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

Abstract

Wilson’s disease is an autosomal recessive disorder caused by more than 500 mutations in ATP7B gene presenting considerably clinical manifestations heterogeneity even in patients with a particular mutation. Previous findings suggested a potential role of additional genetic modifiers and environment factors on phenotypic expression among the affected patients. We conducted clinical and genetic investigations to perform genotype-phenotype correlation in two large families living in a socio-culturally isolated community with the highest prevalence of Wilson’s disease ever reported of 1∶1130. Sequencing of ATP7B gene in seven affected individuals and 43 family members identified a common compound heterozygous genotype, H1069Q/M769H-fs, in five symptomatic and two asymptomatic patients and detected the presence of two out of seven identified single nucleotide polymorphisms in all affected patients. Symptomatic patients had similar clinical phenotype and age at onset (18±1 years) showing dysarthria and dysphagia as common clinical features at the time of diagnosis. Moreover, all symptomatic patients presented Kayser-Fleischer rings and lack of dystonia accompanied by unfavourable clinical outcomes. Our findings add value for understanding of genotype-phenotype correlations in Wilson’s disease based on a multifamily study in an isolated population with high extent of genetic and environmental homogeneity as opposed to majority of reports. We observed an equal influence of presumed other genetic modifiers and environmental factors on clinical presentation and age at onset of Wilson’s disease in patients with a particular genotype. These data provide valuable inferences that could be applied for predicting clinical management in asymptomatic patients in such communities.

Neurological features and management of Wilson disease in children: an evaluation of 12 cases

“…More than 500 mutations of the ATP7B gene have been reported (2,4,17). This variability in the ATP7B mutations may have different effects on the severity of neurological findings, prognosis and treatment response (17). We think that varying severity of clinical course of the neurological findings and different treatment responses in the patients included in this study are related with multifactorial etiopathogenetic causes.…”

“…The close relation between the copper and cholesterol metabolism pathways and frequent hepatosteatosis in patients with WD have led to the assumption that increased copper level may disrupt cholesterol metabolism in the brain and this may be involved in the clinical course of the neurological disorders related with WD (16). More than 500 mutations of the ATP7B gene have been reported (2,4,17). This variability in the ATP7B mutations may have different effects on the severity of neurological findings, prognosis and treatment response (17).…”

Genetic and Clinical Analysis in a Cohort of Patients with Wilson's Disease in Southwestern China

“…Therefore, Arg778Leu could be regarded as a ''hot spot'' mutation in Chinese WD patients. Some studies proposed that there may be a correlation between Arg778Leu mutation and hepatic manifestation (12,13). However, there is still no definite conclusion on the correlation between Arg778Leu mutation and clinical symptoms.…”

The genetics of Wilson disease

“…Direct genotype–phenotype relationships in Wilson disease have been difficult to establish, despite several studies examining correlation (Panagiotakaki et al, 2004; Vrabelova et al, 2005; Nicastro et al, 2010; Cocoş et al, 2014; Usta et al, 2014). The numerous low-frequency and compound heterozygous nature of Wilson disease obfuscate the process of characterizing its numerous genetic variants and their clinical consequences.…”