Soo Heon Kwak1, Chan-Hyeon Jung1, Chang Ho Ahn2, Jungsun Park3, Jeesoo Chae4, Hye Seung Jung1, Young Min Cho2, Dae Ho Lee5, Jong-Il Kim4, Kyong Soo Park6. 1. Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea. 2. Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea; Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea. 3. New Business Division, SK Telecom, Seongnam, Gyeonggi-Do, Republic of Korea. 4. Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea. 5. Department of Internal Medicine, Gachon University Gil Medical Center, Incheon, Republic of Korea. 6. Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea; Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea; Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Republic of Korea. Electronic address: kspark@snu.ac.kr.
Abstract
AIMS: There could be an overlap of monogenic diabetes and early onset type 2 diabetes in those who are diagnosed before age of 30years. Genetic diagnosis in these patients might improve the quality of care. A limited number of studies have used whole exome sequencing (WES) in Asian patients with early onset diabetes, and the clinical utility of WES is largely unknown. METHODS: We performed whole exome capture and massive parallel sequencing in 28 patients with early onset diabetes. Those who had a strong family history of diabetes were preferentially enrolled. Rare and non-silent variants in 29 genes known to cause monogenic diabetes, including 12 maturity-onset diabetes of the young (MODY) genes, were investigated for pathogenicity. RESULTS: The average depth of on-target WES reads was 97 X. A total of four pathogenic or likely pathogenic rare missense variants (p.Leu319Pro in HNF4A, p.His103Tyr and p.Arg74Gln in ABCC8, and p.Leu139Val in HNF1A) in MODY genes were identified in three patients. Although four rare non-silent variants in MODY genes (p.Arg183Cys in PAX4, p.Val139Ile and p.Pro740fs in CEL, and p.Val147Ile in HNF4A) and two rare non-silent variants in monogenic diabetes genes (p.Glu169Lys in WFS1, and p.Pro407Gln in GATA4) were identified, their pathogenicity was uncertain or likely benign. CONCLUSIONS: WES could be an initial option for genetic testing in patients with early onset diabetes. However, sufficient and universal coverage of genes of interest is required. In addition, it could be difficult to interpret variant pathogenicity, and these cases might require further validation.
AIMS: There could be an overlap of monogenic diabetes and early onset type 2 diabetes in those who are diagnosed before age of 30years. Genetic diagnosis in these patients might improve the quality of care. A limited number of studies have used whole exome sequencing (WES) in Asian patients with early onset diabetes, and the clinical utility of WES is largely unknown. METHODS: We performed whole exome capture and massive parallel sequencing in 28 patients with early onset diabetes. Those who had a strong family history of diabetes were preferentially enrolled. Rare and non-silent variants in 29 genes known to cause monogenic diabetes, including 12 maturity-onset diabetes of the young (MODY) genes, were investigated for pathogenicity. RESULTS: The average depth of on-target WES reads was 97 X. A total of four pathogenic or likely pathogenic rare missense variants (p.Leu319Pro in HNF4A, p.His103Tyr and p.Arg74Gln in ABCC8, and p.Leu139Val in HNF1A) in MODY genes were identified in three patients. Although four rare non-silent variants in MODY genes (p.Arg183Cys in PAX4, p.Val139Ile and p.Pro740fs in CEL, and p.Val147Ile in HNF4A) and two rare non-silent variants in monogenic diabetes genes (p.Glu169Lys in WFS1, and p.Pro407Gln in GATA4) were identified, their pathogenicity was uncertain or likely benign. CONCLUSIONS: WES could be an initial option for genetic testing in patients with early onset diabetes. However, sufficient and universal coverage of genes of interest is required. In addition, it could be difficult to interpret variant pathogenicity, and these cases might require further validation.
Authors: Kun Hu; Malgorzata Zatyka; Dewi Astuti; Nicola Beer; Renuka P Dias; Archana Kulkarni; John Ainsworth; Benjamin Wright; Anna Majander; Patrick Yu-Wai-Man; Denise Williams; Timothy Barrett Journal: J Med Genet Date: 2021-05-18 Impact factor: 6.318