Opportunities and challenges for the computational interpretation of rare variation in clinically important genes.

Journal: American journal of human genetics
PMID: 33798442

Abstract

Genome sequencing is enabling precision medicine-tailoring treatment to the unique constellation of variants in an individual's genome. The impact of recurrent pathogenic variants is often understood, however there is a long tail of rare genetic variants that are uncharacterized. The problem of uncharacterized rare variation is especially acute when it occurs in genes of known clinical importance with functionally consequential variants and associated mechanisms. Variants of uncertain significance (VUSs) in these genes are discovered at a rate that outpaces current ability to classify them with databases of previous cases, experimental evaluation, and computational predictors. Clinicians are thus left without guidance about the significance of variants that may have actionable consequences. Computational prediction of the impact of rare genetic variation is increasingly becoming an important capability. In this paper, we review the technical and ethical challenges of interpreting the function of rare variants in two settings: inborn errors of metabolism in newborns and pharmacogenomics. We propose a framework for a genomic learning healthcare system with an initial focus on early-onset treatable disease in newborns and actionable pharmacogenomics. We argue that (1) a genomic learning healthcare system must allow for continuous collection and assessment of rare variants, (2) emerging machine learning methods will enable algorithms to predict the clinical impact of rare variants on protein function, and (3) ethical considerations must inform the construction and deployment of all rare-variation triage strategies, particularly with respect to health disparities arising from unbalanced ancestry representation.

Authors

  • Gregory McInnes
    Biomedical Informatics Training Program, Stanford University, Stanford, California, United States of America.
  • Andrew G Sharo
    Biophysics Graduate Group, University of California, Berkeley, Berkeley, CA 94720, USA; Department of Plant and Microbial Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
  • Megan L Koleske
    Department of Bioengineering and Therapeutics, University of California, San Francisco, San Francisco, CA 94143, USA.
  • Julia E H Brown
    Program in Bioethics, University of California, San Francisco, San Francisco, CA 94143, USA; Institute for Health & Aging, University of California, San Francisco, San Francisco, CA 94143, USA.
  • Matthew Norstad
    Program in Bioethics, University of California, San Francisco, San Francisco, CA 94143, USA; Institute for Health & Aging, University of California, San Francisco, San Francisco, CA 94143, USA.
  • Aashish N Adhikari
    Institute for Human Genetics, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Plant and Microbial Biology, University of California, Berkeley, Berkeley, CA 94720, USA; Illumina, Inc., Foster City, CA 94404, USA.
  • Sheng Wang
    Intensive Care Medical Center, Tongji Hospital, School of Medicine, Tongji University, Shanghai, 200065, People's Republic of China.
  • Steven E Brenner
    Department of Plant and Microbial Biology, University of California, Berkeley, California, USA.
  • Jodi Halpern
    School of Public Health, University of California Berkeley, Berkeley, CA, USA.
  • Barbara A Koenig
    Program in Bioethics, University of California, San Francisco, San Francisco, CA 94143, USA; Institute for Health & Aging, University of California, San Francisco, San Francisco, CA 94143, USA; Institute for Human Genetics, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Social & Behavioral Sciences, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Humanities & Social Sciences, University of California, San Francisco, San Francisco, CA 94143, USA.
  • David C Magnus
    From the Department of Radiology, Stanford University School of Medicine, 300 Pasteur Dr, Stanford, CA 94305-5105.
  • Renata C Gallagher
    Institute for Human Genetics, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Pediatrics, University of California, San Francisco, San Francisco, CA 94143, USA.
  • Kathleen M Giacomini
    Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, 94158, California, USA.
  • Russ B Altman
    Departments of Medicine, Genetics and Bioengineering, Stanford University, Stanford, California, United States of America.

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