The urgency behind this work stems from a dramatic rise in allergic disease across the Asia-Pacific region. Researchers attribute the rapid increase to a convergence of forces: global warming, extensive urbanization, the environmental pollution that accompanies it, and improved sanitation. Each of these factors alters exposure to allergens in distinct ways. Warming climates extend pollen seasons and introduce new plant species to regions that never encountered them before, while urbanization concentrates populations in polluted megacities where particulate matter interacts with inhaled allergens in ways that can amplify airway inflammation. Paradoxically, improved sanitation, which protects against infectious disease, may also skew immune development toward allergic responses, a phenomenon related to the hygiene hypothesis.

The geographical specificities of sensitization are striking. Cedar pollen stands as the main cause of hay fever in Japan, while the mite species Blomia tropicalis predominates in tropical regions. In Western countries, by contrast, sensitization to birch pollen and to the house dust mite Dermatophagoides pteronyssinus is far more prevalent. These differences are not merely academic; they determine which diagnostic panels are useful in a given region and which immunotherapeutic extracts will actually work. Yet many allergens in Eastern countries remain incompletely characterized, and most commercial diagnostic tools remain focused on Western sensitization profiles, leaving clinicians across Asia and the tropics to work with instruments that were never designed for their patients.

Food allergies add another layer of regional complexity. Certain foods consumed primarily in Asia may contribute to the development of region-specific food allergies. In Mongolia, horse milk allergy is relatively common, alongside lactose intolerance, because horse milk is often used as a substitute for children with cow’s milk allergy and fermented mare’s milk, known as airag, is a national staple. In Korea, some important allergens from fruits and vegetables that elicit pollen-food allergy syndrome have yet to be fully characterized. Individuals may also develop allergies to foods encountered for the first time in a foreign country, or to imported products, as a result of cross-reactivity with pollen allergens from their country of origin. The immune system, primed by one set of environmental proteins, can misidentify structurally similar proteins in unfamiliar foods as threats.

Perhaps most surprising is the discovery that allergenic components can be found in traditional and herbal medicines. Researchers have identified Pana g 1, a ginseng allergen homologous to the birch pollen allergen Bet v 1, in some ginseng beverages. Japanese hop, Humulus japonicus, is widespread in far east Asian countries and is now invasive in Western countries, meaning that a weed once confined to one hemisphere is becoming a pollinosis problem in the other. These examples underscore why the editorial’s authors emphasize the need to investigate the similarities and differences between regional particularities in Asia and the tropics and those observed in Western industrialized countries, since cross-reactivity networks span continents.

The five articles collected in the current Research Topic reflect both the rapid growth of knowledge and the critical need to characterize regionally important allergens. Two articles focused on sensitization patterns in eastern China, while three studies addressed molecular diagnosis in Thailand, Colombia, and India. In a retrospective analysis from eastern China, Dermatophagoides pteronyssinus emerged as the most common respiratory allergen source at 37.58 percent, followed by mold at 13.11 percent. Cashew nut was the most frequently identified food allergen at 15.57 percent, followed by cow’s milk at 10.99 percent and egg at 9.33 percent. These findings represent a distinct sensitization pattern that may reflect regional, lifestyle, and cultural differences, and they suggest that cashew nut, rather than peanut, may deserve greater attention in Asian food allergy screening.

One of the Chinese studies, led by Huang and colleagues, investigated differential food sensitization patterns among infants, toddlers, and children. Their results suggest that sensitization patterns emerge early in life, highlighting the need for differentiated allergy risk management and prevention strategies across different developmental stages. This finding carries significant implications for pediatric practice, because it suggests that the window for intervention may open much earlier than previously assumed, and that a one-size-fits-all prevention protocol may fail to protect children at different ages from different allergen threats.

The molecular diagnosis studies from Southeast Asia and South America demonstrate how component-resolved diagnostics can outperform traditional extract-based testing. Kulalert and colleagues in Thailand reported better diagnostic performance of specific IgE measurement for shrimp tropomyosin, the major shellfish allergen protein, than that of the skin prick test and specific IgE measurement using whole shrimp extract. This matters because tropomyosin is a highly cross-reactive protein found across crustaceans and mollusks, and measuring IgE against the purified component rather than a crude extract reduces false positives from IgE that binds irrelevant proteins in the extract. Marrugo and colleagues in Colombia demonstrated that molecular diagnosis using combinations of specific allergens can improve diagnostic accuracy, potentially supporting personalized allergy management in a tropical setting where allergen exposure differs markedly from temperate regions.

