Alain Kitzis, M.-C. Malinge, C. Thèze, M.-P. Reboul, E. Girodon, Mireille Claustres, C. Raynal, David Baux, C. Bareil, Pascale Fanen, Claude Férec, Anne Bergougnoux, V. Colomb-Jung, Patricia Fergelot, M.-P. Audrézet, Guy Lalau, S. Sasorith, Thierry Bienvenu, V. Gaston, Chadia Mekki, and A. Pagin

Subjects
Pulmonary and Respiratory Medicine, Genetics, business.industry, Pediatrics, Perinatology and Child Health, medicine, Missense mutation, medicine.disease, business, Cystic fibrosis, Interpretation (model theory)
Published
2017
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7. Axonemal Dynein Intermediate-Chain Gene (DNAI1) Mutations Result in Situs Inversus and Primary Ciliary Dyskinesia (Kartagener Syndrome)

Author

Jean-Jacques Lafitte, Philippe Godard, Guy Lalau, Marie-Cécile Harricane, Cécile Guichard, Vincent Tack, Marc Zaegel, and Patrice Bouvagnet

Subjects
Male, Heterozygote, congenital, hereditary, and neonatal diseases and abnormalities, Pathology, medicine.medical_specialty, DNA Mutational Analysis, Molecular Sequence Data, Biology, Compound heterozygosity, Nuclear Family, Situs, Report, otorhinolaryngologic diseases, Genetics, medicine, Humans, Genetics(clinical), Amino Acid Sequence, Cilia, Alleles, Genetics (clinical), Primary ciliary dyskinesia, Base Sequence, Kartagener Syndrome, Cilium, Dyneins, Axonemal Dyneins, Exons, Anatomy, medicine.disease, Introns, Pedigree, Alternative Splicing, Situs inversus, medicine.anatomical_structure, Sperm Tail, Mutation, Ciliary Motility Disorders, Female, Situs solitus
Abstract

Kartagener syndrome (KS) is a trilogy of symptoms (nasal polyps, bronchiectasis, and situs inversus totalis) that is associated with ultrastructural anomalies of cilia of epithelial cells covering the upper and lower respiratory tracts and spermatozoa flagellae. The axonemal dynein intermediate-chain gene 1 (DNAI1), which has been demonstrated to be responsible for a case of primary ciliary dyskinesia (PCD) without situs inversus, was screened for mutation in a series of 34 patients with KS. We identified compound heterozygous DNAI1 gene defects in three independent patients and in two of their siblings who presented with PCD and situs solitus (i.e., normal position of inner organs). Strikingly, these five patients share one mutant allele (splice defect), which is identical to one of the mutant DNAI1 alleles found in the patient with PCD, reported elsewhere. Finally, this study demonstrates a link between ciliary function and situs determination, since compound mutation heterozygosity in DNAI1 results in PCD with situs solitus or situs inversus (KS).

Published
2001
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8. 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
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9. 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
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10. CFTR mutation combinations producing frequent complex alleles with different clinical and functional outcomes

Author

Marie des Georges, Caroline Norez, Martine Blayau, Alain Kitzis, Eric Bieth, Alix de Becdelièvre, Frédéric Becq, Thierry Bienvenu, Julie Pajaud, Marie-Claude Pasquet, Emmanuelle Girodon, Guy Lalau, Pascale Fanen, Véronique Ladeveze, Ayman El-Seedy, Faïza Cabet, Institut de Physiologie et Biologie Cellulaires (IPBC), Université de Poitiers-Centre National de la Recherche Scientifique (CNRS), 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), 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)-IFR10, Biochimie et biologie moléculaire, Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), 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 Biologie Pathologie, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Toulouse [Toulouse], Service de génétique clinique [Rennes], Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes]-hôpital Sud, Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), and Université de Rennes (UR)-CHU Pontchaillou [Rennes]-hôpital Sud

