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Missing heritability of Wilson disease: a search for the uncharacterized mutations

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Abstract

Wilson disease (WD), a copper metabolism disorder caused by mutations in ATP7B, manifests heterogeneous clinical features. Interestingly, in a fraction of clinically diagnosed WD patients, mutations in ATP7B appears to be missing. In this review we discuss the plausible explanations of this missing heritability and propose a workflow that can identify the hidden mutations. Mutation analyses of WD generally includes targeted sequencing of ATP7B exons, exon–intron boundaries, and rarely, the proximal promoter region. We propose that variants in the distal cis-regulatory elements and/or deep intronic variants that impact splicing might well represent the hidden mutations. Heterozygous del/ins that remain refractory to conventional PCR-sequencing method may also represent such mutations. In this review, we also hypothesize that mutations in the key copper metabolism genes, like, ATOX1, COMMD1, and SLC31A1, could possibly lead to a WD-like phenotype. In fact, WD does present overlapping symptoms with other rare genetic disorders; hence, the possibility of a misdiagnosis and thus adding to missing heritability cannot be excluded. In this regard, it seems that whole-genome analysis will provide a comprehensive and rapid molecular diagnosis of WD. However, considering the associated cost for such a strategy, we propose an alternative customized screening schema of WD which include targeted sequencing of ATP7B locus as well as other key copper metabolism genes. Success of such a schema has been tested in a pilot study.

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Acknowledgements

We are thankful to the Wilson’s disease patients and their family members. SR was supported by UGC-JRF fellowship from UGC, Govt. of India and SG was supported by a fellowship from DST-SERB, Govt. of India.

Funding

This study received no funding support.

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Author notes

  1. Shubhrajit Roy

    Present address: Post-doctoral Fellow, Physiology Department, Johns Hopkins University, Baltimore, USA

  2. Sampurna Ghosh

    Present address: Department of Biochemistry, Microbiology and Immunology, University of Saskatchewan, Saskatoon, Canada

Authors and Affiliations

  1. S. N. Pradhan Centre for Neurosciences, University of Calcutta, Kolkata, India

    Shubhrajit Roy & Jharna Ray

  2. Department of Genetics, University of Calcutta, 35 Ballygunge Circular Road, Kolkata, 700019, India

    Sampurna Ghosh & Mainak Sengupta

  3. Ramakrishna Mission Vivekananda Educational and Research Institute, Narendrapur, Kolkata, 700 103, India

    Kunal Ray

Authors
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  3. Jharna Ray
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  4. Kunal Ray
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  5. Mainak Sengupta
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Contributions

SR provided pipeline for selecting cis-regulatory element from ENCODE database and contributed to analysis of the result and drafted the manuscript; SG performed in silico analysis following the pipeline for selecting cis-regulatory element from ENCODE database; JR contributed to overall supervision of the project and reviewing of the manuscript; KR contributed to conceptualization of the study critical review of the manuscript and other intellectual inputs; MSG contributed to conceptualization of the study, overall supervision of the project, and reviewing of the manuscript.

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Correspondence to Kunal Ray or Mainak Sengupta.

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Roy, S., Ghosh, S., Ray, J. et al. Missing heritability of Wilson disease: a search for the uncharacterized mutations. Mamm Genome 34, 1–11 (2023). https://doi.org/10.1007/s00335-022-09971-y

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