In India, Ghosh and colleagues evaluated the diagnostic value of recombinant Asp f 10, a secreted aspartic protease from Aspergillus fumigatus, and Asp f 10-specific IgG as a biomarker for allergic bronchopulmonary aspergillosis, a severe inflammatory lung disease caused by hypersensitivity to Aspergillus antigens in patients with asthma or cystic fibrosis. Identifying reliable molecular biomarkers for this condition is critical because current diagnostic criteria rely on a constellation of clinical, radiological, and immunological findings that can be difficult to interpret consistently across different healthcare settings. A specific molecular marker could standardize diagnosis and enable earlier treatment initiation.

Taken together, the studies in this second volume make clear that a rapidly growing body of knowledge is emerging regarding novel allergens from Asian and tropical regions. Certain sensitization patterns may be specific to these geographic areas, which encompass temperate to tropical climates and harbor diverse endemic flora and fauna. Although many of these allergens can exhibit cross-reactivity with allergens from similar sources in other regions, the integration of Asia- and tropics-specific components into diagnostic panels will improve the diagnosis of allergic sensitization in these regions of the world. For the billions of people living across Asia and the tropics, the message is unambiguous: allergy medicine must finally look like the populations it serves, and the molecular tools to make that possible are arriving at precisely the moment they are needed most.

Subject of Research: Editorial: Allergens and allergic sensitization in Asia and the tropics—volume II

Article Title: Editorial: Allergens and allergic sensitization in Asia and the tropics—volume II

Article References: Jeong, K. Y., Jacquet, A., Leung, T. F., & Li, P. H. (2026). Editorial: Allergens and allergic sensitization in Asia and the tropics—volume II. Frontiers in Allergy, 7, Article 1973136. https://doi.org/10.3389/falgy.2026.1973136

Image Credits: AI Generated

DOI: 10.3389/falgy.2026.1973136

Keywords: allergic sensitization, molecular diagnosis, Asia-Pacific allergy, tropical allergens, component-resolved diagnostics, food allergy, Frontiers in Allergy, Editorial, Allergens, allergic, sensitization, Asia

The story begins with a proband—an individual who serves as the starting point for genetic investigation within a family—presenting with chronic hemolytic anemia, a condition in which red blood cells are destroyed faster than the body can replace them. In southern China, β-thalassemia is a common inherited disorder of hemoglobin synthesis, primarily caused by point mutations and small deletions or insertions in the β-globin gene, known as HBB. Hereditary elliptocytosis, by contrast, is a red blood cell membrane disorder characterized by elliptical rather than the normal biconcave-disc-shaped erythrocytes. The coexistence of these two conditions is exceedingly rare and presents a formidable diagnostic challenge because their hematological characteristics overlap in ways that can easily confound clinicians relying on standard blood work alone.

To disentangle the two conditions, the research team deployed a comprehensive molecular toolkit. Hematological and biochemical evaluations were performed alongside hemoglobin fraction analysis, which separates the different types of hemoglobin present in the blood to detect abnormalities in globin chain production. The investigators then turned to third-generation sequencing to analyze both α- and β-globin genes in the proband and available family members. Unlike earlier sequencing platforms, third-generation technology can read long stretches of DNA in a single pass, making it particularly valuable for detecting complex rearrangements and structural variants that shorter-read methods might miss. Whole-exome sequencing was subsequently performed to identify candidate variants across the protein-coding portion of the genome, followed by confirmation through Sanger sequencing, the gold-standard method for validating individual genetic variants.

The results revealed two heterozygous variants in the EPB41 gene, which encodes protein 4.1, a critical structural component of the red blood cell membrane skeleton. The first variant, designated NM_001376013.1(EPB41):c.906-1G>A, affects a splice site—the molecular signal that tells the cellular machinery where to cut and rejoin RNA during gene expression. The second, NM_001376013.1(EPB41):c.731 A>G, represents a single nucleotide substitution that alters the protein’s amino acid sequence. Both variants were confirmed by Sanger sequencing and demonstrated co-segregation with the elliptocytic phenotype in affected family members, meaning that the presence of these mutations tracked precisely with the appearance of elliptical red blood cells across the family pedigree. This pattern of inheritance is a hallmark of causality in genetic analysis and provides strong evidence that the EPB41 variants are responsible for the membrane disorder.

Both EPB41 variants are documented in population genetics databases including gnomAD, which aggregates genome sequences from tens of thousands of individuals worldwide, and dbSNP, a comprehensive database of single nucleotide polymorphisms. The c.731 A>G variant is additionally listed in ClinVar, the National Center for Biotechnology Information’s archive of clinically significant genetic variants, under Variation ID 2194273. The presence of these variants in public databases helps contextualize their rarity and provides a reference point for other clinicians who may encounter similar cases in the future.

