Rare Disease Whole-Genome Sequencing

The most comprehensive test for rare disease

Whole-genome sequencing offers the highest likelihood of finding a diagnosis for rare genetic disease

Benefits of WGS for Rare Disease

Whole-genome sequencing (WGS) for rare disease offers three key advantages over other genetic testing methods:

  1. Potential for superior diagnostic yield
  2. Improved operational efficiency
  3. Decreased cost

Especially important for rare disease cases, whole-genome sequencing is the most comprehensive test for detecting multiple variant types in a single assay.1–8 In a large, randomized controlled trial, the median time to diagnosis in neonatal intensive and pediatric intensive care patients was 13 days with WGS, compared to 107 days with standard testing.9

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Many Different Variant Types are Pathogenic for Rare Disease Cases

WGS testing performed in the Illumina Clinical Services Laboratory represents individuals enrolled in disease-specific clinical trials or as part of philanthropic efforts. As such, the percentage represented here may not be typical of that seen in a standard laboratory. This data is based on 669 total cases.

WGS Can End Rare Disease Diagnostic Odysseys

Whole-genome sequencing for rare disease has the power to help doctors diagnose genetic diseases quickly, helping families avoid long diagnostic odysseys. Of all genomic testing methods, WGS offers the highest likelihood of finding a diagnosis.10 It provides the highest coverage of the human genome, not only in regions not covered by other methods, but even within regions targeted by other methods.11,12 This increased coverage at first-line usage has been shown to reduce the need for unnecessary iterative tests and reduce the length of stay in the NICU.13,14

WGS can also impact patient care. A change in management has been reported in 49–75% of pediatric outpatients who received a diagnosis by WGS.15,16

Expanding Access to WGS for Rare Diseases

By publishing best practices, the Medical Genome Initiative aims to expand access to high-quality WGS for genetic disease diagnosis.

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WGS Identifies Causes of Rare Disease

Ending Sawyer’s 8-Year Diagnostic Odyssey

Sawyer was admitted to the NICU at birth, but he and his family left the hospital without a diagnosis. The next 8 years involved failed targeted sequencing, chromosomal microarray analysis (CMA), and whole-exome sequencing tests. Finally, whole-genome sequencing identified a TRIP12 variant causing Sawyer’s condition.

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A Decade Later, A Diagnosis for Sophia

After seven years and dozens of specialists, genetic tests, and MRIs, Sophia and her family were exhausted and left without an answer. Two years later, WGS enabled Sophia’s medical team to identify a WDR45 mutation and diagnose her with Beta-propeller protein-associated neurodegeneration (BPAN).

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Online Course: Clinical Sequencing in Rare Disease

This course offers an overview of pediatric rare disease, available testing options, and clinical implementation of genomic sequencing. It may be relevant to laboratory providers, healthcare providers, healthcare organizations, and others interested in a review of genomics in the rare disease population. This course was made possible through an educational grant from Illumina.

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Hear from Experts on Rare Disease WGS

Standardization of Clinical WGS for Rare Disease

Dr. Christian Marshall of The Hospital for Sick Children explains how laboratory and clinical best practices can enable whole-genome sequencing for genetic disease diagnosis.

WGS and the End of the Diagnostic Odyssey

Dr. Vandana Shashi of Duke University and Kimberly LeBlanc of the Undiagnosed Diseases Network discuss how WGS can short-circuit the diagnostic odyssey for patients with rare disease.

Rapid Whole-Genome Sequencing of Critically Ill Children

Dr. Shimul Chowdhury of Rady Pediatric Genomic and Systems Medicine Institute explains how rapid WGS can help pinpoint the causes of rare disease in children.

Rare Disease News

Study Assesses WGS in Newborns with Suspected Rare Disease

NICUSeq is a multi-center research study evaluating whether the clinical management of acutely ill newborns is altered with WGS.

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Whole-Genome Sequencing for NICU Infants in California

Project Baby Bear is a pilot program studying the use of WGS for rapid diagnosis and early treatment of infants at neonatal intensive care sites.

