title: A classification model relative to splicing for variants of unknown clinical significance: application to the CFTR gene.
abstract: Molecular diagnosis of cystic fibrosis and cystic fibrosis transmembrane regulator (CFTR)-related disorders led to the worldwide identification of nearly 1,900 sequence variations in the CFTR gene that consist mainly of private point mutations and small insertions/deletions. Establishing their effect on the function of the encoded protein and therefore their involvement in the disease is still challenging and directly impacts genetic counseling. In this context, we built a decision tree following the international guidelines for the classification of variants of unknown clinical significance (VUCS) in the CFTR gene specifically focused on their consequences on splicing. We applied general and specific criteria, including comprehensive review of literature and databases, familial genetics data, and thorough in silico studies. This model was tested on 15 intronic and exonic VUCS identified in our cohort. Six variants were classified as probably nonpathogenic considering their impact on splicing and eight as probably pathogenic, which include two apparent missense mutations. We assessed the validity of our method by performing minigenes studies and confirmed that 93% (14/15) were correctly classified. We provide in this study a high-performance method that can play a full role in interpreting the results of molecular diagnosis in emergency context, when functional studies are not achievable.
authors: CHU Montpellier, Hôpital Arnaud de Villeneuve, Laboratoire de Génétique Moléculaire, Montpellier, France. caroline.raynal@inserm.fr
authors: Caroline
authors: C
authors: Raynal
authors: David
authors: D
authors: Baux
authors: Corinne
authors: C
authors: Theze
authors: Corinne
authors: C
authors: Bareil
authors: Magali
authors: M
authors: Taulan
authors: Anne-Françoise
authors: AF
authors: Roux
authors: Mireille
authors: M
authors: Claustres
authors: Sylvie
authors: S
authors: Tuffery-Giraud
authors: Marie
authors: M
authors: des Georges
mesh_terms: D002460:Cell Line; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics*; D006801:Humans; D008957:Models, Genetic; D012326:RNA Splicing
chemical_list: C505032:CFTR protein, human; D019005:Cystic Fibrosis Transmembrane Conductance Regulator