Beyond the membrane disorder, the molecular investigation uncovered a frameshift mutation in the HBB gene, designated NM_000518.5:c.126_129delCTTT. Frameshift mutations occur when the deletion or insertion of nucleotides is not a multiple of three, disrupting the reading frame that determines how the genetic code is translated into protein. In this case, the deletion of four nucleotides—CTTT—shifts the frame and produces a nonfunctional β-globin protein, consistent with a diagnosis of β-thalassemia. The identification of this mutation alongside the EPB41 variants confirmed that the proband was carrying two independent genetic disorders simultaneously, each contributing to the overall clinical picture in distinct ways.

Pathogenicity assessment followed the American College of Medical Genetics and Genomics guidelines, a standardized framework that classifies genetic variants on a five-tier scale ranging from benign to pathogenic. The ACMG criteria incorporate multiple lines of evidence, including population frequency, computational predictions, functional data, and segregation patterns within families. By applying these rigorous standards, the researchers ensured that their classification of the EPB41 variants and the HBB frameshift was not merely speculative but grounded in established clinical genetics practice.

The integration of peripheral blood morphology—the microscopic examination of red blood cell shape and size—with family segregation analysis and molecular genetic findings ultimately supported a unified diagnosis of co-inherited hereditary elliptocytosis and β-thalassemia. This multi-pronged approach illustrates why no single diagnostic modality is sufficient when dealing with complex anemias. Blood smears can reveal the elliptocytic cells characteristic of the membrane disorder, while hemoglobin fraction analysis points toward the thalassemia component, but only genetic sequencing can definitively identify the underlying molecular lesions responsible for each condition.

The significance of this report extends beyond the individual family involved. By expanding the genotype–phenotype spectrum of EPB41-associated hereditary elliptocytosis, the study adds to the growing catalog of known disease-causing variants in this gene, which may help other clinicians recognize similar presentations in their own patients. The co-inheritance scenario also serves as a cautionary tale for diagnostic medicine: when a patient presents with anemia that does not fit neatly into a single diagnostic category, clinicians should consider the possibility that multiple genetic disorders are operating concurrently. The case underscores the diagnostic utility of combining traditional morphological assessment with modern molecular techniques, a synergy that is increasingly essential as the complexity of inherited blood disorders becomes better appreciated.

Funding for this work was partially provided by the Lishui Science and Technology Bureau Project under Grant No. 2023GYX49. The research was conducted in accordance with the ethical standards of institutional and national research committees and the 1964 Helsinki Declaration and its later amendments. Informed consent was obtained from all individual participants involved in the study, and the authors declared no competing interests. The article is published open access under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, ensuring that the findings are freely available to clinicians, researchers, and patients worldwide who may benefit from this detailed molecular characterization of a rare dual diagnosis.

Subject of Research: Co-inheritance of β-thalassemia and EPB41-associated hereditary elliptocytosis in a Chinese family

Article Title: Co-inherited β-thalassemia and hereditary elliptocytosis associated with EPB41 mutations in a Chinese family: a case report

Article References: Wu, Y., Lin, M., Hu, X., Huang, J., & Liu, S. (2026). Co-inherited β-thalassemia and hereditary elliptocytosis associated with EPB41 mutations in a Chinese family: a case report. Annals of Hematology. https://doi.org/10.1007/s00277-026-07322-4

Image Credits: AI Generated

DOI: 10.1007/s00277-026-07322-4

Keywords: β-thalassemia, hereditary elliptocytosis, EPB41, HBB, genetic sequencing, red blood cell membrane, hemolytic anemia, whole-exome sequencing, ACMG guidelines, co-inheritance, case report, molecular diagnosis

The study, led by Mehmet Burak Mutlu of the Detagen Genetic Diseases Evaluation Center in Kayseri together with collaborators from hospitals and universities across Türkiye, divided participants into two clinically meaningful groups. Those with isolated autism had no co-occurring neurodevelopmental, neurological, dysmorphic, congenital, or systemic findings. Those with complex autism presented with at least one such additional feature, such as developmental delay or intellectual disability, epilepsy, characteristic facial features, congenital anomalies, or abnormalities on brain imaging. This distinction turned out to be the single most important predictor of whether sequencing would yield an answer.

The numbers were striking. Among the 22 patients with isolated autism, only two received an established molecular diagnosis, a yield of 9.1 percent with a wide 95 percent confidence interval of 1.1 to 29.2 percent that reflects the small size of that subgroup. Among the 298 patients with complex presentations, by contrast, 102 received established diagnoses, a yield of 34.2 percent. The difference was statistically significant, with a p-value of 0.017. In practical terms, a child with autism plus epilepsy or intellectual disability was several times more likely to receive a genetic explanation from exome sequencing than a child whose autism appeared in isolation.

