More education and training needed to better incorporate genome sequencing for precision medicine in rare diseases

The future of precision medicine in rare diseases has been explored in a new review published in Journal of Internal Medicine.

With the decreasing cost of DNA sequencing, genomic sequencing is emerging as a primary method of precision diagnostics in rare diseases, explained the authors. In this context, molecular diagnoses reveal valuable information on the cause of symptoms, disease progression, familial risk and, in some cases, unlock access to targeted therapies.

Genome sequencing can also detect a broad range of genetic aberrations, including those in non-coding regions that yield data to be reanalysed periodically in the future as new evidence emerges, they added.

Compared to other next-generation targeted sequencing (NGS) approaches, such as gene panels and exome sequencing, genome sequencing offers the ability to confidently capture single nucleotide variants and several structural variants, along with short repeats in tandem. Currently, some form of precision treatment is available for over 500 rare diseases. As a definitive molecular diagnosis is required for targeted treatments, genetic diagnostics becomes critical to the success of precision medicine.

Furthermore, between 40% and 72% of rare diseases are genetic and only a fraction of these patients receive the correct diagnosis, the researchers explained.

Genome sequencing could help alleviate this challenge. If used as a first-line investigation in patients with rare diseases, it could shorten the time to diagnosis.

Implementing precision medicine for rare diseases in clinical practice poses challenges. More effort is needed to educate and train current and future health care professionals and inform the general population, say the authors. Genomics and precision medicine should also be systematically incorporated into training programs for all healthcare professionals, they stressed. Continuing medical education and professional development can help inform existing medical professionals ordering genomic testing.

To realize the full potential of precision medicine in rare diseases, international collaboration between stakeholders will be needed, along with scalable and global approaches to promote responsible data sharing.

There is also a need to develop next-generation functional assays to comprehensively and systematically evaluate the thousands of variants from genome sequencing data, the researchers explained.

Several European initiatives for precision medicine in rare diseases have been introduced, including the NHS Genomic Medicine Service in the UK and the Genomic Medicine Sweden initiative, launched in 2017.

In clinical practice, the main strength of NGS lies in its ability to interrogate multiple genomic regions simultaneously, something that quickly becomes very laborious with conventional Sanger sequencing, the authors wrote. This has made NGS-based DNA sequencing suitable for diagnosing the Mendelian [rare diseases] characterized by genetic heterogeneity, for example, nonsyndromic hearing loss and intellectual disability, they added.

Despite the benefits of genome sequencing, recommendations for specific clinical indications are lacking or available only through guidelines issued by expert groups or scientific societies.

Additionally, although genome sequencing is appropriate for most patients eligible for exome sequencing, the researchers caution that special consideration is needed for subcategories, such as in patients with suspected mosaic disorders.

In the past, requests for genetic testing were mainly done by clinical geneticists. Nowadays, other kinds of specialists are ordering the tests, including pediatricians, oncologists, and cardiologists, among others. To improve patient management, the study authors recommend organizational structures that prioritize interdisciplinary teams.

Typically, a clinical genome sequencing is also analyzed with the aid of virtual genetic panels or lists of genes with a proven causal association to a specific disorder or group of disorders which can be used to filter genome sequencing data.

However, due to the rarity of some disorders, it is difficult to decide which genes should be included in the panel, the authors note.

The literature has also pointed to the benefits of genome sequencing over standard genetic testing, with NICUs serving as the primary setting for early adoption of genome sequencing. Previous research shows rapid genome sequencing has a significantly higher diagnostic yield than standard of care and can save an average of $100,440 per person.

When it comes to clinical interpretation of genome sequencing data, the authors emphasize that only variants with a high probability of being causative should be reported to patients and healthcare professionals. Regular re-evaluation of variant classification is also important.

Overall, implementing genome sequencing in large-scale clinical care requires a tremendous educational effort and a multidisciplinary approach to integrate multimodal data, the authors wrote. The interpretation of the variants must also become more solid. Combined with the development of orphan drugs, refined diagnostics will boost precision medicine and improve health outcomes for patients with rare diseases.

Diagnosing all rare diseases is an extremely challenging task and success will depend on innovative approaches, data sharing, precision therapy outcome monitoring and close collaboration with patient advocacy groups, concluded the researchers.


Thesis B, Boileau C, Boycott KM, et al. Precision medicine in rare diseases: what’s next? J Trainee Med. Published online 21 May 2023. doi:10.1111/joim.13655

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