A study of Mutation in ATP7B gene and its correlation with clinical phenotype and radiological features in Wilson Disease patients

Abstract

Introduction Wilson Disease (WD) is an autosomal recessive disease caused by mutations in the ATP7B gene. Clinical manifestations of WD are variable. Identification of prevalent mutations in a given population is necessary to provide mutation-based molecular diagnosis. Previous studies have detected common mutations in this part of the world and our study aimed to correlate genotype with clinical and radiological features. Methods A descriptive cross-sectional observational study was conducted over a period of two years in a tertiary care hospital and neurology referral unit of Kolkata, India. All WD patients within the study period and meeting the inclusion criteria were included. Demographic data collection, clinical examination and relevant laboratory investigations were done. Magnetic resonance imaging of brain and cognitive assessment by Mini Mental Score Exam (MMSE) were also performed. Blood was collected for genetic analyses. PCR-Sanger sequencing of exons 2,4,6,8,10,14,16,18 of ATP7B gene was done based on previous reports of mutation hotspots of ATP7B gene for WD in Eastern India. Genotype phenotype correlation was attempted using two supervised machine learning methods, viz. logistic regression with an elastic-net penalty and the random forest. Results Of 52 WD patients were included in the study, 57.7% were males. The mean age at diagnosis was 13.96 years. Majority (61.8%) of the patients had dystonia on presentation, followed by dysarthria (41.2%), tremor (17.6%) and ataxia (11.8%). The mean MMSE and Frontal Assessment Battery score were 23.74 and 10.63 respectively and both were lower than the normal baseline values.Out of the total cohort of 52 patients,15(28.8%) harbored previously reported common mutations from this part of the country. Of the 15, 12 had the same mutation of c.813C>A(p.cys271Ter).The presence of common mutationswas associated with several distinct clinical phenotypes in the mathematical models but larger sample sizes are needed to corroborate the correlation. Conclusions WD patients in eastern India have significant genotypic and phenotypic diversity. Further studies with larger samples and screening of remaining exons are warranted.