Whole-exome sequencing works by reading the protein-coding portions of the genome, the roughly one to two percent of DNA that contains most known disease-causing variants. In this study, sequencing data were processed through a standard bioinformatics pipeline, with reads aligned using the Burrows-Wheeler Aligner and variants called and refined with the Genome Analysis Toolkit, the tools that form the backbone of most clinical sequencing laboratories worldwide. Single-nucleotide variants and small insertions and deletions were then classified according to the criteria jointly published by the American College of Medical Genetics and Genomics and the Association for Molecular Pathology, the framework that governs whether a variant is called pathogenic, likely pathogenic, or uncertain.

The researchers were deliberately strict about what counted as an established diagnosis. A finding qualified only if the patient carried pathogenic or likely pathogenic variants linked to disorders defined in the Online Mendelian Inheritance in Man catalog, or if the variants occurred in genes carrying definitive, strong, or moderate evidence from ClinGen, the Clinical Genome Resource that curates gene-disease relationships. This conservatism matters because the literature on autism genetics is littered with premature claims, and the field has moved toward frameworks that separate well-established diagnoses from speculative ones. By holding themselves to this standard, the authors produced a yield figure that can be compared meaningfully with international cohorts.

Beyond the established diagnoses, the study also surfaced a further layer of findings that the authors treated with appropriate caution. Twelve additional patients carried pathogenic or likely pathogenic variants in candidate or emerging genes, genes suspected of involvement in neurodevelopmental disorders but not yet backed by definitive evidence. Including these, the overall rate of pathogenic or likely pathogenic findings rose to 116 of 320 patients, or 36.3 percent. The authors argue that such candidate-gene results should always be reported separately and interpreted as hypothesis-generating rather than diagnostic, a distinction that has real consequences for families who may otherwise be told they have a definitive answer when they do not.

The remaining results illustrate the messy middle ground of clinical genomics. Variants of uncertain significance, genetic changes that cannot currently be classified as benign or disease-causing, were identified in 147 patients, nearly half the cohort. In 57 patients, no variant related to autism or neurodevelopmental disorders was found at all. These categories are not dead ends. Uncertain variants can be reclassified as evidence accumulates, and negative results can be revisited as new genes are discovered, which is why many centers recommend periodic reanalysis of sequencing data. But they highlight the gap between the promise of genomic medicine and its current limits, particularly for patients whose presentations do not fit known syndromes.

Why does a molecular diagnosis matter so much? For families, an etiological answer can end years of diagnostic odyssey, provide a realistic prognosis, clarify recurrence risk for future pregnancies, and connect families to condition-specific support communities. For clinicians, a precise diagnosis can change management directly. Many of the genes implicated in autism-related neurodevelopmental disorders carry risks for treatable complications, including epilepsy, cardiac anomalies, or metabolic problems, and some monogenic conditions have targeted therapies or surveillance protocols. A genetic result transforms autism from a behavioral description into a medical diagnosis with a concrete care pathway.

The Turkish cohort itself fills an important gap. Most large exome-sequencing studies of autism have been conducted in North American and European populations, and data on yield and variant spectra in Turkish patients have been limited. Population-specific cohorts matter because variant frequencies, founder effects, and rates of consanguinity can all influence which genetic causes appear and how they are inherited. The study’s supplementary material catalogs the pathogenic and likely pathogenic variants, uncertain variants, and compound heterozygous cases in detail, along with segregation analyses where family members were available for testing, providing a resource for clinicians in the region and for the broader research community.

The study was approved by the Harran University Clinical Research Ethics Committee and conducted under the Declaration of Helsinki, with written informed consent obtained from all participants or their legal guardians. The authors received no specific funding for the work and declare no competing interests. Published open access under a Creative Commons license, the paper arrived with the caveats of an early-release version subject to final edits, but its core message is already clear and consistent with the international literature: whole-exome sequencing earns its place in the autism diagnostic workup, especially when autism travels with other clinical findings. As the authors conclude, sequencing supports etiological clarification in clinically complex autism, while candidate-gene findings should be handled as leads, not verdicts. For the growing number of families navigating an autism diagnosis, that nuance may be the most valuable result of all.

