Rare Disease Genomics

Committed to ending diagnostic odysseys for rare disease

Technology innovation and collaboration in health care to ensure families receive a diagnosis early

Rare Disease Genomics and Precision Medicine

Understanding the genomics of rare disease can help doctors pinpoint the cause of undiagnosed disorders, helping families avoid years of hospital visits and unnecessary tests. Although the definition of rare disease varies across the globe, they affect 1 in 2,000 people.1,2 There are more than 7,000 known rare diseases3 and more discovered every year. Collectively, 2–6% of the population (> 150 million people) is affected by a rare disease.3,4,5

On average, the long search for a rare disease diagnosis—the “diagnostic odyssey”—takes 5 to 7 years,6 8 physicians,7 and 2 to 3 misdiagnoses.7 Given that 80% of rare diseases are genetic or have a genetic component, comprehensive genomic sequencing increases the potential of uncovering an underlying etiology in patients.8 Next-generation sequencing (NGS) offers the highest likelihood of rare disease diagnosis9,10 and the fastest path to ending the diagnostic odyssey.9

The Future is Now for Rare Disease Genomics

Learn how whole-genome sequencing can be deployed to hunt for a diagnosis and bring new levels of understanding in ending the diagnostic odyssey.

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The Value of Genomics for Rare Disease Diagnosis

Genomics is driving a fundamental shift in rare disease diagnosis, from symptom analysis to molecular etiology assessment. Understanding the biological basis of disease can lead to better care and targeted treatment, with predictable, evidence-based outcomes. This type of molecular diagnosis in rare disease genomics is the basis for precision medicine.

Molecular diagnosis of rare disease is a critical step that can benefit patients, their families, physicians, and other care providers. According to the American College of Genetics and Genomics (ACMG), the identification of the genetic etiology of an individual’s disease has utility for the patient, their family, and society at large.11

Every Diagnosis Matters

The power of genomics for rare disease diagnosis is providing new hope for people around the world.

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Benefits of Rare Disease Genomics

Tailored Disease Management

An understanding of rare disease mechanisms allows physicians to refer patients to appropriate specialists, select tailored therapeutics, and offer disease-specific follow-up.

Reduced Expenses

By avoiding lengthy diagnostic odysseys, genomic diagnoses for rare disease can help prevent costly tests and procedures and limit unnecessary referrals.

Reproductive Counseling

Defining the inheritance pattern of a rare disease informs recurrence risks for patients and both their immediate and extended families, supporting informed family planning.

Psychosocial Benefits

In addition to avoiding the stress associated with diagnostic odysseys, receiving a molecular diagnosis brings affected families together in a community of rare disease support groups.

Societal Benefits

Understanding the genomics of rare disease can help identify new drug targets and improve the efficiency of care.

Rare Disease Patient Stories

Ending Carson & Chase’s 6-Year Diagnostic Odyssey

Carson was initially diagnosed with cerebral palsy, but his brother, Chase, proved that to be a misdiagnosis. After four more years, whole-genome sequencing helped diagnose Carson and Chase definitively with mitochondrial enoyl CoA reductase protein-associated neurodegeneration (MEPAN).

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A Diagnosis for Donovan

The list of Donovan’s symptoms raised suspicion of more than 20 different conditions and aligned with nearly a dozen medical specialties. After 6 years, whole-genome sequencing identified a variant in the SKI gene, and Donovan was diagnosed with Shprintzen-Goldberg syndrome.

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Genomic Methods for Rare Disease Diagnosis

Whole-Genome Sequencing for Rare Diseases

Whole-genome sequencing is the most comprehensive method for rare disease testing. It examines the entire genome and has the capability to assess variants in both coding and noncoding regions of the genome.12-19

Whole-Exome Sequencing for Rare Diseases

Whole-exome sequencing evaluates the exons, the coding regions of the genome, for variants associated with disease.9,10,20

Targeted Sequencing for Rare Diseases

Targeted sequencing analyzes specific genes associated with a rare disease or rare disease family.

Chromosomal Microarrays

Chromosomal microarray (CMA) technology identifies large chromosomal variation and specific, well-described variants across the genome.

Compare Genomic Methods for Rare Disease Diagnosis

Diagnostic yield is the statistic most commonly used to compare genomic testing methods for rare disease. This refers to the likelihood that a test will provide information needed to establish a molecular diagnosis. Diagnostic yield can vary significantly depending on the patient population being studied and the inclusion criteria.

Whole-Genome Sequencing

In most studies, whole-genome sequencing (WGS) shows the highest diagnostic yield of all methods. It broadly covers the genome (> 97%) and is capable of detecting multiple variant types (single nucleotide variants, indels, structural variants, copy number variants, repeat expansions, mitochondrial variants, and paralogs).12-19

Whole-Exome Sequencing

Whole-exome sequencing (WES) has the next highest diagnostic yield. Compared to WGS, WES has less genomic coverage (covering ~1.5% of the genome) and detects fewer variant types. However, WES is less expensive than WGS and generally has higher rates of reimbursement.9,10,20

Targeted Sequencing

Targeted sequencing for rare disease assesses specific genes. The largest panels cover less than 0.5% of the genome.