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LeukoSEQ Evaluates Sequencing as Diagnostic Tool for Rare Disease

LeukoSEQ is a clinical trial designed to evaluate whole-genome sequencing as a first-line diagnostic tool for leukodystrophies.

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Featured Rare Disease WGS Publications

Medical Genome Initiative Provides WGS Guidance for Rare Disease Cases

WGS offers clear diagnostic benefits for patients with rare disease, but there are barriers to widespread adoption. The Medical Genome Initiative supports standards development for clinical WGS.

WGS as a First-line Test for Intellectual Disability

Different types of genetic variants underlie intellectual disability. This study evaluates WGS versus chromosomal microarray analysis (CMA) as a first-line diagnostic test.

WGS as a First-tier Test at a Dysmorphology Clinic in Mexico

The diagnostic odyssey is often amplified for patients in resource-limited areas. In this paper, the authors report on the impact of making WGS available to these patients.

  1. 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.
  2. Sanghvi RV, Buhay CJ, Powell BC, et al. Characterizing reduced coverage regions through comparison of exome and genome sequencing data across 10 centers. Genet Med. 2018;20(8):855-866. doi:10.1038/gim.2017.192
  3. Dolzhenko E, van Vugt JJFA, 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
  4. Gross A, Ajay SS, Rajan V, et al. Copy number variants in clinical WGS: deployment and interpretation for rare and undiagnosed disease. Genetic Med. 2019;21(5):1121-1130.
  5. Alfares A, Aloraini T, Subaie LA, et al. Whole-genome sequencing offers additional but limited clinical utility compared with reanalysis of whole-exome sequencing. Genet Med. 2018;20(11):1328-1333. doi:10.1038/gim.2018.41
  6. Lindstrand A, Eisfeldt J, Pettersson M, et al. From cytogenetics to cytogenomics: whole genomes sequencing as a first-line test comprehensively captures the diverse spectrum of disease-causing genetic variation underlying intellectual disability. Genome Med. 2019;11(1):68.
  7. Chen, X, Sanchis-Juan, A., French, CE et al. Spinal muscular atrophy diagnosis and carrier screening from genome sequencing data. Genet Med. 2020; 22:945–953. https://doi.org/10.1038/s41436-020-0754-0
  8. 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. http://doi.org/10.1093/bioinformatics/btv710.
  9. 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;3:6. Published 2018 Feb 9. doi:10.1038/s41525-018-0045-8
  10. Clark, M.M., Stark, Z., Farnaes, L. et al. Meta-analysis of the diagnostic and clinical utility of genome and exome sequencing and chromosomal microarray in children with suspected genetic diseases. npj Genomic Med. 2018;3:16. https://doi.org/10.1038/s41525-018-0053-8
  11. Meienberg J, Bruggmann R, Oexle K, Matyas G. Clinical sequencing: is WGS the better WES? Hum Genet. 2016;135(3):359-362. doi:10.1007/s00439-015-1631-9
  12. Belkadi A, Bolze A, Itan Y, et al. Whole-genome sequencing is more powerful than whole-exome sequencing for detecting exome variants. Proc Natl Acad Sci U S A. 2015 Apr 28;112(17):5473-8. doi: 10.1073/pnas.1418631112
  13. Farnaes L, Hildreth A, Sweeney NM, et al. Rapid whole-genome sequencing decreases infant morbidity and cost of hospitalization. NPJ Genom Med. 2018;3:10. Published 2018 Apr 4. doi:10.1038/s41525-018-0049-4
  14. Stark Z, Lunke S, Brett GR, et al. Meeting the challenges of implementing rapid genomic testing in acute pediatric care. Genet Med. 2018;20(12):1554-1563. doi:10.1038/gim.2018.37
  15. Scocchia A, Wigby KM, Masser-Frye D, et al. Clinical whole genome sequencing as a first-tier test at a resource-limited dysmorphology clinic in Mexico. NPJ Genom Med. 2019;4:5. Published 2019 Feb 14. doi:10.1038/s41525-018-0076-1
  16. Bick D, Fraser PC, Gutzeit MF, et al. Successful application of whole genome sequencing in a medical genetics clinic. J Pediatr Genet. 2016;6(2):61-76.