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
Learn how whole-genome sequencing can be deployed to hunt for a diagnosis and bring new levels of understanding in ending the diagnostic odyssey.View Video
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
An understanding of rare disease mechanisms allows physicians to refer patients to appropriate specialists, select tailored therapeutics, and offer disease-specific follow-up.
By avoiding lengthy diagnostic odysseys, genomic diagnoses for rare disease can help prevent costly tests and procedures and limit unnecessary referrals.
Defining the inheritance pattern of a rare disease informs recurrence risks for patients and both their immediate and extended families, supporting informed family planning.
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.
Understanding the genomics of rare disease can help identify new drug targets and improve the efficiency of care.
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).Watch Video
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.Watch Video
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 evaluates the exons, the coding regions of the genome, for variants associated with disease.9,10,20
Targeted sequencing analyzes specific genes associated with a rare disease or rare disease family.
Chromosomal microarray (CMA) technology identifies large chromosomal variation and specific, well-described variants across the genome.
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.
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 (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 for rare disease assesses specific genes. The largest panels cover less than 0.5% of the genome.
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
The authors compiled data and results from 37 different studies comprising 20,068 children to compare performance of WGS, WES, and CMA.View Publication
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.View Publication
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.View Course Details
Evidence Street®, the Blue Cross Blue Shield Association technology review organization, issued a positive review supporting whole-genome sequencing.
This pilot program serves babies in intensive care by rapidly pinpointing the cause of rare disease, offering hope to infants and families.
NICUSeq is a multi-center study evaluating whether whole-genome sequencing can alter clinical care for acutely ill newborns.
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.Learn More
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.
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.
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.