Sep 17, 2013

A systematic approach to assessing the clinical significance of genetic variants

Clinical Genetics
H DuzkaleMatthew S Lebo

Abstract

Molecular genetic testing informs diagnosis, prognosis, and risk assessment for patients and their family members. Recent advances in low-cost, high-throughput DNA sequencing and computing technologies have enabled the rapid expansion of genetic test content, resulting in dramatically increased numbers of DNA variants identified per test. To address this challenge, our laboratory has developed a systematic approach to thorough and efficient assessments of variants for pathogenicity determination. We first search for existing data in publications and databases including internal, collaborative and public resources. We then perform full evidence-based assessments through statistical analyses of observations in the general population and disease cohorts, evaluation of experimental data from in vivo or in vitro studies, and computational predictions of potential impacts of each variant. Finally, we weigh all evidence to reach an overall conclusion on the potential for each variant to be disease causing. In this report, we highlight the principles of variant assessment, address the caveats and pitfalls, and provide examples to illustrate the process. By sharing our experience and providing a framework for variant assessment, includi...Continue Reading

  • References44
  • Citations62

References

  • References44
  • Citations62

Citations

Mentioned in this Paper

Genetic Screening Method
Computer Programs and Programming
High-Throughput Nucleotide Sequencing
Poly(A) Tail
Online Mendelian Inheritance In Man
In Vitro [Publication Type]
Decision Trees
High-Throughput DNA Sequencing
Benefit-Risk Assessment
Variation (Genetics)

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