Medical Genome Initiative Resources and Publications

Analytical Validation of Clinical Whole Genome Sequencing for Germline Disease Diagnostics: Best Practices and Performance Standards
Marshall CR, Chowdhury S, Taft RJ, Lebo MS, Buchan JG, Harrison SM, Rowsey R, Klee EW, Liu P, Worthey EA, Jobanputra V, Dimmock D, Kearney HM, Bick D, Kulkarni S, Belmont JW, Stavropoulos DJ, Lennon NJ, on behalf of the Medical Genome Initiative.

Whole-genome sequencing (WGS) has shown promise in becoming a first-tier diagnostic test for patients with rare genetic disorders, however, standards addressing the definition and deployment practice of a best-in-class test are lacking. To address these gaps, the Medical Genome Initiative, a consortium of leading health care and research organizations in the US and Canada, was formed to expand access to high quality clinical WGS by publishing best practices. Here, we present consensus recommendations on clinical WGS analytical validation with a focus on test development, upfront considerations for test design, test validation practices, and metrics to monitor test performance. This work also provides insight into the current state of WGS testing at each member institution, including the utilization of reference and other standards across sites. Importantly, members of this Initiative strongly believe that clinical WGS is an appropriate first-tier test for patients with rare genetic disorders and at minimum is ready to replace chromosomal microarray analysis and whole-exome sequencing. The recommendations presented here should reduce the burden on laboratories introducing WGS into clinical practice and support safe and effective WGS testing for diagnosis of germline disease.

*This manuscript is currently under review and may be accessed here. Feedback from the community is encouraged and appreciated. Please send your comments to

Rare Disease Statistics

Up to 3.5-5.9%

of the population worldwide is affected by a rare disease (RD).1-6

Over 7,000

rare diseases have been identified.1,3,6,7

Among rare diseases listed by Orphanet,

~80% are either exclusively genetic or have genetic subtypes.8

Half of Rare Disease cases impact children

and 30% of children affected by a RD will not survive beyond the age of 5 years.3,6

The average diagnostic odyssey lasts approximately

5-7 years.


Average healthcare cost per discharge is

$12,000-$77,000 higher

in patients with a confirmed genetic diagnosis or other indicators of genetic disease compared to those without.11

For critically ill infants with a Rare Disease, a rapid diagnosis can be critical for timely and appropriate medical intervention.
An early diagnosis can prevent a long, expensive diagnostic journey.12-15

Genetic Testing Approaches for Rare Disease Diagnosis

  • Current standard of care for rare disease may include single gene testing, multi-gene panel testing, chromosomal microarray (CMA) and/or whole-exome sequencing (WES).
  • Whole genome sequencing (WGS) is the only test that can detect nearly all types of genetic variants. (Table 1) 16,17


Table 1


  1. Nguengang Wakap, S, Lambert DM, Orly A, et al. Europ J Hum Genet.2019:
  2. Ferreira CR. The Burden of Rare Diseases. American Journal of Medical Genetics. 2019;179(6):885-892.
  3. Eurodis. About rare diseases. Accessed October 18, 2019.
  4. Genetic and Rare Disease Information Center. FAQs about rare disease. Updated November 30, 2017. Accessed October 18, 2019
  5. Posada De La Paz, M. et al. Rare Diseases Epidemiology: Update and Overview. Advances in Experimental Medicine and Biology. 2017; 1031:589-604.
  6. Global Genes. Rare disease facts. Accessed October 18, 2019.
  7. Online Mendelian Inheritance in Man. Updated October 17, 2019. Accessed October 18, 2019.
  8. Bick D, Jones M, Taylor SL, et al. Case for genome sequencing in infants and children with rare, undiagnosed or genetic diseases. Journal of Medical Genetics. Published Online First: 25 April 2019. doi: 10.1136/jmedgenet-2019-106111
  9. Orphanet. About Rare Diseases. Updated October 18, 2019. Accessed October 18, 2019.
  10. Global Commission. Ending the diagnostic odyssey for children with a rare disease. Published February 19, 2019. Accessed October 18, 2019.
  11. Gonzaludo N, Belmont JW, Gainullin VG, Taft RJ. Estimating the burden and economic impact of pediatric genetic disease. Gen Med. 2018;
  12. Soden SE, Saunders CJ, Willig LK, et al. Effectiveness of exome and genome sequencing guided by acuity of illness for diagnosis of neurodevelopmental disorders. Sci Transl Med. 2014;6(265): 265ra168.
  13. Petrikin JE, Cakici JA, Clark MM, et al. The NSIGHT1-randomized controlled trial: rapid whole-genome sequencing for accelerated etiologic diagnosis in critically ill infants. NPJ Genom Med. 2018 Feb 9;3:6. doi: 10.1038/s41525-018-0045-8.
  14. Willig LK, Petrikin JE, Smith LD, et al. Whole-genome sequencing for identification of Mendelian disorders in critically ill infants: a retrospective analysis of diagnostic and clinical findings. Lancet Respir Med. 2015;3(5): 377–387. doi:10.1016/S2213-2600(15)00139-3.
  15. Kingsmore F, Cakici JA, Clark MM et al. A randomized controlled trial of the analytic and diagnostic performance of singleton and trio, rapid genome and exome sequencing in ill infants. A J Hum Gen, 2019;105:1-15.
  16. Lionel AC, Costain G, Monfared N, et al. Improved diagnostic yield compared with targeted gene sequencing panels suggests a role for whole-genome sequencing as a first-tier genetic test. Genet Med. 2017; Aug 3. doi: 10.1038/gim.2017.119.
  17. Sanghvi RV,Buhay CJ, Powell, V et al. Characterizing reduced coverage regions through comparison of exome and genome sequencing data across 10 centers. Genet Med. 2017; doi:
  18. Dolzhenko E, van Vugt JJ, Shaw RJ, et al. Detection of long repeat expansions from PCR-free whole-genome sequence data. Genome Res. 2017; 27(11):1895-1903. doi: 10.1101/gr.225672.117
  19. Chen, X., Schulz-Trieglaff, O., Shaw, R., et al. Manta: Rapid detection of structural variants and indels for germline and cancer sequencing applications. Bioinformatics, 2016;32(8):1220–1222.

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