Advancing Rare Disease Diagnostics: Genomic Tools, Implementation and the Path to Timely Care

Recent key publications

Applying National Whole-genome Sequencing Findings for Rare Diseases in Clinical Practice: The Imperative of a Multidisciplinary Approach.
Ann Lab Med 2026; 46:94-103. doi:10.3343/alm.2025.0112. Park KS, Shin S, Park JHet al.

Link to full article:https://pubmed.ncbi.nlm.nih.gov/40958716/

National whole-genome sequencing programmes for rare diseases have grown considerably in scope, yet translating population-level genomic data into meaningful clinical decisions remains far from straightforward. This study traces the diagnostic journey of the First Korean Whole-Genome Sequencing Pilot Project for Rare Diseases, showing how hospital-driven reanalysis combined with close multidisciplinary collaboration more than doubled the original diagnostic rate. The authors detail how sharper phenotypic characterization, the identification of previously undetected variants and broader family recruitment each contributed to this improvement; making clear that national genomic datasets only reach their true value when subjected to repeated, expert-guided interpretation within a real clinical setting. For those working to improve outcomes in genomic medicine, the study offers a practical and timely reference point.

UK recommendations for chimerism testing and monitoring following allogeneic haematopoietic stem cell transplantation (HSCT): Best practice consensus guidelines from the British Society for Blood and Marrow Transplant and Cellular Therapies (BSBMTCT), NHS England Genomic Laboratory Hub (GLH) Haematological Malignancies Working Group, UK Cancer Genetics Group (UKCGG) and the UK National External Quality Assessment Service for Leucocyte Immunophenotyping (UK NEQAS LI).
Br J Haematol 2025; 207:1802-1814. doi:10.1111/bjh.70061. Clark A, Clouston H, Rao Ket al.

Link to full article:https://pubmed.ncbi.nlm.nih.gov/40926330/

Decisions about withdrawing immunosuppression or giving donor lymphocyte infusions after allogeneic stem cell transplantation depend heavily on accurate chimerism assessment, yet how this is done in practice has varied considerably between centres. This consensus guideline, produced jointly by four UK national bodies, draws on expert input and available evidence to set out clear recommendations covering laboratory methods, lineage-specific monitoring and the clinical thresholds that should guide intervention in both malignant and non-malignant conditions, across adult and paediatric populations. The document also takes on the practical matters of technical standards and external quality assurance and looks at how chimerism monitoring fits alongside measurable residual disease testing. For haematologists, transplant physicians and laboratory staff dealing with the day-to-day complexities of post-transplant care, it offers a much-needed common reference point aimed at bringing greater consistency to practice and, ultimately, better outcomes for patients.

Rare but relevant: Genetic liver disease in the general medical setting.
Clin Med (Lond) 2025; 25:100535. doi:10.1016/j.clinme.2025.100535. Allouni S, Ala A.

Link to full article:https://pubmed.ncbi.nlm.nih.gov/41270864/

Genetic liver diseases are individually uncommon yet taken together they account for a meaningful share of the chronic liver disease seen in everyday clinical practice. Wilson disease, hereditary haemochromatosis and alpha-1 antitrypsin deficiency tend to present with vague, non-specific symptoms, which too often leads to delayed diagnosis and harm that could have been avoided. As genomic medicine continues to mature, the NHS Genomic Medicine Service being a clear example of this shift, generalists find themselves well placed to identify at-risk patients earlier and steer them toward appropriate investigation and referral before serious complications arise. This review offers a practical, evidence-grounded update on recognizing and managing these three conditions. It also draws attention to emerging treatment options and underscores why systematic cascade testing of family members remains so important in an era where precision medicine is increasingly within reach.

Whole-genome analysis of plasma fibrinogen reveals population-differentiated genetic regulators with putative liver roles.Blood 2024; 144:2248-2265. doi:10.1182/blood.2023022596. Huffman JE, Nicholas J, Hahn Jet al.

Link to full article:https://pubmed.ncbi.nlm.nih.gov/39226462/

Plasma fibrinogen plays a central role in blood clotting and behaves as an acute-phase protein, yet the genetic factors shaping its levels have never been fully worked out, especially across populations of different ancestral backgrounds. This study, the largest and most ancestrally diverse of its kind, draws on whole-genome sequencing data from the NHLBI TOPMed Program together with genotype information from more than 163,000 participants. The analysis uncovered 54 associated loci, 18 of which had not been previously reported. Several of these signals are carried predominantly by variants more frequent in individuals of African ancestry, a finding that speaks directly to the value of moving beyond the historically narrow demographic scope of genomic research. Taken together, the results point to shared regulatory mechanisms connecting fibrinogen to inflammation, liver physiology and thrombotic disease, and open new avenues for understanding how this protein influences human health at a broader level.

Comparing the performance of exome and genome sequencing for rare disease diagnostics: A randomized implementation effectiveness trial.
Genet Med 2026; 28:101605. doi:10.1016/j.gim.2025.101605. Hayeems RZ, Ungar WJ, Marshall CRet al.

Link to full article:https://pubmed.ncbi.nlm.nih.gov/41084864/

Exome and genome sequencing are now widely used in rare disease diagnostics, but solid comparative data from properly randomized trials has been hard to come by. This study addresses that gap through a large implementation effectiveness trial in which 1,048 trios were randomly assigned to receive either exome or genome sequencing through a centralised provincial programme. The diagnostic yields came out nearly the same 33.8% for exome sequencing and 33.6% for genome sequencing with turnaround times running broadly parallel as well, though how well each approach performed did vary depending on the clinical phenotype. For health systems weighing whether and how to fund genome-wide diagnostics, the trial offers some of the most reliable comparative evidence available to date.

Newborn screening for rare diseases: expanding the paradigm in the genomic era.
J Perinat Med 2026; 54:116-122. doi:10.1515/jpm-2025-0363. Grošelj U

Link to full article: https://pubmed.ncbi.nlm.nih.gov/41002024/

Newborn screening stands at a pivotal juncture, with genomic technologies offering the potential to expand its scope from a limited set of metabolic disorders to hundreds of treatable rare diseases. This review examines the challenges between traditional public health frameworks and the emerging paradigm of personalized medicine, analysing how classical screening criteria must be reinterpreted in the genomic era. Key challenges, including condition selection, variant interpretation, consent models and health-system readiness, are critically assessed alongside international pilot programmes that are actively reshaping the landscape. This article provides essential guidance for navigating this transition on balancing innovation with equity and ethical rigor.

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