High prevalence of copy number variations in the Japanese participants with suspected <scp>MODY</scp>

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  • Satoshi Tanaka
    Institute for Comprehensive Medical Sciences Tokyo Women's Medical University Tokyo Japan
  • Hiroyuki Akagawa
    Institute for Comprehensive Medical Sciences Tokyo Women's Medical University Tokyo Japan
  • Kenkou Azuma
    Institute for Comprehensive Medical Sciences Tokyo Women's Medical University Tokyo Japan
  • Sayaka Higuchi
    Institute for Comprehensive Medical Sciences Tokyo Women's Medical University Tokyo Japan
  • Atsushi Ujiie
    Department of Diabetes, Endocrinology and Hematology Dokkyo Medical University Saitama Medical Center Saitama Japan
  • Koshi Hashimoto
    Department of Diabetes, Endocrinology and Hematology Dokkyo Medical University Saitama Medical Center Saitama Japan
  • Naoko Iwasaki
    Institute for Comprehensive Medical Sciences Tokyo Women's Medical University Tokyo Japan

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<jats:title>Abstract</jats:title><jats:p>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 <jats:italic>HNF4A</jats:italic> and 1 in <jats:italic>HNF1B</jats:italic>. 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 <jats:italic>HNF4A</jats:italic> or <jats:italic>HNF1B</jats:italic>, indicating a limitation of WES‐only screening.</jats:p>

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