High prevalence of copy number variations in the Japanese participants with suspected MODY

• Published in: Clinical genetics Vol. 106; no. 3; pp. 293 - 304
• Main Authors: Tanaka, Satoshi, Akagawa, Hiroyuki, Azuma, Kenkou, Higuchi, Sayaka, Ujiie, Atsushi, Hashimoto, Koshi, Iwasaki, Naoko
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.09.2024
• Subjects: Adolescent; Adult; Asian People - genetics; Copy number; copy number variation; Diabetes; Diabetes mellitus; Diabetes Mellitus, Type 2 - epidemiology; Diabetes Mellitus, Type 2 - genetics; DNA Copy Number Variations - genetics; East Asian People; Exome Sequencing; Female; Genetic Predisposition to Disease; Genetic Testing; Hepatocyte Nuclear Factor 1-beta - genetics; Hepatocyte nuclear factor 4; Hepatocyte Nuclear Factor 4 - genetics; Humans; Japan - epidemiology; Japanese; Male; maturity‐onset diabetes of the young; Middle Aged; MODY; multiplex ligation‐dependent probe amplification; Multiplex Polymerase Chain Reaction; Mutation - genetics; Prevalence; whole exome sequencing; Whole genome sequencing; Young Adult; Japan; multiplex ligation‐dependent probe amplification; MODY; copy number variation; maturity‐onset diabetes of the young; Japanese; whole exome sequencing
• DOI: 10.1111/cge.14544
• ISSN: 0009-9163; 1399-0004

Maturity‐Onset Diabetes of the Young (MODY) is a diabetes mellitus subtype caused by a single gene. The detection rate of the responsible gene is 27% in the United Kingdom, indicating that the causative gene remains unknown in the majority of clinically diagnosed MODY cases. To improve the detection rate, we applied comprehensive genetic testing using whole exome sequencing (WES) followed by Multiplex Ligation‐dependent Probe Amplification (MLPA) and functional analyses. Twenty‐one unrelated Japanese participants with MODY were enrolled in the study. To detect copy number variations (CNVs), WES was performed first, followed by MLPA analysis for participants who were negative on the basis of WES. Undetermined variants were analyzed according to their functional properties. WES identified 7 pathogenic and 3 novel likely pathogenic variants in the 21 participants. Functional analyses revealed that 1 in 3 variants was pathogenic. MLPA analysis applied to the remaining 13 undetermined samples identified 4 cases with pathogenic CNVs: 3 in HNF4A and 1 in HNF1B. Pathogenic variants were identified in 12 participants (12/21, 57.1%) – relatively high rate reported to date. Notably, one‐third of the participants had CNVs in HNF4A or HNF1B, indicating a limitation of WES‐only screening. Comprehensive genetic testing using WES, and MLPA and functional analyses for Japanese MODY patients identified pathogenic variants in 57.1% of the participants – including HNF4A, GCK, HNF1A, HNF1B, ABCC8, and WFS1. Of note, one‐third of the pathogenic variants were CNVs, suggesting that CNVs must be included in MODY genetic screening.