A Bergougnoux1, K Délétang2, A Pommier2, J Varilh2, F Houriez3, J P Altieri4, M Koenig5, C Férec6, M Claustres2, G Lalau7, T Bienvenu3, M P Audrézet8, A Pagin7, E Girodon3, C Raynal4, M Taulan-Cadars2. 1. CHU de Montpellier, Laboratoire de Génétique Moléculaire, Montpellier, France; Université de Montpellier, Laboratoire de Génétique de Maladies Rares, EA7402 Montpellier, France. Electronic address: anne.bergougnoux@inserm.fr. 2. Université de Montpellier, Laboratoire de Génétique de Maladies Rares, EA7402 Montpellier, France. 3. AP-HP, HUPC, Hôpital Cochin, Laboratoire de Génétique et Biologie Moléculaires, Paris, France. 4. CHU de Montpellier, Laboratoire de Génétique Moléculaire, Montpellier, France. 5. CHU de Montpellier, Laboratoire de Génétique Moléculaire, Montpellier, France; Université de Montpellier, Laboratoire de Génétique de Maladies Rares, EA7402 Montpellier, France. 6. Inserm, UMR1078 Génétique, Génomique Fonctionnelle et Biotechnologies, France; Univ Brest, EFS, IBSAM, Brest, France; CHU de Brest, Laboratoire de Génétique Moléculaire, Brest, France. 7. Service de Toxicologie et Génopathies, Institut de Biochimie et Biologie Moléculaire, Centre Hospitalier Régional Universitaire, Lille, France. 8. CHU de Brest, Laboratoire de Génétique Moléculaire, Brest, France.
Abstract
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.
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.
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