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

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. 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. 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). 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.