Dr Binukumar BK
01 July 2020
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In 1912, American-born British neurologist, Dr. Samuel Alexander Kinnier Wilson first presented a curious series of patients in his doctoral thesis on the pathologic findings of "lenticular degeneration" in the brain associated with cirrhosis of the liver. Later A.J. Glazebrook in 1945 and John Cumings in 1948 linked copper accumulation with the basal ganglia (brain) and hepatic (liver) pathology. The disease later came to be known after Kinnier Wilson who first described the disease.
H.C Hall in 1921 originally proposed the genetic inheritance of this disease is an autosomal recessive pattern. This observation was later confirmed by A.G Bearn in 1953 by analysis of the genetic ratios among patients. It took almost 30 years from Dr.Bearn’s observation to assign Wilson's disease genetic locus to the long arm of chromosome 13. In a major breakthrough in the genetics of Wilson’s disease, the ATP7B gene mutation was identified and cloned in 1993.
Copper is a nice reddish metal widely present in nature and also an important nutrient. essential for human health.
Wilson’s disease is now a well studied and prevalent genetic disease. It is an autosomal recessive disorder of copper transport due to mutations in the ATP7B gene, responsible for transport of copper into bile from hepatocytes and its incorporation into apoceruloplasmin to form ceruloplasmin resulting in excessive accumulation of copper in the liver and extrahepatic tissues. Clinical features of Wilson’s disease therefore result from toxic accumulation of copper in liver, brain and kidney
Earlier the diagnosis of Wilson’s disease was entirely suspected based on the neurological manifestations and associated liver complications, but this dramatically changed when Kayser-Fleischer (K-F) rings were identified as present in a subset of clinically affected patients. K-F ring is mainly present in neuro Wilson’s disease patients. K-F ring, a rusty brown ring around the cornea is the single most important diagnostic sign in neroWilson’s disease. It is found in 95% of patients belonging to neuro WD but it is not entirely specific for Wilson’s disease diagnosis. Diagnostic testing of Wilson’s disease improved in the last decades by the incorporating of routine testing for liver biochemical parameters and liver biopsy to evaluate histology, quantify hepatic copper concentration, measure elevated 24 hr urine copper excretion. The plasma ceruloplasmin concentrations, another important biochemical parameter, is routinely recommended for the preliminary screening even though its levels overlap with other diseases as well.
Most of these biochemical parameters are not reliable for the diagnosis of Wilson’s disease and are many occasions, time consuming. These biochemical parameters can also overlap with other liver related diseases as well. Along with the phenotypic characterization of patients most of the time clinicians are now dependent on the molecular genetic testing of Wilson's disease gene, ATP7B for confirmation of the diagnosis.
The last decade has seen the rapid development in genetic technologies which has made genetic testing affordable. Consequently, a number of studies have reported genetic variations in Wilson's disease from across the world. In addition, some of the genetic variants are characterised by severe or mild phenotypes which makes molecular diagnosis an important part of the prognostication and management of the disease. A number of groups have previously attempted to create a comprehensive resource integrating data and genetic evidence on Wilson's disease. The major limitation in such an approach was the lack of a uniform system to annotate the pathogenicity of generic variants for clinical interpretation, which precluded their widespread application in clinical settings.
The recent guidelines on the annotation of genetic sequences variants put forward by the American College of Medical Genetics and the Association of Molecular Pathologists provides a uniform framework for systematic integration of evidence on each of the variants and classifies them based on the evidence obtained to infer their pathogenicity.
The WilsonGen resource for Clinical Genomics of Wilson’s Disease
We at CSIR-IGIB have created a comprehensive resource of genetic variants in ATP7B gene and systematically annotated using the ACMG & AMP guidelines for assessing pathogenicity. The resource therefore serves as a central point for clinicians and geneticists working on WD and to the best of our knowledge is the most comprehensive and only clinically annotated resource for WD. The resource is available at URL http://clingen.igib.res.in/WilsonGen/. This is the largest Wilson's disease genetic variants resource comprising 656 pathogenic/likely pathogenic variants reported classified according to ACMG & AMP guidelines.
Early diagnosis of Wilson's disease would enable clinicians to initiate early treatment to prevent morbidity and mortality. Prognosis of Wilson's disease therefore depends on early diagnosis and institution of chelation therapy before irreversible damage occurs. Owing to the non-specificity of biochemical tests, molecular genetic confirmation enables accurate diagnosis of Wilson's disease.
There are more than 600 disease causing variants (including deletions, substitutions, duplications and SNPs) in the gene ATP7B. Generally, a very limited number of mutations are screened largely owing to logistic constraints. Unfortunately, neither a comprehensive epidemiological survey nor a Pan-India level molecular genetics study has been performed from India so far with limited attempt at genotypic phenotypic correlation among WD patients within the regional confines in the country.
Indian Collaborative Research on Wilson’s Disease
While a number of studies previously attempted to characterise the clinical and molecular characteristics of Wilson's disease in India, many of the studies were from single centres, limiting the applicability of the findings for diagnosis and treatment across the country. This was due to the gap in a systematic and collaborative approach to understand the disease and also engage clinicians and clinical researchers on a unified platform and protocol.
The Indian Collaborative Research on Wilson’s Disease (ICROWD) is a multi-institutional research effort initiated at CSIR-IGIB as part of the GUaRDIAN initiative on Rare Genetic Diseases to understand the clinical and molecular characteristics of Wilson's disease. The initiative fills in the gap of systematic understanding of the genetic epidemiology and genotype phenotype correlations in WD. Through a pan-Indian collaborative network, the initiative provides clinical workup, molecular characterization and key insights into the disease pathophysiology and progression. The ICROWD is a pan-India network encompassing over 60 clinicians and researchers from over 20 clinical and research centres across the country working in the area of WD. Going further, the major emphasis of the programme would be to build methods and tools for clinical scale validation of pathogenicity of variants.
The Indian Collaborative Research on Wilson’s Disease (ICROWD) is a multi-institutional research effort initiated at CSIR-IGIB as part of the GUaRDIAN initiative on Rare Genetic Diseases to understand the clinical and molecular characteristics of Wilson's disease. The initiative fills in the gap of systematic understanding of the genetic epidemiology and genotype phenotype correlations in WD. Through a pan-Indian collaborative network, the initiative provides clinical workup, molecular characterization and key insights into the disease pathophysiology and progression. The ICROWD is a pan-India network encompassing over 60 clinicians and researchers from over 20 clinical and research centres across the country working in the area of WD. Going further, the major emphasis of the programme would be to build methods and tools for clinical scale validation of pathogenicity of variants.
The programme extensively uses cellular systems, model organisms and patients specific cell lines to understand the molecular correlates of disease pathophysiology as well as for the validation of pathogenicity of variants identified. This approach utilises the power of genome-editing using CRISPR-Cas technologies for gene correction as well as cellular and molecular systems for readout. In our hope, going forward this would help provide a precise understanding of genotype phenotype correlations and potentially lead to insights which could help in better management of the disease as well as for development of novel strategies for therapy.
References
Kumar, M., Gaharwar, U., Paul, S. et al.
WilsonGen a comprehensive clinically annotated genomic variant resource for Wilson’s Disease.
Sci Rep 10, 9037 (2020). https://doi.org/10.1038/s41598-020-66099-2
About the Author
Dr Binukumar BK is a senior scientist at the CSIR Institute of Genomics and Integrative Biology (CSIR-IGIB) in Delhi. All opinions expressed in this article are personal. More about his research can be found at BK Lab page
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