Subject of Research: Molecular diagnostic yield of whole-exome sequencing in a Turkish autism spectrum disorder cohort

Article Title: Whole-exome sequencing in a Turkish autism spectrum disorder cohort: a retrospective study of molecular diagnostic yield in isolated and complex presentations

Article References: Mutlu, M. B., Sanrı, A., Yaralı, O., Sezer, Ö., Kılıçaslan, F., Gümüş, H., Kumandaş, S., & Öz, Ö. (2026). Whole-exome sequencing in a Turkish autism spectrum disorder cohort: a retrospective study of molecular diagnostic yield in isolated and complex presentations. BMC Psychiatry. https://doi.org/10.1186/s12888-026-08739-x

Image Credits: AI Generated

DOI: 10.1186/s12888-026-08739-x

Keywords: autism spectrum disorder, whole-exome sequencing, molecular diagnosis, genetic testing, neurodevelopmental disorders, diagnostic yield, variants of uncertain significance, ClinGen, ACMG criteria, Turkish cohort, clinical genetics, developmental delay

The research team, led by Juan Felipe Morantes Rubiano of Hospital Pablo Tobón Uribe and Universidad Pontificia Bolivariana, reviewed the records of 478 adults with suspected acute meningoencephalitis who underwent FAME testing at two tertiary hospitals in Medellín between 2019 and 2023. The cohort had a median age of 51 years and was 55 percent male. Of these patients, 353 were immunocompetent and 125 were immunosuppressed, a distinction that matters because clinicians have historically been reluctant to apply any restrictive testing rules to patients whose weakened immune systems can blunt the usual inflammatory signals of infection. Overall, only 14.8 percent of the FAME panels returned a positive result, a figure that immediately illustrates the scale of low-yield testing in routine practice.

The study’s design deserves careful attention because it differs from a classic diagnostic accuracy trial. The authors explicitly framed their work as a diagnostic stewardship evaluation rather than an assessment of how well spinal fluid chemistry detects confirmed central nervous system infection. The reason is subtle but important: the FAME panel itself is an imperfect reference standard, capable of missing genuine infections and occasionally detecting latent viruses that are not causing disease. Rather than claiming that routine measurements can diagnose meningoencephalitis, the researchers asked a narrower and more honest question: which cytochemical parameters predict that a FAME panel will come back positive? The target condition was therefore panel positivity, not microbiologically confirmed infection.

The differences between positive and negative cases were striking. Patients with positive panels had a median cerebrospinal fluid leukocyte count of 189 cells per cubic millimeter, compared with just 3 cells per cubic millimeter in those with negative panels. Protein concentration, a marker of blood-brain barrier disruption and inflammation, was also markedly higher in positive cases, with a median of 167 milligrams per deciliter versus 47 milligrams per deciliter. Glucose, which bacteria and viruses consume as they multiply, was lower in positive cases, at a median of 31 milligrams per deciliter compared with 62. Among all the parameters evaluated, protein showed the greatest discriminative capacity, with an area under the receiver operating characteristic curve of 0.793, while opening pressure, the pressure measured when the needle first enters the spinal canal, showed the weakest, at 0.666.

From these data, the team constructed a practical screening rule. Of the 478 tests performed, 287, or 60 percent, were carried out on samples without pleocytosis, defined as fewer than 10 white cells per cubic millimeter of fluid. In this low-cell-count group, the FAME positivity rate was only 5.5 percent. When the researchers added a second condition, requiring protein below 50 milligrams per deciliter, they identified 192 samples, or 40.1 percent of the total, in which positivity fell to just 2.6 percent. In other words, applying a combined threshold of at least 10 leukocytes per cubic millimeter or at least 50 milligrams per deciliter of protein would have flagged the samples most likely to be positive and spared the rest.

The clinical stakes of such a rule depend on what would have been missed. Under a narrow definition of clinically relevant results, meaning a positive test that would actually change patient management, only 0.5 percent of the low-yield samples would have contained such a finding. Under a broader definition, counting any confirmed true positive regardless of its management impact, the figure rose to 1.0 percent. These numbers quantify the trade-off at the heart of diagnostic stewardship: a modest risk of overlooking rare positives in exchange for a substantial reduction in testing that rarely helps. The combined threshold would have increased overall diagnostic yield by 55.4 percent while cutting low-yield testing by 40.1 percent, gains that translate directly into lower costs and faster laboratory turnaround for the samples that matter.

Perhaps the most consequential finding concerns immunosuppressed patients, a group usually excluded from restrictive testing guidelines because clinicians fear that their blunted inflammatory responses will produce false reassurance. In this cohort, the negative predictive value of the combined threshold was 97.4 percent overall and 96.0 percent in immunosuppressed patients, with a confidence interval of 86.5 to 98.9 percent for the latter group. That suggests the rule may be applicable even to patients with compromised immunity, though the authors caution that one clinically significant case in this subgroup would have been missed under the broader definition. The finding is hypothesis-generating rather than definitive, and the researchers emphasize that prospective validation is required before such thresholds are adopted into clinical pathways.