Subjects
Heterozygote, Cystic Fibrosis, [SDV]Life Sciences [q-bio], Mutant, Mutation, Missense, Cystic Fibrosis Transmembrane Conductance Regulator, Biology, Gene mutation, medicine.disease_cause, Cystic fibrosis, 03 medical and health sciences, 0302 clinical medicine, Gene Frequency, Genetics, medicine, Missense mutation, Humans, Allele, Genetics (clinical), Alleles, Genetic Association Studies, 030304 developmental biology, 0303 health sciences, Mutation, Heterozygote advantage, medicine.disease, Phenotype, Recombinant Proteins, Protein Structure, Tertiary, Amino Acid Substitution, 030220 oncology & carcinogenesis, Mutant Proteins, France, HeLa Cells
Abstract

International audience; Genotype-phenotype correlations in cystic fibrosis (CF) may be difficult to establish because of phenotype variability, which is associated with certain CF transmembrane conductance regulator (CFTR) gene mutations and the existence of complex alleles. To elucidate the clinical significance of complex alleles involving p.Gly149Arg, p.Asp443Tyr, p.Gly576Ala, and p.Arg668Cys, we performed a collaborative genotype-phenotype correlation study, collected epidemiological data, and investigated structure-function relationships for single and natural complex mutants, p.[Gly576Ala;Arg668Cys], p.[Gly149Arg;Gly576Ala;Arg668Cys], and p.[Asp443Tyr;Gly576Ala;Arg668Cys]. Among 153 patients carrying at least one of these mutations, only three had classical CF and all carried p.Gly149Arg in the triple mutant. Sixty-four had isolated infertility and seven were healthy individuals with a severe mutation in trans, but none had p.Gly149Arg. Functional studies performed on all single and natural complex mutants showed that (1) p.Gly149Arg results in a severe misprocessing defect; (2) p.Asp443Tyr moderately alters CFTR maturation; and (3) p.Gly576Ala, a known splicing mutant, and p.Arg668Cys mildly alter CFTR chloride conductance. Overall, the results consistently show the contribution of p.Gly149Arg to the CF phenotype, and suggest that p.[Arg668Cys], p.[Gly576Ala;Arg668Cys], and p.[Asp443Tyr;Gly576Ala;Arg668Cys] are associated with CFTR-related disorders. The present study emphasizes the importance of comprehensive genotype-phenotype and functional studies in elucidating the impact of mutations on clinical phenotype.

Published
2012
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11. 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
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12. The very low penetrance of cystic fibrosis for the R117H mutation: a reappraisal for genetic counselling and newborn screening

Author

Brigitte Simon-Bouy, Georges, Bénédicte Gérard, Harriet Corvol, Emmanuelle Girodon, Raphaele Nove-Josserand, Catherine Costa, Michael A. Morris, Delphine Feldmann, Annick Clement, G. Bellis, Sylvie Leroy, Christine Binquet, J. Leclerc, A Iron, Laurence Faivre, M Roussey, Anne Munck, Mireille Claustres, F. Huet, Elodie Gautier, Claire Bonithon-Kopp, E. Houssin, Emmanuelle Génin, Isabelle Sermet-Gaudelus, S. Perez-Martin, Eric Bieth, Pierre Boisseau, Cabet-Bey F, Christine Clavel, J. Flori, Dominique Hubert, N. Wizla, Marie-Pierre Audrézet, Gabriel Bellon, A. Haloun, Guy Lalau, d'Acremont G, T Bienvenu, Christel Thauvin-Robinet, Gilles Rault, C. Alberti-Boulmé, Claude Férec, Michel Goossens, and R. Medina

Subjects
medicine.medical_specialty, Heterozygote, Cystic Fibrosis, Genetic counseling, Population, FRANCE, Cystic Fibrosis Transmembrane Conductance Regulator, Genetic Counseling, Penetrance, Kaplan-Meier Estimate, Compound heterozygosity, Cystic fibrosis, Gastroenterology, Neonatal Screening, Internal medicine, CYSTIC_FIBROSIS, Genotype, Genetics, Medicine, Humans, Allele, education, Genetics (clinical), Newborn screening, education.field_of_study, business.industry, Infant, Newborn, medicine.disease, SCREENING, Cross-Sectional Studies, Phenotype, Mutation, business
Abstract

