24 Apr 2024

Rare disease genomics


Exploring the genetic basis of rare diseases

In the USA, a disease is defined as rare if it affects fewer than 1 in 200,000 within the general population [1]. As such, you’d be forgiven to think that rare diseases have a negligible impact on the clinical landscape. In reality, the cumulative impact of rare diseases is substantial: it’s thought that some 300,000 people in the USA alone suffer from a rare disease – the equivalent to 1 in 10 citizens. Astonishingly, this means that rare diseases match the approximate prevalence of type 2 diabetes in the USA [2].

Rare diseases exhibit varied and often complex etiologies, and can be categorized as single gene, multifactorial, chromosomal, or non-genetic. To date, around 7,000 rare diseases have been classified, many causing chronic illness, disability, and sometimes premature death. It has been estimated that 80% of rare diseases have a genetic origin [3].

Diagnosis has been a longstanding issue in the arena of rare diseases. Traditional diagnostic methods have been largely heuristic, relying on clinical observations and evaluation against medical literature. This approach can lead to long delays or misdiagnoses that result in unnecessary treatments that could bring severe side effects.

Since most rare diseases have a genetic cause, genomics technology has emerged as a game-changer. In particular, the emergence of next generation sequencing (NGS) technology has dramatically improved the cost, accuracy, and accessibility of genetic testing for rare diseases.

Beyond diagnostics, recent years have seen novel gene therapies developed to combat rare diseases of genetic origin at their source. In this blog, we’ll discover how genomics research is helping to diagnose rare diseases, identify causative genetic faults, and guide personalized treatment.

The diagnosis dilemma

One of the primary obstacles facing clinicians in combatting rare diseases is gaining an accurate diagnosis. Achieving a definitive molecular diagnosis is highly valuable, revealing potential therapeutic routes and enabling informed family planning. Despite the clear benefits of rare disease diagnosis, patients often face a drawn-out diagnostic journey, requiring extensive testing and workups across multiple institutions. On average, it takes 4.8 years to receive an accurate diagnosis for a rare disease [4].

The challenge of gaining a molecular diagnosis for rare diseases lies in their genetic complexity. Many are caused by extremely rare variants, which may not have been previously characterized or associated with any known disorder. A great deal of variability can also manifest within classified disease-associated variants, which can range from point mutations to indels, short tandem repeats (STRs), and structural variants (SVs). The first port of call for clinicians seeking to gain a rare disease diagnosis, is to interrogate the exome for known disease-associated variants.

Whole exome sequencing

A substantial proportion of variants associated with rare diseases can be found in the genome’s protein-coding regions, known as the exome, which accounts for just 2% of the human genome. It’s estimated that approximately 85% of rare inherited diseases stem from mutations within the exome [5]. Whole exome sequencing (WES) efficiently captures the majority of disease-associated variants while minimizing sequencing costs and data size/complexity compared to whole-genome sequencing (WGS).

Studies have shown that WES can pick up pathogenic variants in approximately of all rare disease patients, making it a valuable diagnostic tool for a significant proportion of affected individuals, including those with complex genetic etiologies.

Despite its wide success in the clinic, a significant number of rare diseases cannot be detected by WES alone. Since WES provides non-uniform coverage and is limited by the specificity of capture probes used, it is limited in detecting some variant types, such as SVs and STRs.

Whole genome sequencing (short reads)

When WES fails to yield a molecular diagnosis, short-read whole genome sequencing can be implemented as a follow-up. The main benefit of short-read WGS over WES is the detection of variants in non-coding regions. For example, STRs often manifest in non-coding regions, contributing to a loss of protein/RNA function [6]. STRs in noncoding regions have been implicated in a number of inherited rare diseases, including Huntington’s disease and amyotrophic lateral sclerosis (ALS).

While short-read WGS is cost-effective and enlightening in cases where key disease associated variants are located in noncoding regions, the approach fails to provide comprehensive genome coverage. Sequence gaps are commonplace, while the approach provides limited sensitivity, especially for variants larger than 350bp. To gain the best possible genome coverage, long-read sequencing platforms can be employed.

Figure 1: Long read sequencing provides enhanced coverage for a more comprehensive genome mapping versus short read GS

Whole Genome Sequencing (long reads)

Many of the shortcomings of short-read WGS can be overcome by employing long-read sequencing technology. While short-read sequencing is limited to reads of 50-350bp, long-read sequencing technology produces reads tens of thousands of bp long, enabling unparalleled genome coverage for comprehensive variant detection.

One of the most popular long-read sequencing platforms is HiFi sequencing from PacBio. The long reads (>25Kb) and high accuracy (>99.9%) of HiFi sequencing enables comprehensive genome assemblies, unmatched variant detection with base-pair resolution, plus phasing to highlight maternal and paternal haplotypes. With long-read sequencing platforms like this, it’s not only possible to resolve larger SVs, but also accurately detect small variants in challenging regions of the genome, making for a complete clinical tool for rare disease diagnosis.

