Rare diseases or orphan diseases are defined as a condition that affects fewer than 200,000 people in the U.S. This definition was created by Congress in the Orphan Drug Act of 1983, and there may be as many as 7,000 rare diseases. The total number of Americans living with a rare disease is estimated at 25-30 million. However, if global prevalence is considered, rare diseases are not that rare and are known to affect more than 350 million people. Most of the rare diseases (approximately 55% of the 7,000 cataloged rare diseases) can be explained by a genetic cause.
Impact of Delayed Diagnosis
Many patients and their families undergo an excruciating diagnostic odyssey involving years of multi-modality evaluations. This mainly due to a lack of clear guidelines for the diagnostic evaluations of rare diseases, Due to the delay in deciphering an accurate diagnosis, valuable time is lost that could be utilized for treatment intervention, changes in medical management, and use of occupational/physical and/or speech therapies.
With the advent of next-generation sequencing technology, it is now possible to use a single all-encompassing test to diagnose most genetic disorders. This comprehensive test is called Whole Genome Sequencing (WGS).
WGS is capable of detecting a wide spectrum of genetic abnormalities like single nucleotide variants (SNV), structural variants (SV), copy number variants (CNV), as well as repeat disorders in coding and non-coding regions.
WGS has the potential to deliver genetic diagnoses with a high level of accuracy, thereby possibly eliminating or reducing the duration of the patient’s diagnostic odyssey. However, clinical implementation of WGS in genetic diagnostic laboratories is still riddled with many technical and informatics challenges.
Importance of Best Practices and Common Standards
Currently, common acceptable international standards for WGS does not exist. Developing standards for WGS will help inexperienced diagnostic laboratories to reliably offer this powerful tool for the benefit of rapidly and accurately diagnosing rare diseases. However, developing standards for clinical WGS is particularly challenging due to the broad range of clinical settings, test indications, and rapidly evolving technical improvements.
The Medical Genome Initiative (MGI) was formed in recognition of these challenges and the need for best practice consensus recommendations to guide the implementation of WGS for clinical care. The main goal and mission of MGI is to expand access to high-quality clinical WGS for the diagnosis of genetic diseases, through the publication of common laboratory and clinical best practices.
Furthermore, MGI is a consortium comprised of leading North American healthcare and research organizations and is governed by a steering committee comprised of one representative from each member institution. Representation includes the following organizations:
- Baylor College of Medicine
- Broad Institute of MIT and Harvard
- Hudson Alpha Institute for Biotechnology
- Illumina Inc.
- Mayo Clinic
- New York Genome Center
- Rady Children’s Hospital
- Stanford Health Care
- The Hospital for Sick Children
Baylor Genetics’ Contribution to MGI
Dr. Shashikant Kulkarni, CSO and SVP at Baylor Genetics, currently serves as a Chairperson of MGI. Dr. Pengfei Liu, Associate Clinical Director at Baylor Genetics, has also contributed towards these guidelines.
The MGI consortium has published three seminal publications towards defining best practices in WGS
- The Medical Genome Initiative: Moving Whole-Genome Sequencing for Rare Disease Diagnosis to the Clinic.
- This article provided the overview of MGI goals and background of the current status 2.
- Best Practices for the Analytical Validation of Clinical Whole-Genome Sequencing Intended for the Diagnosis of Germline Disease.
- Published by NPJ Genome Medicine
- This paper presents consensus recommendations on clinical WGS analytical validation for the diagnosis of individuals with suspected germline disease, including practical advice for test development optimization, validation practices and ongoing quality management 3.
- Clinical utility of genomic testing: A measurement toolkit.
- Whole genome sequencing is emerging as the most robust strategy for achieving timely diagnoses in undiagnosed rare disease populations. Evidence of clinical utility and cost-effectiveness is required for WGS to be accepted into practice, commissioned in a health system, or receive reimbursement. Defining and measuring clinical utility is complex and context specific. This publication addresses the need to develop a standardized framework and define measurement best practices to optimize the evidence base for decision makers and health care systems invested in providing high quality genome diagnostics 4.
- Ferreira CR. The burden of rare diseases. Am J Med Genet A. 2019;179(6):885–92.
- Marshall, C.R., Bick, D., Belmont, J.W., Taylor SL., Ashley E, Dimmock D, Jobanputra V., Kearney HM., Kulkarni S., Rehm H. The Medical Genome Initiative: moving whole-genome sequencing for rare disease diagnosis to the clinic. Genome Med. 2020; 12:48. https://doi.org/10.1186/s13073-020-00748
- 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. Analytical validation of clinical whole genome sequencing for germline disease diagnostics: Best practices and performance standards.
- Hayeems RZ, Dimmock DP, Bick DP, Belmont JW, Green RC, Lanpher B, Jobanputra V, Mendoza R, Kulkarni S, Grove ME, Taylor SL, Ashley E, on behalf of the Medical Genome Initiative. Clinical utility of genomic testing: A measurement toolkit. NPJ Medicine (IN PRESS)