Background: Cystic fibrosis (CF) is caused by compound heterozygosity or homozygosity of CF transmembrane conductance regulator gene (CFTR) mutations. Phenotypic variability associated with certain mutations makes genetic counselling difficult, notably for R117H, whose disease phenotype varies from asymptomatic to classical CF. The high frequency of R117H observed in CF newborn screening has also introduced diagnostic dilemmas. The aim of this study was to evaluate the disease penetrance for R117H in order to improve clinical practice. Methods: The phenotypes in all individuals identified in France as compound heterozygous for R117H and F508del, the most frequent CF mutation, were described. The allelic prevalences of R117H (p R117H), on either intron 8 T5 or T7 background, and F508del (p F508del) were determined in the French population, to permit an evaluation of the penetrance of CF for the [R117H]+[F508del] genotype. Results: Clinical details were documented for 184 [R117H]+[F508del] individuals, including 72 newborns. The disease phenotype was predominantly mild; one child had classical CF, and three adults' severe pulmonary symptoms. In 5245 healthy adults, p F508del was 1.06%, p R117H;T7 0.27% and p R117H;T5 ,0.01%. The theoretical number of [R117H;T7]+[F508del] individuals in the French population was estimated at 3650, whereas only 112 were known with CF related symptoms (3.1%). The penetrance of classical CF for [R117H;T7]+[F508del] was estimated at 0.03% and that of severe CF in adulthood at 0.06%. Conclusions: These results suggest that R117H should be withdrawn from CF mutation panels used for screening programmes. The real impact of so-called disease mutations should be assessed before including them in newborn or preconceptional carrier screening programmes .

Published
2009

13. A new largeCFTRrearrangement illustrates the importance of searching for complex alleles

Author

Isabelle Sermet, Emmanuelle Girodon, P. Ruszniewski, P. Levy, Thierry Bienvenu, Guy Lalau, D. Bondeux, Florence Niel, J.P. Martin, Michel Goossens, Marie Legendre, R. Boukari, J. Derelle, Catherine Costa, and Eric Bieth

Subjects
Adult, Male, Adolescent, Cystic Fibrosis, Genetic counseling, DNA Mutational Analysis, Mutation, Missense, Cystic Fibrosis Transmembrane Conductance Regulator, Biology, medicine.disease_cause, Genotype, Genetics, medicine, Humans, Missense mutation, Genetic Testing, Allele, Child, Alleles, Genetics (clinical), Sequence Deletion, Genetic testing, Chromosome Aberrations, Mutation, Polymorphism, Genetic, Base Sequence, medicine.diagnostic_test, Haplotype, Infant, Newborn, Infant, Gene rearrangement, Middle Aged, Haplotypes, Female
Abstract

The p.Val754Met variant, described in 1996 in a CF patient, has been considered a CF mutation. However, biochemical aspects, results of functional studies and, finally, the identification of a complex deletion removing exons 3 to 10 and 14b to 16 in cis of p.Val754Met in a CF patient, argue against a strong deleterious effect. An inventory through the French CF network of patients carrying p.Val754Met led to the registration of seven patients (CF: n=4; idiopathic chronic pancreatitis: n=3) and six healthy individuals, all heterozygous for the variation. Extensive CFTR gene analysis was carried out, including the search for large rearrangements and other possible mutations. The complex deletion, whose breakpoints are described here, was found only in the four CF patients, in association with the same haplotype. This data, added to the fact that the p.[Phe508del]+[Val754Met] genotype was found in a healthy individual, bring further arguments against the association of p.Val754Met with CF. We thus suggest looking for a possible complex allele whenever p.Val754Met is detected and considering it neutral regarding genetic counseling when found in isolation.

Published
2006
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15. 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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