A new era for rare disease therapeutics

Traditionally, therapeutic options for rare diseases have been sparce, with many patients being served with only symptomatic treatment. Although most patients today still face very few treatment options after receiving a molecular diagnosis, rare disease genomics has opened the door to exciting possibilities, particularly in personalized medicine and gene therapies, several of which have successfully broken into the clinic.

The burgeoning clinical applications of gene therapy is heartening for rare disease sufferers. A number of gene therapies have been approved by the FDA, with many more showing promising signs in clinical trials.

In many cases, the outcomes are overwhelmingly positive: a novel gene therapy for hereditary angioedema (HAE) was heralded as a “medical magic wand” following a 2023 trial [7]. After a single treatment, patients with painful and potentially life-threatening swellings saw a substantial improvement in their symptoms, enabling most participants to come off chronic medication and return to life as normal.

The Luxturna success story

One of the first rare disease gene therapies to garner widespread success in the clinic was Luxturna. Approved by the FDA in 2017, Luxturna is a powerful treatment for Leber congenital amaurosis (LCA), a rare inherited retinal disorder that causes severe vision loss and blindness in children [8]. Luxturna leverages adeno-associated virus (AAV) vectors to deliver a functional version of a faulty gene directly into the retinal cells of affected individuals.

The impact of Luxturna on patients with LCA has been nothing short of remarkable, with thousands of pediatric patients achieving significant improvements in visual function and quality of life following treatment [9].

For many patients who once faced a lifetime of impaired vision, Luxturna offers hope and the prospect of regaining functional vision. This is just one example of a myriad of rare diseases being targeted by gene therapies. In addition to gene therapies that act to directly modify somatic cell DNA in vivo, other gene therapies modify cells ex vivo for reimplantation into the body.

A bright future ahead for rare disease genomics research

We have highlighted the importance of rare disease genomics research – from diagnostics to novel gene therapies, NGS and gene editing technology are empowering clinicians with the ability to interrogate and tweak the human genome like never before.

At Eremid®, we’re driving rare disease genomics research with our Genomics Services Lab. Featuring a wide variety of cutting-edge sequencing platforms, and the expertise to perform many genomics analyses from WES to WGS and HiFi sequencing from PacBio, we have the ability to elevate your rare disease research.

The future ahead is bright. As sequencing technology becomes increasingly powerful and affordable, substantial opportunities lie ahead in the arena of rare disease diagnostics and therapeutics.


  1. Nguengang Wakap, S., Lambert, D. M., Olry, A., Rodwell, C., Gueydan, C., Lanneau, V., Murphy, D., Le Cam, Y., Rath, A. (2020). Estimating cumulative point prevalence of rare diseases: analysis of the Orphanet database. European Journal of Human Genetics, 28(2), 165–173. https://doi.org/10.1038/s41431-019-0508-0
  2. Marwaha, S., Knowles, J. W., Ashley, E. A. (2022). A guide for the diagnosis of rare and undiagnosed disease: beyond the exome. Genome Medicine, 14(1), 23. https://doi.org/10.1186/s13073-022-01026-w
  3. Fu, M. P., Merrill, S. M., Sharma, M., Gibson, W. T., Turvey, S. E., Kobor, M. S. (2023). Rare diseases of epigenetic origin: Challenges and opportunities. Frontiers in Genetics, 14, 1113086. https://doi.org/10.3389/fgene.2023.1113086
  4. Hartin, S. N., Means, J. C., Alaimo, J. T., Younger, S. T. (2020). Expediting rare disease diagnosis: a call to bridge the gap between clinical and functional genomics. Molecular Medicine, 26(1), 117. https://doi.org/10.1186/s10020-020-00244-5
  5. Choi, M., Scholl, U. I., Ji, W., Liu, T., Tikhonova, I. R., Zumbo, P., Nayir, A., Bakkaloğlu, A., Ozen, S., Sanjad, S., Nelson-Williams, C., Farhi, A., Mane, S., Lifton, R. P. (2009). Genetic diagnosis by whole exome capture and massively parallel DNA sequencing. PNAS USA, 106(45), 19096–19101. https://doi.org/10.1073/pnas.0910672106
  6. Gatchel, J. R., Zoghbi, H. Y. (2005). Diseases of unstable repeat expansion: mechanisms and common principles. Nature Reviews Genetics, 6(10), 743–755. https://doi.org/10.1038/nrg1691
  7. The Guardian (2023). Gene therapy hailed as ‘medical magic wand’ for hereditary swelling disorder. https://www.theguardian.com/science/2024/jan/31/gene-therapy-hailed-as-medical-magic-wand-for-hereditary-swelling-disorder
  8. United States FDA (2017). FDA approves novel gene therapy to treat patients with a rare form of inherited vision loss. https://www.fda.gov/news-events/press-announcements/fda-approves-novel-gene-therapy-treat-patients-rare-form-inherited-vision-loss
  9. Gao, J., Hussain, R. M., Weng, C. Y. (2020). Voretigene Neparvovec in Retinal Diseases: A Review of the Current Clinical Evidence. Clinical Ophthalmology, 14, 3855–3869. https://doi.org/10.2147/OPTH.S231804
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