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Updated: Jun 26, 2025

Array Comparative Genomic Hybridization Array CGH for Detection of Genomic Copy Number Variants
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High prevalence of copy number variations in the Japanese participants with suspected MODY

Satoshi Tanaka1,2, Hiroyuki Akagawa1,3, Kenkou Azuma1

  • 1Institute for Comprehensive Medical Sciences, Tokyo Women's Medical University, Tokyo, Japan.

Clinical Genetics
|May 11, 2024
PubMed

Insights

Comprehensive genetic testing identified pathogenic variants in 57.1% of Maturity-Onset Diabetes of the Young (MODY) cases. Whole exome sequencing combined with MLPA analysis revealed limitations in WES-only screening for copy number variations.

Area of Science:

  • Genetics
  • Endocrinology
  • Molecular Biology

Background:

  • Maturity-Onset Diabetes of the Young (MODY) is a monogenic form of diabetes mellitus.
  • Current genetic detection rates for MODY are low, leaving causative genes unidentified in most cases.
  • Improved diagnostic strategies are needed to enhance MODY gene detection.

Purpose of the Study:

  • To increase the diagnostic yield of genetic testing in MODY patients.
  • To evaluate the effectiveness of whole exome sequencing (WES) combined with Multiplex Ligation-dependent Probe Amplification (MLPA) and functional analyses for MODY.
  • To identify novel pathogenic variants and copy number variations (CNVs) in MODY.

Main Methods:

  • Whole exome sequencing (WES) was performed on 21 unrelated Japanese participants with MODY.
  • Multiplex Ligation-dependent Probe Amplification (MLPA) was used to detect copy number variations (CNVs) in WES-negative cases.
  • Functional analyses were conducted to assess undetermined variants.

Main Results:

  • WES identified 7 pathogenic and 3 likely pathogenic variants.
  • Functional analyses confirmed 1 in 3 variants as pathogenic.
  • MLPA identified 4 cases with pathogenic CNVs (3 in HNF4A, 1 in HNF1B).
  • Overall, pathogenic variants were identified in 12 participants (57.1%), a high detection rate.
  • CNVs in HNF4A or HNF1B were found in one-third of participants, highlighting WES limitations.

Conclusions:

  • Comprehensive genetic testing significantly improves the detection rate of pathogenic variants in MODY.
  • Combining WES with MLPA is crucial for identifying CNVs, which may be missed by WES alone.
  • This integrated approach enhances MODY diagnosis and understanding of its genetic basis.
Keywords:
JapaneseMODYcopy number variationmaturity‐onset diabetes of the youngmultiplex ligation‐dependent probe amplificationwhole exome sequencing

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