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Purpose <p>The objective of this study was to investigate the protein-coding regions of the NR1D2 gene in patients clinically diagnosed with maturity-onset diabetes of the young (MODY), including those without pathogenic variants in known MODY genes (MODY-X), and to characterize the potential functional relevance of detected variants.</p> Methods <p>The variants present in the exons and adjacent intronic regions of the <i>NR1D2</i> gene in patients with MODY were subjected to comparative analysis with those observed in healthy individuals and patients with type 2 diabetes mellitus. The maximum credible allele frequency was set to be 0.0001. The potential impact of rare variants was evaluated using variety in silico prediction tools, including PolyPhen-2, SIFT, MutationTaster2025, FATHMM-XF, REVEL, CADD, and DynaMut2.</p> Results <p>Two extremely rare NR1D2 missense variants were identified in three MODY-X patients: p.I148V (rs148928938) in exon 4 and p.R286W (rs768518229) in exon 5, with allele frequencies of 74 per million and 3 per million in gnomAD, respectively. In silico predictions indicated a more consistent deleterious profile for p.I148V, whereas p.R286W demonstrated heterogeneous and predominantly benign or borderline predictions. The clinical manifestations exhibited by the carriers were found to be variable, which is consistent with the metabolic heterogeneity that is characteristic of MODY.</p> Conclusion <p>The findings suggest that these variants may function as metabolic modifiers contributing to phenotypic variability in MODY-X. Prospective family-based studies and functional assays are needed to clarify their biological significance.</p>

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Evaluation of rare NR1D2 variants in MODY-X: clinical, genetic, and in silico insights

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月6日

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  • Cagatay Aydogan,
  • Deniz Kanca-Demirci,
  • Nurdan Gul,
  • Sukran Poyrazoglu,
  • Bengu Tokat,
  • Ummu Mutlu,
  • Oguz Ozturk,
  • Hulya Yilmaz-Aydogan,
  • Ilhan Satman

摘要

Purpose

The objective of this study was to investigate the protein-coding regions of the NR1D2 gene in patients clinically diagnosed with maturity-onset diabetes of the young (MODY), including those without pathogenic variants in known MODY genes (MODY-X), and to characterize the potential functional relevance of detected variants.

Methods

The variants present in the exons and adjacent intronic regions of the NR1D2 gene in patients with MODY were subjected to comparative analysis with those observed in healthy individuals and patients with type 2 diabetes mellitus. The maximum credible allele frequency was set to be 0.0001. The potential impact of rare variants was evaluated using variety in silico prediction tools, including PolyPhen-2, SIFT, MutationTaster2025, FATHMM-XF, REVEL, CADD, and DynaMut2.

Results

Two extremely rare NR1D2 missense variants were identified in three MODY-X patients: p.I148V (rs148928938) in exon 4 and p.R286W (rs768518229) in exon 5, with allele frequencies of 74 per million and 3 per million in gnomAD, respectively. In silico predictions indicated a more consistent deleterious profile for p.I148V, whereas p.R286W demonstrated heterogeneous and predominantly benign or borderline predictions. The clinical manifestations exhibited by the carriers were found to be variable, which is consistent with the metabolic heterogeneity that is characteristic of MODY.

Conclusion

The findings suggest that these variants may function as metabolic modifiers contributing to phenotypic variability in MODY-X. Prospective family-based studies and functional assays are needed to clarify their biological significance.