title: Are all the previously reported genetic variants in limb girdle muscular dystrophy genes pathogenic?
abstract: Hundreds of variants in autosomal genes associated with the limb girdle muscular dystrophies (LGMDs) have been reported as being causative. However, in most cases the proof of pathogenicity derives from their non-occurrence in hundreds of healthy controls and/or from segregation studies in small families. The limited statistics of the genetic variations in the general population may hamper a correct interpretation of the effect of variants on the protein. To clarify the meaning of low-frequency variants in LGMD genes, we have selected all variants described as causative in the Leiden Open Variation Database and the Human Gene Mutation Database. We have systematically searched for their frequency in the NHLBI GO Exome Sequencing Project (ESP) and in our internal database. Surprisingly, the ESP contains about 4% of the variants previously associated with a dominant inheritance and about 9% of those associated with a recessive inheritance. The putative disease alleles are much more frequent than those estimated considering the disease prevalence. In conclusion, we hypothesize that a number of disease-associated variants are non-pathogenic and that other variations are not fully penetrant, even if they affect the protein function, suggesting a more complex genetic mechanisms for such heterogeneous disorders.
authors.affiliation: Laboratorio di Genetica Medica, Dipartimento di Biochimica, Biofisica e Patologia Generale, Seconda Università di Napoli, Napoli, Italy.|Telethon Institute of Genetics and Medicine (TIGEM), Napoli, Italy.
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Di Fruscio
authors.affiliation: Laboratorio di Genetica Medica, Dipartimento di Biochimica, Biofisica e Patologia Generale, Seconda Università di Napoli, Napoli, Italy.|Telethon Institute of Genetics and Medicine (TIGEM), Napoli, Italy.
authors.forename: Arcomaria
authors.initials: A
authors.lastname: Garofalo
authors.affiliation: Telethon Institute of Genetics and Medicine (TIGEM), Napoli, Italy.
authors.forename: Margherita
authors.initials: M
authors.lastname: Mutarelli
authors.affiliation: Laboratorio di Genetica Medica, Dipartimento di Biochimica, Biofisica e Patologia Generale, Seconda Università di Napoli, Napoli, Italy.|Telethon Institute of Genetics and Medicine (TIGEM), Napoli, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Savarese
authors.affiliation: Laboratorio di Genetica Medica, Dipartimento di Biochimica, Biofisica e Patologia Generale, Seconda Università di Napoli, Napoli, Italy.|Telethon Institute of Genetics and Medicine (TIGEM), Napoli, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Nigro
mesh_terms: D017668:Age of Onset; D000483:Alleles; D003598:Cytoskeletal Proteins / Q000235:genetics*; D030541:Databases, Genetic; D049029:Dystrophin-Associated Proteins / Q000235:genetics*; D059472:Exome; D005260:Female; D005787:Gene Frequency; D005799:Genes, Dominant; D005808:Genes, Recessive; D014644:Genetic Variation; D006801:Humans; D008297:Male; D049288:Muscular Dystrophies, Limb-Girdle / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics*; D034521:Nuclear Matrix-Associated Proteins / Q000235:genetics*; D019683:Penetrance
chemical_list: D003598:Cytoskeletal Proteins; D049029:Dystrophin-Associated Proteins; D009419:Nerve Tissue Proteins; D034521:Nuclear Matrix-Associated Proteins