The decreasing cost of DNA sequencing has contributed to an uptick in genomic sequencing for precision diagnostics in rare diseases.
As DNA sequencing costs decrease, genomic sequencing is emerging as a primary method of precision diagnostics in rare diseases, the authors explained. In this setting, “molecular diagnoses reveal valuable information about the cause of symptoms, disease progression, familial risk, and in certain cases, unlock access to targeted therapies.”
Genome sequencing can also detect a wide range of genetic aberrations, including those in noncoding regions that yield data to be periodically reanalyzed in the future when new evidence emerges, they added.
Compared with other targeted next-generation sequencing (NGS) approaches, like gene panels and exome sequencing, genome sequencing offers the possibility to confidently capture single nucleotide variants and different structural variants, along with short tandem repeats. Currently, some form of precision treatment is available for over 500 rare diseases. Because a definitive molecular diagnosis is necessary for targeted treatments, genetic diagnostics becomes paramount for the success of precision medicine.
In addition, 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 practices does come with challenges. More effort is needed to educate and train current and future health care professionals and inform the general population, the authors said. Genomics and precision medicine should also be systematically incorporated into the training curriculums for all health care professionals, they stressed. Continuing medical education and professional development can help inform existing medical professionals who order genomic tests.
To actualize the full potential of precision medicine in rare diseases, international collaboration across stakeholders will be necessary, along with scalable and global approaches to promote responsible data sharing.
There is also a need to develop “next-generation functional tests” to comprehensively and systematically evaluate the thousands of variants from genome sequencing data, the researchers explained.
Several European initiatives have been introduced for precision medicine in rare diseases, including the National Health Service Genomic Medicine Service in the United Kingdom and the Genomic Medicine Sweden initiative, launched in 2017.
In clinical practice, the core strength of NGS lies in its ability “to simultaneously interrogate multiple genomic regions, something that quickly becomes very labor intensive with conventional Sanger sequencing,” the authors wrote. “This has made NGS-based DNA sequencing suitable for the diagnostics of Mendelian [rare diseases] characterized by genetic heterogeneity—for example, nonsyndromic hearing loss and intellectual disability,” they added.
Despite the advantages of genome sequencing, recommendations for specific clinical indications are lacking or only available through guidelines issued by expert groups or scientific societies.
In addition, although genome sequencing is appropriate for most patients eligible for exome sequencing, the researchers caution special consideration is warranted for subcategories, like in patients with suspected mosaic disorders.
In the past, requesting genetic tests was mostly done by clinical geneticists. Nowadays, other types 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 cross-disciplinary teams.
Typically, a clinical genome sequencing is also analyzed with the help of virtual gene panels, “or lists of genes with a proven causality association to a specific disorder or group of disorders that can be used to filter the genome sequencing data.”
However, due to the rarity of some disorders, it is difficult to decide on which genes should be included in the panel, the authors noted.
Literature has also pointed to the advantages of genome sequencing over standard-of-care genetic testing, with neonatal intensive care units serving as a main setting for the early adoption of genome sequencing. Previous research shows rapid genome sequencing has a significantly higher diagnostic yield compared with 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 stress that only variants with a high probability of being causative should be reported back to patients and health care providers. Regular reevaluation of variant classification is also important.
Overall, “the implementation of genome sequencing in clinical care at large scale requires a massive educational effort and a multidisciplinary approach to integrate multimodal data,” the authors wrote. Variant interpretation must also become more robust. Combined with orphan drug development, 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, monitoring of outcomes linked to precision therapeutics, and tight collaboration with patient advocacy groups,” the researchers concluded.
Tesi B, Boileau C, Boycott KM, et al. Precision medicine in rare diseases: what is next? J Intern Med. Published online May 21, 2023. doi:10.1111/joim.13655