The concept of diagnostic stewardship, as opposed to antimicrobial stewardship, is gaining traction in infectious diseases. The idea is to intervene at the moment a test is ordered rather than after a result returns, ensuring that expensive diagnostics are directed at patients in whom they are most likely to change outcomes. Molecular syndromic panels like FAME test for a fixed menu of pathogens, including herpes simplex viruses, enteroviruses, cryptococcus, and several others, and each run carries a significant cost. When the pre-test probability of a positive result is low, as it evidently is in the majority of samples in this study, the marginal value of the panel diminishes. Simple, cheap cytochemical measurements performed on the same spinal fluid sample can serve as an inexpensive triage layer.

The study also illustrates the methodological caution needed when evaluating syndromic diagnostics. Because FAME served as the reference standard, the analysis cannot distinguish between true infections that the panel missed and latent viral detections that the panel flagged without clinical consequence. Herpes simplex virus DNA, for example, can persist in cerebrospinal fluid after treatment, and latent infections can produce positive results that do not reflect active disease. The authors’ decision to define their target as panel positivity rather than confirmed infection keeps the conclusions within defensible bounds, and their framing of the results as hypothesis-generating reflects that restraint. Any future implementation would need to weigh the rare missed positives against the systemic benefits of reduced testing, ideally through prospective studies that follow patients longitudinally.

For hospitals confronting the economics of molecular diagnostics, the Colombian data offer a concrete starting point for local evaluation. The thresholds involved, 10 leukocytes per cubic millimeter and 50 milligrams per deciliter of protein, are not exotic measurements but values already reported in every cerebrospinal fluid analysis, making implementation straightforward wherever FAME testing is available. The authors, who also included Laura Restrepo Álvarez, Andrea Mazo Cañola, Juan Pablo Villa Franco, Santiago Atehortúa Muñoz, Jorge Hernando Donado Gómez, and Paulina González Obando, received no direct monetary funding and declare no competing interests. If prospective validation confirms their findings, the humble spinal fluid cell count and protein level, measurements that have been part of neurology for more than a century, may become the first filter in a smarter, more sustainable diagnostic pathway for one of medicine’s most urgent syndromes.

Subject of Research: Cerebrospinal fluid cytochemical parameters as predictors of FilmArray Meningitis/Encephalitis panel positivity for diagnostic stewardship

Article Title: Cerebrospinal fluid cytochemical parameters as predictors of FilmArray Meningitis/Encephalitis panel positivity: a diagnostic stewardship approach in immunocompetent and immunocompromised patients

Article References: Morantes Rubiano, J. F., Restrepo Álvarez, L., Mazo Cañola, A., Villa Franco, J. P., Atehortúa Muñoz, S., Donado Gómez, J. H., & González Obando, P. (2026). Cerebrospinal fluid cytochemical parameters as predictors of FilmArray Meningitis/Encephalitis panel positivity: a diagnostic stewardship approach in immunocompetent and immunocompromised patients. BMC Infectious Diseases. https://doi.org/10.1186/s12879-026-14575-x

Image Credits: AI Generated

DOI: 10.1186/s12879-026-14575-x

Keywords: meningitis, encephalitis, cerebrospinal fluid, FilmArray, diagnostic stewardship, molecular diagnosis, pleocytosis, CSF protein, immunocompromised patients, diagnostic accuracy, BMC Infectious Diseases, Colombia

England’s genomic diagnostics are coordinated through seven NHS Genomics Laboratory Hubs, or GLHs, each responsible for clinical genomics services in its region, including genetic testing, molecular diagnosis, treatment planning, and counselling for families affected by inherited conditions. Since 2024, these hubs have been required under guidance from the Association for Clinical Genomic Science, the professional body representing clinical genomics scientists in the United Kingdom, to submit the variants they identify to public databases such as ClinVar. That guidance is explicit about why the obligation matters: prompt and accurate molecular diagnosis is crucial for targeting treatment and optimising patient care, and it is therefore described as the professional responsibility of the clinical genomics community to ensure that data is shared appropriately and responsibly.

ClinVar, maintained by the US National Center for Biotechnology Information, functions as a shared clinical evidence base for variant interpretation. When a laboratory identifies a change in a patient’s DNA, the clinical significance of that change, whether it is pathogenic, benign, or of uncertain significance, depends on the accumulated evidence from every patient in whom it has previously been observed. Each new submission strengthens the collective ability to interpret variants accurately, supports the reclassification of variants as knowledge evolves, and feeds directly into research on rare disease. When laboratories withhold their findings from this shared pool, they create structural blind spots that selectively limit the evidence available to every other diagnostic service, clinician, and researcher who depends on it.

