1325-P: Effectiveness of Comprehensive Gene Panel-Based Next-Generation Sequencing with Phenotype-Driven Bioinformatics Analysis for Diagnosis of Atypical Diabetes

Abstract

Atypical diabetes is considered to be different from the common forms of diabetes (types 1 and 2); however, it may share pathogenetic and phenotypic features with the common forms of diabetes. Targeted next-generation sequencing focused on genes causing monogenic diabetes has been reported to be useful for diagnosis of a few subtypes of atypical diabetes caused by genetic defects, such as MODY. In this study, considering the clinically heterogeneous nature of atypical diabetes, we developed a comprehensive gene panel containing 383 monogenic diabetes causing genes and genes associated with common forms of diabetes, and conducted targeted next-generation sequencing in 3 patients with previously confirmed and 10 patients with suspected atypical diabetes. In addition, phenotype-driven bioinformatics analysis using genetic and phenotypic information was performed to identify causal variants from sequencing data. A total of 11 mutations including 2 gross deletions were identified, which led to diagnosis of four previously undiagnosed patients and identification of potentially pathogenic variants of interest in other three patients. Of note, a novel missense mutation of Rab GAP domain of TBC1D4 was identified in a diabetic patient with severe insulin resistance. The TBC1D4 locus has been reported to be associated with type 2 diabetes and insulin resistance. In silico structural analysis suggested that the mutation would cause pathogenesis by functional and structural modification of TBC1D4, insulin-dependent phosphorylation of which is necessary for GLUT4 translocation mediated glucose uptake in skeletal muscle and adipose tissues. The results from this study indicate that comprehensive genetic screening analyzing genes associated with common and rare subtypes of diabetes can identify causal variants efficiently, thereby aiding early diagnosis of atypical diabetes. Disclosure J. Hosoe: None. H. Kadowaki: Research Support; Spouse/Partner; Astellas Pharma Inc., Daiichi Sankyo Company, Limited, Eli Lilly and Company, Kowa Pharmaceutical, Kyowa Hakko Kirin Co., Ltd., Mitsubishi Tanabe Pharma Corporation, MSD, Nippon Boehringer Ingelheim, Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi, Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company Limited. Speaker's Bureau; Spouse/Partner; Astellas Pharma Inc., AstraZeneca, Mitsubishi Tanabe Pharma Corporation, MSD, Nippon Boehringer Ingelheim, Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited. F. Miya: None. M. Takakura: None. H. Waki: Research Support; Self; Astellas Pharma Inc., Kyowa Hakko Kirin Co., Ltd., MSD K.K., Nippon Boehringer Ingelheim Co Ltd, Novo Nordisk Foundation, Ono Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited, The Cell Science Research Foundation. T. Sasako: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk Inc. T. Kato: None. T. Tsunoda: None. N. Shojima: None. T. Yamauchi: Research Support; Self; Astellas Pharma Inc., Daiichi Sankyo Company, Limited, Eli Lilly and Company, Kissei Pharmaceutical Co., Ltd., Kowa Pharmaceutical Europe Co. Ltd., Kyowa Hakko Kirin Co., Ltd., Merck & Co., Inc., Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi-Aventis, Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited. Speaker's Bureau; Self; Astellas Pharma Inc., AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Merck & Co., Inc., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi-Aventis, Takeda Pharmaceutical Company Limited. T. Kadowaki: Research Support; Self; Astellas Pharma Inc., Daiichi Sankyo Company, Limited, Eli Lilly and Company, Kowa Pharmaceutical, Kyowa Hakko Kirin Co., Ltd., Mitsubishi Tanabe Pharma Corporation, MSD, Nippon Boehringer Ingelheim, Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi, Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company Limited. Speaker's Bureau; Self; Astellas Pharma Inc., AstraZeneca, Mitsubishi Tanabe Pharma Corporation, MSD, Nippon Boehringer Ingelheim, Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited.