Rare diseases collectively affect 3.5–5.9% of the global population, thus emphasising their public health significance. Diagnosing rare diseases in adults remains more challenging than in infants due to multiple causes, such as complexities in genotype-phenotype correlations, lower diagnostic yields, and the prevalence of non-genetic causes. In the recent years, advances in genomic medicine, including exome sequencing (ES) and genome sequencing (GS), show promise in diagnosing neurological conditions, and these techniques are gradually being integrated in clinical care.
In this month’s suggested read, we will explore how genomic medicine and sequencing techniques can be thoroughly used for the diagnosis of different diseases, depending on several parameters, such as the probability that the condition stems from genetic causes or not.
Over two hundred patients showing various symptoms and who were currently undiagnosed were presented with a three-step diagnosis pipeline: first, they were classified in two groups depending on whether the condition was thought to be of genetic cause or not. Then, the probable genetic group was diagnosed using ES and GS in order to identify copy number alterations, deletions or hotspot mutations in their genome, whilst the uncertain group was clinically evaluated using immunologic tests and imaging. Depending on the results, a clinical application as set up for each individual patient, such as a targeted treatment, tailored surveillance or drug prescription.
An important aspect of this “personalised healthcare” is to make sure that the data analysis was as dynamic as possible, by updating the databases routinely and conduct analyses every few months in order to identify the smallest of nucleotide variants amongst the patients. This ensured that the genetic approach yields were maximised. Furthermore, the diagnostic rate was found to be impacted by clinical factors. For instance, a family history of diseases significantly improved the diagnosis rate, with 42.9% instead of 23.8%. This emphasises the importance of inheritance patterns and familial studies in identifying genetic causes. Likewise, earlier symptom onset showed a trend of higher diagnostic yield, although not statistically significant. This suggests that earlier manifestations may provide more identifiable genetic clues.
To summarise this study, adults with undiagnosed diseases face complexities due to overlapping genetic and non-genetic aetiologies, and paediatric-onset cases in adults showed prolonged diagnostic journeys due to delayed access to advanced molecular tools. Furthermore, continuous updates and reanalysis of genomic data were critical in resolving cases previously considered unsolvable. These genetic diagnoses enabled tailored therapies, with successful drug repurposing for several conditions. However, despite these successes, significant gaps in applying treatments underscore the need for expanded research and clinical trials.
We at 4bases celebrate December as the month of rare disease research and the Telethon! We present the WholEx pro sequencing kit, powered by new-generation sequencing technologies and specialised in whole exome sequencing of over 22,000 genes and the identification of genetic variants.
Ahn JH, Yoon JG, Cho J, Lee S, Kim S, Kim MJ, Kim SY, Lee ST, Chu K, Lee SK, Kim HJ, Youn J, Jang JH, Chae JH, Moon J, Cho JW. Implementing genomic medicine in clinical practice for adults with undiagnosed rare diseases. NPJ Genom Med. 2024 Nov 28;9(1):63. doi: 10.1038/s41525-024-00449-1. PMID: 39609445; PMCID: PMC11604660.
