title: Therapeutic implications of novel mutations of the RFX6 gene associated with early-onset diabetes.
abstract: Identification of the genetic defect underlying early-onset diabetes is important for determining the specific diabetes subtype, which would then permit appropriate treatment and accurate assessment of recurrence risk in offspring. Given the extensive genetic and clinical heterogeneity of the disease, high-throughput sequencing might provide additional diagnostic potential when Sanger sequencing is ineffective. Our aim was to develop a targeted next-generation assay able to detect mutations in several genes involved in glucose metabolism. All 13 known MODY genes, genes identified from a genome-wide linkage study or genome-wide association studies as increasing the risk of type 2 diabetes and genes causing diabetes in animal models, were included in the custom panel. We selected a total of 102 genes by performing a targeting re-sequencing in 30 patients negative for mutations in the GCK, HNF1α, HNF4α, HNF1β and IPF1 genes at the Sanger sequencing analysis. Previously unidentified variants in the RFX6 gene were found in three patients and in two of them we also detected rare variants in WFS1 and ABCC8 genes. All patients showed a good therapeutic response to dipeptidyl peptidase-4 (DPP4) inhibitors. Our study reveals that next-generation sequencing provides a highly sensitive method for identification of variants in new causative genes of diabetes. This approach may help in understanding the molecular etiology of diabetes and in providing more personalized treatment for each genetic subtype.
authors.affiliation: Medical Genetics Unit, Meyer Children's University Hospital, Florence, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Artuso
authors.affiliation: Medical Genetics Unit, Department of Clinical and Experimental Biomedical Sciences 'Mario Serio', University of Florence, Florence, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Provenzano
authors.affiliation: Medical Genetics Unit, Meyer Children's University Hospital, Florence, Italy.
authors.forename: B
authors.initials: B
authors.lastname: Mazzinghi
authors.affiliation: Medical Genetics Unit, Meyer Children's University Hospital, Florence, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Giunti
authors.affiliation: Medical Genetics Unit, Department of Clinical and Experimental Biomedical Sciences 'Mario Serio', University of Florence, Florence, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Palazzo
authors.affiliation: Medical Genetics Unit, Meyer Children's University Hospital, Florence, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Andreucci
authors.affiliation: Department of Pediatrics, University of Chieti, Chieti, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Blasetti
authors.affiliation: Department of Pediatrics, University of Chieti, Chieti, Italy.
authors.forename: R M
authors.initials: RM
authors.lastname: Chiuri
authors.affiliation: DINOGMI, University of Genoa, Genova, Italy.
authors.forename: F E
authors.initials: FE
authors.lastname: Gianiorio
authors.affiliation: DINOGMI, University of Genoa, Genova, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Mandich
authors.affiliation: Section of Geriatric Cardiology and Medicine, Department of Cardiovascular Medicine, Careggi Hospital, Florence, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Monami
authors.affiliation: Diabetes Agency, Careggi Hospital, Florence, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Mannucci
authors.affiliation: 1] Medical Genetics Unit, Meyer Children's University Hospital, Florence, Italy [2] Medical Genetics Unit, Department of Clinical and Experimental Biomedical Sciences 'Mario Serio', University of Florence, Florence, Italy [3] FiorGen Foundation for Pharmacogenomics, Sesto Fiorentino, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Giglio
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D004268:DNA-Binding Proteins / Q000235:genetics*; D003920:Diabetes Mellitus / Q000175:diagnosis* / Q000188:drug therapy / Q000235:genetics*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000627:therapeutic use; D005260:Female; D056726:Genetic Association Studies / Q000379:methods*; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors / Q000235:genetics*; D055815:Young Adult
chemical_list: D004268:DNA-Binding Proteins; D054873:Dipeptidyl-Peptidase IV Inhibitors; D000071701:Regulatory Factor X Transcription Factors; C547964:Rfx6 protein, human; D014157:Transcription Factors