Chromosomal Microarrays

Chromosomal microarray methods cover < 0.01% of the genome. CMA focuses specifically on regions of the genome with well-characterized disease-causing variants. CMA tends to have significantly lower diagnostic yield than WES and WGS.9

Published Method Comparisons

Meta-analysis of the Diagnostic and Clinical Utility of Genome and Exome Sequencing and Chromosomal Microarray in Children with Suspected Genetic Diseases

The authors compiled data and results from 37 different studies comprising 20,068 children to compare performance of WGS, WES, and CMA.

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Effect of Genetic Diagnosis on Patients with Previously Undiagnosed Disease

The Undiagnosed Diseases Network is funded by the National Institutes of Health to evaluate the most challenging cases. In this paper, the authors compare their experiences utilizing WGS and WES to aid in the diagnosis of rare disease patients.

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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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Featured News in Rare Disease Genomics

Progress for Patients with Rare Disease

Evidence Street®, the Blue Cross Blue Shield Association technology review organization, issued a positive review supporting whole-genome sequencing.

Project Baby Bear

This pilot program serves babies in intensive care by rapidly pinpointing the cause of rare disease, offering hope to infants and families.

Clinical Trial for Newborns with Suspected Rare Disease

NICUSeq is a multi-center study evaluating whether whole-genome sequencing can alter clinical care for acutely ill newborns.

Donating WGS to Help Find Answers

The iHope Network strives to end years-long diagnostic odysseys and find answers for underserved children facing rare and undiagnosed diseases. The first published iHope paper demonstrated a diagnostic yield of 68.3% with whole-genome sequencing.

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The Impact of Precision Genomics on Rare Disease

Escape from Limbo Land

In this podcast episode, Heather Renton of Syndromes Without A Name (SWAN) Australia discusses her daughter’s rare disease, the diagnostic odyssey, and the impact of NGS.

A Message of Hope from Illumina

COVID-19 brings additional challenges to families faced with a rare disease. We recognize this burden on the rare disease community and remain committed to ending the diagnostic odyssey.

One Mother’s Quest for a Diagnosis

As a small child, Shubao suffered from hypertonia. Whole-genome sequencing identified a variant in both copies of his PDHX gene, resulting in a tailored treatment. He showed almost immediate improvement.

  1. NIH Genetic and Rare Disease Information Center (GARD) FAQs About Rare Disease. Accessed 27 Mar 2020.
  2. European Commission Public Health Steering Group. Accessed 27 Mar 2020.
  3. Nguengang Wakap, S., Lambert, D.M., Olry, A. et al. Estimating cumulative point prevalence of rare diseases: analysis of the Orphanet database. Eur J Hum Genet. 2020;28:165–173. https://doi.org/10.1038/s41431-019-0508-0
  4. Ferreira CR. The burden of rare diseases. Am J Med Genet A. 2019;179(6):885-892. doi:10.1002/ajmg.a.61124
  5. Walker CE, Mahede T, Davis G, et al. The collective impact of rare diseases in Western Australia: an estimate using a population-based cohort. Genet Med. 2017;19(5):546-552. doi:10.1038/gim.2016.143
  6. Global Commission to End the Diagnostic Odyssey for Children with a Rare Disease. 2019.
  7. Rare Disease Impact Report: Insights from patients and the medical community. globalgenes.org/wp-content/uploads/2013/04/ShireReport-1.pdf.
  8. Bick D, Jones M, Taylor SL, Taft RJ, Belmont J. Case for genome sequencing in infants and children with rare, undiagnosed or genetic diseases. J Med Genet. 2019;56(12):783-791. doi:10.1136/jmedgenet-2019-106111.
  9. Clark MM, 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 Genom Med. 2018;3:16. https://doi.org/10.1038/s41525-018-0053-8
  10. Vissers LE, Gilissen C, Veltman JA. Genetic studies in intellectual disability and related disorders. Nat Rev Genet. 2016;17(1):9-18. doi:10.1038/nrg3999
  11. ACMG Board of Directors. Clinical utility of genetic and genomic services: a position statement of the American College of Medical Genetics and Genomics. Genet Med. 2015;17(6):505-507. doi:10.1038/gim.2015.41
  12. 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. 2018;20(4):435-443. doi:10.1038/gim.2017.119
  13. 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
  14. Dolzhenko E, van Vugt JJ, Shaw RJ, Bekritsky, 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.
  15. Gross, A.M., Ajay, S.S., Rajan, V. et al. Copy-number variants in clinical genome sequencing: deployment and interpretation for rare and undiagnosed disease. Genet Med. 2019;21:1121–1130. https://doi.org/10.1038/s41436-018-0295-y
  16. 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
  17. Lindstrand A, Eisfeldt J, Pettersson M, et al. From cytogenetics to cytogenomics: whole-genome 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. Published 2019 Nov 7. doi:10.1186/s13073-019-0675-1
  18. Chen X, Sanchis-Juan A, French CE, et al. Spinal muscular atrophy diagnosis and carrier screening from genome sequencing data. Genet Med. 2020;22(5):945-953. doi:10.1038/s41436-020-0754-0
  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. doi:10.1093/bioinformatics/btv710
  20. Srivastava S, Love-Nichols JA, Dies KA, et al. Meta-analysis and multidisciplinary consensus statement: exome sequencing is a first-tier clinical diagnostic test for individuals with neurodevelopmental disorders. Genet Med. 2019;21(11):2413-2421. doi:10.1038/s41436-019-0554-6