Homozygosity for Non-H1069Q Missense Mutations in ATP7B Gene and Early Severe Liver Disease: Report of Two Families and a Meta-analysis

Abstract

Most patients with Wilson's disease (WD) are compound heterozygote, which complicates establishing genotype-phenotype correlations. We identified five patients who presented with early and/or severe hepatic disease who are homozygous for W939C missense mutation on exon 12 of ATP7B. We therefore conducted a meta-analysis to determine the phenotype of patients homozygous for missense or nonsense mutations in all ATP7B exons.The meta-analysis showed that 69% and 31% of patients are homozygous for H1069Q and non-H1069Q mutations, respectively. Compared to patients with H1069Q, those with non-H1069Q mutations were significantly more likely to have a hepatic phenotype, severe liver disease, a mixed phenotype, and less likely to have a neurologic phenotype. Compared to patients with nonsense mutations, those with non-H1069Q ones were equally likely to present with a hepatic phenotype and to have severe liver disease. Mean age at symptom onset in the non-H1069Q versus the H1069Q group was 15.5 versus 20.5years (p<0.001).Our data suggest that mutation W939C and other non-H1069Q missense mutations are associated with early disease onset, a hepatic phenotype, and a high risk of hepatic failure in homozygous patients. Early identification of such patients by genetic screening is important for timely initiation of treatment and prevention of complications.

Characterization of mutation spectrum and identification of novel mutations in ATP7B gene from a cohort of Wilson disease patients: Functional and therapeutic implications

“…Correspondingly, in the present study, p.(Leu795Phe) mutation in homozygous form was associated with neurological manifestation, which is in concordance with the previous study reported by Aggarwal et al (2013). Similarly, p.(Lys1010Arg) mutation in the ATP7B gene fraternized with hepatic phenotype in this study, which was also previously reported in three Lebanon patients (Usta et al, 2012).…”

“…(). Similarly, p.(Lys1010Arg) mutation in the ATP7B gene fraternized with hepatic phenotype in this study, which was also previously reported in three Lebanon patients (Usta et al., ). However, phenotypic variability displayed by many mutations is not uncommon and compound heterozygous ATP7B genotypes further intertwine the phenotypic outcome of the disease that is evidenced in our study, which showed that heterozygous p.(Leu795Phe) mutation in association with p.(Cys271*) in a patient exhibited hepatic phenotype.…”

Genotype-Phenotype Correlations in a Mountain Population Community with High Prevalence of Wilson’s Disease: Genetic and Clinical Homogeneity

“…It is unknown why a particular genotype is not associated to a specific behavior of the disease, albeit some authors have tried to establish a correlation between the type of presentation, age at onset or clinical course and the presence of a specific mutation in heterozygous or homozygous state [20], [21], [34], [35].…”

Wilson’s disease in Lebanon and regional countries: Homozygosity and hepatic phenotype predominance

“…In a cohort of Egyptian patients, genotypic and phenotypic profiles were described, but no prevalent mutation was identified[ 12 ]. Moreover, previous reports from Lebanon on a limited number of families suggested an association of liver presentation with homozygous missense mutations: Gly691Arg and non-His1069Trp in exons 7 and 14 of the ATP7B gene respectively[ 13 , 14 ]. Whether a specific WD mutation prevails in Lebanon is not known.…”