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Background <p>Genetic studies have reported the <i>ATP7B</i> c.3316 G &gt; A variant in Wilson disease (WD). However, the phenotypic characteristics of <i>ATP7B</i> c.3316 G &gt; A remained unclear. We aimed to explore the <i>ATP7B</i> c.3316 G &gt; A genotype-phenotype correlation and its clinical characteristics in patients of WD.</p> Methods <p>A single-center cohort study enrolled 44 WD patients with c.3316 G &gt; A variant from 43 unrelated Chinese families (19 males [43.2%], 25 females [56.8%]), and randomly selected 44 hospitalized WD patients with <i>ATP7B</i> mutations other than c.3316 G &gt; A as the comparison group. All phenotypic data were collected before chelation therapy. Phenotypic analyses included age of onset, clinical subtype, Kayser-Fleischer ring (KFR), copper metabolism profiles (serum copper [SCu], serum copper oxidase [SCO], ceruloplasmin [CP]), Unified Wilson’s Disease Rating Scale Part I (UWDRS-I), and Child-Turcotte-Pugh (CTP) scores. Genotype-phenotype associations were quantified in subgroup analyses.</p> Results <p>The c.3316 G &gt; A cohort harbored 21 distinct <i>ATP7B</i> mutations, including 4 nonsense, 1 frameshift, 1 synonymous, and 15 missense variants. Group analysis showed that c.3316 G &gt; A heterozygosity showed delayed age of onset compared with non-c.3316 G &gt; A patients (<i>p</i> &lt; 0.001), hepatic predominance over neurological presentations (<i>p</i> &lt; 0.001), attenuated neurological severity (UWDRS-I: <i>p</i> = 0.001), lower KFR positivity (<i>p</i> = 0.033), and relatively elevated SCu, SCO, and CP (<i>p</i> &lt; 0.001). No gender-related phenotypic disparities were observed within either cohort. Subgroup analysis within c.3316 G &gt; A cohort, co-mutation with- (<i>n</i> = 20) versus without- (<i>n</i> = 24) c.2333 G &gt; T revealed no significant differences in onset age, clinical subtypes, and copper metabolism profiles. Notably, cis-arranged relationship between c.3316 G &gt; A and c.588C &gt; A emerged via Haploview software (v4.2) (<i>D’</i> = 1.0, LOD = 4.63, <i>r</i><sup>2</sup> = 0.239).</p> Conclusion <p>The c.3316 G &gt; A variant is associated with a distinct “mild” subphenotype characterized by delayed onset, neurologic sparing, lower KFR positivity, and milder copper dysregulation in patients of WD. Its cis-arranged relationship with the <i>ATP7B</i> c.588C &gt; A variant provides critical insights into WD genetic diagnosis.</p>

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The ATP7B c.3316 G > A variant is associated with mild subphenotype in Wilson disease: a single-center cohort study

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  • 发表日期：

    2026年2月14日

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  • Lisheng Liu,
  • Mingjuan Fang,
  • Wenlong Ai,
  • Shan Shu,
  • Wen Zhao,
  • Yan Yan,
  • Nan Cheng,
  • Wenbin Hu,
  • Yin Xu

摘要

Background

Genetic studies have reported the ATP7B c.3316 G > A variant in Wilson disease (WD). However, the phenotypic characteristics of ATP7B c.3316 G > A remained unclear. We aimed to explore the ATP7B c.3316 G > A genotype-phenotype correlation and its clinical characteristics in patients of WD.

Methods

A single-center cohort study enrolled 44 WD patients with c.3316 G > A variant from 43 unrelated Chinese families (19 males [43.2%], 25 females [56.8%]), and randomly selected 44 hospitalized WD patients with ATP7B mutations other than c.3316 G > A as the comparison group. All phenotypic data were collected before chelation therapy. Phenotypic analyses included age of onset, clinical subtype, Kayser-Fleischer ring (KFR), copper metabolism profiles (serum copper [SCu], serum copper oxidase [SCO], ceruloplasmin [CP]), Unified Wilson’s Disease Rating Scale Part I (UWDRS-I), and Child-Turcotte-Pugh (CTP) scores. Genotype-phenotype associations were quantified in subgroup analyses.

Results

The c.3316 G > A cohort harbored 21 distinct ATP7B mutations, including 4 nonsense, 1 frameshift, 1 synonymous, and 15 missense variants. Group analysis showed that c.3316 G > A heterozygosity showed delayed age of onset compared with non-c.3316 G > A patients (p < 0.001), hepatic predominance over neurological presentations (p < 0.001), attenuated neurological severity (UWDRS-I: p = 0.001), lower KFR positivity (p = 0.033), and relatively elevated SCu, SCO, and CP (p < 0.001). No gender-related phenotypic disparities were observed within either cohort. Subgroup analysis within c.3316 G > A cohort, co-mutation with- (n = 20) versus without- (n = 24) c.2333 G > T revealed no significant differences in onset age, clinical subtypes, and copper metabolism profiles. Notably, cis-arranged relationship between c.3316 G > A and c.588C > A emerged via Haploview software (v4.2) (D’ = 1.0, LOD = 4.63, r2 = 0.239).

Conclusion

The c.3316 G > A variant is associated with a distinct “mild” subphenotype characterized by delayed onset, neurologic sparing, lower KFR positivity, and milder copper dysregulation in patients of WD. Its cis-arranged relationship with the ATP7B c.588C > A variant provides critical insights into WD genetic diagnosis.