title: In silico prediction of the deleterious effect of a mutation: proceed with caution in clinical genetics.
abstract: When a sequence variation is found in a candidate gene for a disease, it is important to establish whether this change is neutral or responsible for the observed disorders in a patient. To answer this question, in the absence of further experimental investigations, several simulation programs have been proposed to predict whether a nonsynonymous single-nucleotide polymorphism is likely to have or not have a deleterious effect on the phenotype. In this work, we tested two such programs, PolyPhen and SIFT, using two kinds of targets. The first ones concerned the products of the hemoglobin and glucose-6-phosphate dehydrogenase genes, which are abundantly documented. The second concerned two systems for which much less information is available: (a) the TNFRSF1A gene, implicated in tumor necrosis factor receptor-associated periodic syndrome, and (b) the MEFV gene, which is believed to be involved in familial Mediterranean fever. Our data suggest that, from a practical point of view, these programs should not be used to decide, in the absence of other tests or arguments, whether the sequence variation found in a patient is or is not responsible for the disease. The consequence of an erroneous prediction may be disastrous in the perspective of genetic counseling.
authors.affiliation: Service de Biochimie et de Génétique Moléculaire and INSERM U468, Hôpital Henri-Mondor, 94010 Créteil, France.
authors.forename: Dimitri
authors.initials: D
authors.lastname: Tchernitchko
authors.forename: Michel
authors.initials: M
authors.lastname: Goossens
authors.forename: Henri
authors.initials: H
authors.lastname: Wajcman
mesh_terms: D003598:Cytoskeletal Proteins; D010505:Familial Mediterranean Fever / Q000235:genetics; D005817:Genetic Counseling; D030342:Genetic Diseases, Inborn / Q000235:genetics*; D005954:Glucosephosphate Dehydrogenase / Q000235:genetics; D006454:Hemoglobins / Q000235:genetics; D006801:Humans; D015810:Linkage Disequilibrium; D008957:Models, Genetic; D009154:Mutation; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011237:Predictive Value of Tests; D011506:Proteins / Q000235:genetics; D000071198:Pyrin; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics; D012984:Software
chemical_list: D003598:Cytoskeletal Proteins; D006454:Hemoglobins; C000604192:MEFV protein, human; D011506:Proteins; D000071198:Pyrin; D047888:Receptors, Tumor Necrosis Factor, Type I; D005954:Glucosephosphate Dehydrogenase