{"title":"The Genomic Landscape of Wilson Disease in a Pan India Disease Cohort and Population-Scale Data.","authors":"Mukesh Kumar, Srishti Sharma, Sanjay Pandey, Geetha Mammayil, Aslam Pala Kuzhiyil, Srijaya Sreesh, Riyaz Arakkal, Divya M Radhakrishnan, Roopa Rajan, Deepak Amalnath, Reena Gulati, Naresh Tayade, Shine Sadasivan, Arun Valsan, Jagadeesh Menon, Mahesh Kamate, Sandeep Kumar Mathur, Radha Mahadevan, Bhavna Dhingra, Rajneesh Rajan, Kuldeep Singh, Shalimar, Suja K Geevarghese, Vikram S Kumar, John Menachery, Aminu Aliyar, Rahul C Bhoyar, Bani Jolly, Abhinav Jain, Arvinden Vittal Rangan, Trisha Moitra, Aditi Mhaske, Vishu Gupta, Vigneshwar Senthivel, Anushree Mishra, Arti Saini, Utkarsh Gaharwar, Sridhar Sivasubbu, Vinod Scaria, Binukumar B K","doi":"10.1002/mdc3.14266","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Wilson's disease (WD) results from pathogenic ATP7B gene variations, causing copper accumulation mainly in the liver, brain, and kidneys.</p><p><strong>Objectives: </strong>In India, despite studies on ATP7B variants, WD often goes undiagnosed, with the prevalence, carrier rate, and mutation spectrum remaining unknown.</p><p><strong>Methods: </strong>A multicenter study examined genetic variations in WD among individuals of Indian origin via whole exome sequencing. The study used the InDelible structural variants calling pipeline and conducted molecular dynamic simulations on variants of uncertain significance (VUS) in ATP7B AlphaFold protein structures. Additionally, a high-throughput gene screening panel for WD was developed.</p><p><strong>Results: </strong>This study examined 128 clinically diagnosed cases of WD, revealing 74 genetically confirmed cases, 22 with ATP7B variants, and 32 without. Twenty-two novel ATP7B gene variants were identified, including a 322 bp deletion classified as a structural variant. Molecular dynamics simulations highlighted the potential deleterious effects of 11 ATP7B VUS. Gene burden analysis suggested associations with ANO8, LGR4, and CDC7. ATP7B gene hotspots for pathogenic variants were identified. Prevalence and carrier rates were determined as one in 18,678 and one in 67, respectively. A multiplex sequencing panel showed promise for accurate WD diagnosis.</p><p><strong>Conclusions: </strong>This study offers crucial insights into WD's genetic variations and prevalence in India, addressing its underdiagnosis. It highlights the novel genetic variants in the ATP7B gene, the involvement of other genes, a scalable, cost-effective multiplex sequencing panel for WD diagnosis and management and promising advancements in WD care.</p>","PeriodicalId":19029,"journal":{"name":"Movement Disorders Clinical Practice","volume":" ","pages":""},"PeriodicalIF":2.6000,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Movement Disorders Clinical Practice","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1002/mdc3.14266","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CLINICAL NEUROLOGY","Score":null,"Total":0}
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Abstract
Background: Wilson's disease (WD) results from pathogenic ATP7B gene variations, causing copper accumulation mainly in the liver, brain, and kidneys.
Objectives: In India, despite studies on ATP7B variants, WD often goes undiagnosed, with the prevalence, carrier rate, and mutation spectrum remaining unknown.
Methods: A multicenter study examined genetic variations in WD among individuals of Indian origin via whole exome sequencing. The study used the InDelible structural variants calling pipeline and conducted molecular dynamic simulations on variants of uncertain significance (VUS) in ATP7B AlphaFold protein structures. Additionally, a high-throughput gene screening panel for WD was developed.
Results: This study examined 128 clinically diagnosed cases of WD, revealing 74 genetically confirmed cases, 22 with ATP7B variants, and 32 without. Twenty-two novel ATP7B gene variants were identified, including a 322 bp deletion classified as a structural variant. Molecular dynamics simulations highlighted the potential deleterious effects of 11 ATP7B VUS. Gene burden analysis suggested associations with ANO8, LGR4, and CDC7. ATP7B gene hotspots for pathogenic variants were identified. Prevalence and carrier rates were determined as one in 18,678 and one in 67, respectively. A multiplex sequencing panel showed promise for accurate WD diagnosis.
Conclusions: This study offers crucial insights into WD's genetic variations and prevalence in India, addressing its underdiagnosis. It highlights the novel genetic variants in the ATP7B gene, the involvement of other genes, a scalable, cost-effective multiplex sequencing panel for WD diagnosis and management and promising advancements in WD care.
期刊介绍：
Movement Disorders Clinical Practice- is an online-only journal committed to publishing high quality peer reviewed articles related to clinical aspects of movement disorders which broadly include phenomenology (interesting case/case series/rarities), investigative (for e.g- genetics, imaging), translational (phenotype-genotype or other) and treatment aspects (clinical guidelines, diagnostic and treatment algorithms)
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