The freedom of information responses indicate that three of the seven hubs, the South East hub led by Guy’s and St Thomas’ NHS Foundation Trust, the South West hub led by North Bristol NHS Trust, and the North East and Yorkshire hub led by The Newcastle upon Tyne Hospitals NHS Foundation Trust, are not routinely submitting variants to ClinVar. The laboratories point to good intentions and say they lack the necessary staff and technology to meet the requirement, adding that they intend to implement it as soon as possible. Even among the four hubs that are routinely submitting, the investigation found significant backlogs of variants that remain unsubmitted, along with inconsistencies and gaps in what has been shared.

For families affected by rare genetic conditions, the consequences of this fragmented data landscape are not abstract. Sophie Muir, whose son’s variant in the CACNA1C gene, associated with a severe multisystem disorder, was not picked up through NHS testing, describes the effect of inconsistent submission practices on the diagnostic pathway. ClinVar, she explains, functions as the shared clinical evidence base on which variant interpretation depends, and uneven participation creates blind spots that selectively limit the evidence available for rare disease diagnosis, variant reclassification, and research. Muir, who chairs the rare disease charity the Timothy Syndrome Alliance, argues that the failure amounts to a betrayal of the public investment in genomic medicine.

Other clinicians and researchers echo that concern. Jack Underwood, a forensic psychiatry registrar, observes that there is a loop that is broken when variants are not submitted to ClinVar, a reference to the feedback cycle through which each diagnosed patient’s data helps interpret the next. Professor John Sayer, an expert in rare inherited kidney diseases, is more direct, warning that patients ultimately are missing out because this is not happening. In a field where a single confirmed molecular diagnosis can end a diagnostic odyssey lasting years or even decades, and where treatment decisions, surveillance regimes, and family planning all hinge on accurate variant interpretation, the absence of shared evidence translates directly into prolonged uncertainty and delayed care.

The laboratories themselves cite practical constraints as the principal reason for the delay. Staffing was the issue most frequently mentioned in the freedom of information responses, reflecting the chronic workforce pressures that have affected NHS laboratory services across the board. Some hubs also blamed the time taken to develop the policies needed to govern submission, alongside technology and infrastructure issues that complicate the extraction and formatting of variant data for external databases. Those hubs that have not yet implemented routine ClinVar submissions say they plan to do so this year, suggesting that the gap, while significant, may be transitional rather than permanent.

Yet the explanations have done little to reassure critics who see the problem as symptomatic of something larger. Clare Turnbull, Professor of Cancer Genetics at the Institute of Cancer Research in London, frames the delay in variant sharing as part of a wider issue of lagging NHS information technology systems hobbling progress and innovation in genomic medicine. The United Kingdom invested heavily in the 100,000 Genomes Project and built the NHS Genomic Medicine Service on the promise that publicly funded sequencing would generate a continuously improving knowledge base. When the laboratories at the sharp end of that service cannot feed their clinically interpreted findings back into shared databases, the value of that national investment is diminished for every patient who follows.

The question of stewardship is central to the criticism. Muir points out that the GLHs are generating clinically interpreted data within a publicly funded system, and that public funds are going in to pay for genetic testing that is then not being shared. Sayer agrees that variant sharing maximises the value of the public investment in genetic testing and adds a further ethical dimension: knowing someone’s genetics is privileged information, and if a patient has consented to their data being used for the greater good, then failing to allow that information to be shared betrays the patient’s trust. Consent, in other words, is being given on the understanding that participation in genomic medicine is collective, an understanding that the current submission failures undermine.

For Muir and families like hers, the stakes are measured in time that rare disease patients do not have. The diagnostic odyssey for a rare genetic condition frequently involves years of inconclusive tests, and every variant that sits unsubmitted in a laboratory backlog is evidence that could have shortened that journey for another child. We do not have time on our side, she says, noting that families, children, researchers, clinicians, patient advocacy organisations, and the life sciences sector all need this data. The BMJ investigation makes clear that the technical requirement to share variant data exists, that the professional guidance is unambiguous, and that the remaining obstacles are organisational rather than scientific. Whether the three non-compliant hubs deliver on their stated intention to implement routine submissions this year will determine whether England’s genomic medicine service can close a gap that, until now, has been quietly limiting the power of one of the most ambitious publicly funded healthcare data systems in the world.

Subject of Research: NHS genomic laboratories' inconsistent sharing of genetic variant data in public databases for rare disease diagnosis

Article Title: NHS labs fails to share data vital for diagnosis and care of rare diseases

Article References: NHS labs fails to share data vital for diagnosis and care of rare diseases. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: NHS, genomics, rare diseases, ClinVar, genetic variants, variant interpretation, Genomics Laboratory Hubs, The BMJ, data sharing, molecular diagnosis, patient advocacy, genetic testing

Researchers at Dongguan Maternal and Child Health Care Hospital in China retrospectively analyzed 99 children born small for gestational age who had either failed to show catch-up growth, presented with multisystem anomalies, or both. Using trio-based whole-exome sequencing, in which the affected child and both parents are sequenced together, the team searched for the genetic roots of these children’s conditions. The results were striking: a confirmed molecular diagnosis was established in 59 of the 99 children, a diagnostic yield of 59.6 percent.

