1660-P: Exome Sequencing in a Family with Multiple Cases of Early-Onset Diabetes Reveals a Candidate Causative Mutation in the PTF1A Gene

Abstract

Maturity-onset diabetes of the young (MODY) is characterized by early-onset diabetes with dominant inheritance. To date, 14 causative genes have been proposed for MODY, however the disease-causing genetic variants in numerous cases of early-onset diabetes with features of MODY remain unknown. The aim of this study was to investigate the genetic background of a family with multiple cases of early-onset diabetes using exome sequencing to identify a causative gene. The Japanese family that we examined included eight members with diabetes, three of whom were diagnosed with the disease before the age of 35. All three of these individuals were lean (BMI <25 kg/m2). Serum C-peptide was detectable and GAD antibody was negative in all three cases. We first performed exome sequencing for two of these three members with early-onset diabetes. No mutations of the 14 known MODY genes were detected in these two family members. We therefore predicted that the familial aggregation of early-onset diabetes in this family was due to a rare non-synonymous variant in genes other than 14 MODY genes. We selected non-synonymous variants identified with exome sequencing and then excluded common variants with minor allele frequency of >1% in the 1000 genomes project or the Japanese exome database. As a result, we identified rare 399 non-synonymous variants shared by two members sequenced. Among the variants, we found a heterozygous S18F mutation in PTF1A [rs761787095, chr10:23192583C>T(GRCh38)]. Following this, we genotyped the remaining family member with early-onset diabetes, who was finally confirmed to share the heterozygous S18F mutation in PTF1A. Interestingly, the PTF1A gene has been implicated in pancreas development. Thus, the S18F mutation in PTF1A may be a causative mutation for early-onset diabetes. Family-based comprehensive exome sequencing is a promising strategy to elucidate the complex genetic background of diabetes. Disclosure D. Tanaka: None. S. Okamoto: None. Y. Liu: None. K. Iizuka: Speaker’s Bureau; Self; Kowa Company, Ltd., Novo Nordisk Inc. Y. Hamamoto: Research Support; Self; Sumitomo Dainippon Pharma Co., Ltd. Speaker’s Bureau; Self; Novo Nordisk Inc. Y. Horikawa: None. D. Yabe: Research Support; Self; ARKRAY, Astellas Pharma Inc., AstraZeneca K.K., Eli Lilly Japan K.K., Japan Agency for Medical Research and Development, Japan Society for the Promotion of Science, Kowa Company, Ltd., Nippon Boehringer Ingelheim Co. Ltd., Sanofi K.K., Sanwa Kagaku Kenkyusho, Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited. Speaker’s Bureau; Self; Abbott, ARKRAY, Astellas Pharma Inc., AstraZeneca K.K., Bayer Yakuhin, Ltd., Daiichi Sankyo, Eli Lilly Japan K.K., Fukuda Denshi, Kowa Company, Ltd., Kyowa Hakko Kirin Co., Ltd., LifeScan, Inc., Medtronic, Nippon Boehringer Ingelheim Co. Ltd., Novartis Pharma K.K., Novo Nordisk Inc., Novo Nordisk Inc., Sanofi K.K., Sanwa Kagaku Kenkyusho, Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited, Teijin Pharma Limited. Other Relationship; Self; Japan Diabetes Society. N. Inagaki: Research Support; Self; Astellas Pharma Inc., Drawbridge Health, Japan Tobacco Inc., Kissei Pharmaceutical Co., Ltd., Kyowa Hakko Kirin Co., Ltd., Life Scan Japan, Nippon Boehringer Ingelheim Co. Ltd., Novartis Pharma K.K., Novo Nordisk Pharma Ltd.,, Sanofi K.K., Sanwa Kagaku Kenkyusho, Terumo Medical Corporation. Speaker’s Bureau; Self; Astellas Pharma Inc., Merck & Co., Inc., Mitsubishi Tanabe Pharma Corporation, Nippon Boehringer Ingelheim Co. Ltd., Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited. Funding Japan Society for the Promotion of Science (18K08509)