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Background <p>Wilson disease (WD) is a rare autosomal recessive disorder caused by mutations in <i>ATP7B</i>, leading to impaired copper metabolism. Although WD is classically considered a monogenic disease, patients carrying identical <i>ATP7B</i> mutations frequently exhibit striking variability in clinical presentation, age at onset, and treatment outcomes. This heterogeneity is thought to be shaped by variants in modifier genes involved in copper homeostasis and copper-induced cell death, as well as by polymorphisms in drug-metabolizing enzymes that may influence therapeutic response and prognosis.</p> Methods and Results <p>To investigate the genetic contributors to this inherent variability, we examined three unrelated WD patients who were all homozygous for the <i>ATP7B</i> p.Cys271X mutation but differed markedly in age at onset, clinical features, and responses to therapy. Whole-exome sequencing revealed distinct pathogenic variants across several putative modifier loci, including <i>NOS2</i>,<i> APOE</i>,<i> CYP2D6</i>,<i> AGPAT2</i>,<i> ABCB4</i>,<i> APOB</i>,<i> FASN</i>,<i> AQP1</i>,<i> CYP1A1</i>,<i> ACSL4</i>,<i> STEAP3</i>,<i> NOX3</i>,<i> NQO1</i>,<i> LOXL3</i>,<i> ANKK1</i>, and <i>PNPO</i>. These gene-specific differences aligned with the patients’ diverse clinical manifestations, supporting the hypothesis that modifier variants play a meaningful role in shaping WD severity, age at onset, and pharmacological outcomes.</p> Conclusions <p>Our findings emphasize that, despite its Mendelian inheritance, WD exhibits substantial genetic complexity driven by modifier loci, underscoring the potential for genotype-guided, personalized management strategies. We acknowledge that this study results are exploratory in nature and limited by the small sample size (<i>N</i> = 3); however, the rarity of WD and the difficulty of identifying and recruiting individuals who are homozygous for the same pathogenic <i>ATP7B</i> variant—and for whom detailed longitudinal phenotypic and therapeutic data are available—pose significant challenges to conducting larger-scale investigations.</p>

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Exploratory associations of candidate modifier variants with disease severity, age at onset, and drug response in three Wilson disease patients sharing the same ATP7B mutation

  • 期刊论文

  • 发表日期：

    2026年3月27日

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  • Arpan Saha,
  • Preyangsee Dutta,
  • Aratrika Dutta,
  • Tithi Dutta,
  • Sumanta Sarkar,
  • Atanu Biswas,
  • Mainak Sengupta

摘要

Background

Wilson disease (WD) is a rare autosomal recessive disorder caused by mutations in ATP7B, leading to impaired copper metabolism. Although WD is classically considered a monogenic disease, patients carrying identical ATP7B mutations frequently exhibit striking variability in clinical presentation, age at onset, and treatment outcomes. This heterogeneity is thought to be shaped by variants in modifier genes involved in copper homeostasis and copper-induced cell death, as well as by polymorphisms in drug-metabolizing enzymes that may influence therapeutic response and prognosis.

Methods and Results

To investigate the genetic contributors to this inherent variability, we examined three unrelated WD patients who were all homozygous for the ATP7B p.Cys271X mutation but differed markedly in age at onset, clinical features, and responses to therapy. Whole-exome sequencing revealed distinct pathogenic variants across several putative modifier loci, including NOS2, APOE, CYP2D6, AGPAT2, ABCB4, APOB, FASN, AQP1, CYP1A1, ACSL4, STEAP3, NOX3, NQO1, LOXL3, ANKK1, and PNPO. These gene-specific differences aligned with the patients’ diverse clinical manifestations, supporting the hypothesis that modifier variants play a meaningful role in shaping WD severity, age at onset, and pharmacological outcomes.

Conclusions

Our findings emphasize that, despite its Mendelian inheritance, WD exhibits substantial genetic complexity driven by modifier loci, underscoring the potential for genotype-guided, personalized management strategies. We acknowledge that this study results are exploratory in nature and limited by the small sample size (N = 3); however, the rarity of WD and the difficulty of identifying and recruiting individuals who are homozygous for the same pathogenic ATP7B variant—and for whom detailed longitudinal phenotypic and therapeutic data are available—pose significant challenges to conducting larger-scale investigations.