Trio-based whole-exome sequencing works by capturing and reading the protein-coding portions of the genome—the exome—in all three members of a family. Because the parents’ sequences are available for comparison, scientists can determine whether a suspicious variant was inherited from a carrier parent or arose spontaneously in the child. This segregation analysis is critical for interpreting variants correctly, since the same DNA change can be harmless in one context and disease-causing in another.

The study’s methodology went beyond simple sequence analysis. In addition to examining single-nucleotide and small insertion-deletion variants, the researchers mined the sequencing read-depth data to infer copy-number variants—large deletions or duplications of chunks of chromosomes that conventional exome pipelines often miss. Sequence variants were confirmed by Sanger sequencing, the older but highly accurate method of reading individual DNA fragments. Variants were then classified using the standards developed by the American College of Medical Genetics and Genomics and the Association for Molecular Pathology for sequence variants, and the ACMG/ClinGen criteria for copy-number variants.

Only pathogenic or likely pathogenic findings whose inheritance pattern fit the family data were counted as molecular diagnoses. This conservative approach matters in clinical genetics, where over-interpretation of ambiguous variants can lead to false diagnoses. The team also identified four variants that remained classified as variants of uncertain significance—changes that could not be confidently labeled benign or disease-causing and therefore did not count toward the diagnostic yield.

Breaking down the 59 diagnoses, the researchers found considerable diversity in the underlying genetic architecture. Monogenic disorders—single-gene defects—accounted for the largest share, explaining 44 children, or 74.6 percent of the diagnosed cases. Copy-number variants explained 13 children, or 22.0 percent. Notably, two children received dual diagnoses, carrying both a disease-causing sequence variant and a pathogenic copy-number variant, a reminder that a single genetic explanation is not always sufficient.

The diagnostic yield differed meaningfully between the two clinical presentations. Among children with isolated failed catch-up growth—those born small who never caught up but had no other anomalies—trio-WES produced a diagnosis in 52.9 percent of cases, or 9 of 17 children. Among children with multisystem anomalies, the yield rose to 61.0 percent, or 50 of 82 children. The higher yield in the multisystem group aligns with genetic principles: when developmental disturbances affect multiple organ systems, a shared underlying genetic cause becomes more likely, and the genome search has more clinical features to anchor interpretations.

The clinical implications are considerable. A molecular diagnosis does more than attach a name to a condition. It can redirect management toward condition-specific surveillance and treatment, inform parents about recurrence risks for future pregnancies, and spare families a prolonged diagnostic odyssey of repetitive and often invasive testing. For children born small for gestational age, identifying a specific genetic syndrome may reveal risks—such as endocrine dysfunction, renal anomalies, or tumor predisposition—that would otherwise be missed. Genetic counselling grounded in an identified inheritance model allows clinicians to tell parents precisely whether the condition could recur in a subsequent child.

The authors are careful to draw boundaries around their conclusions. The 99 children in this study were not a random sample of all children born small for gestational age; they were a clinically selected, high-risk subgroup who had already raised concern because of persistent growth failure or anomalies affecting multiple systems. The researchers explicitly caution that the 59.6 percent diagnostic yield should not be generalized to the overall SGA population, most of whom are simply constitutionally small and healthy. Applying expensive genome-wide testing to every child born small, without clinical red flags, would produce far lower yields and risk incidental and ambiguous findings.

Still, the study adds to a growing body of evidence that trio-based genomic sequencing should be considered early rather than late in the evaluation of children with unexplained growth failure and congenital anomalies. As sequencing costs continue to fall and analytical tools improve—including methods that detect copy-number variants from exome data without separate chromosome microarray testing—the case for a single comprehensive genetic test at the start of the diagnostic journey grows stronger. For families facing the anxiety of a child who is not growing as expected, a faster path to answers may now be within reach.

Subject of Research: Use of trio-based whole-exome sequencing to diagnose genetic disorders in children born small for gestational age with failed catch-up growth or multisystem anomalies

Article Title: Clinical application of trio-based whole-exome sequencing in children born small for gestational age with failed catch-up growth or multisystem anomalies

Article References: Jiang, Z., Zhong, X., Lin, P., Yan, T., He, W., Guo, L., Xie, Y., Yuan, H., & Cheng, S. (2026). Clinical application of trio-based whole-exome sequencing in children born small for gestational age with failed catch-up growth or multisystem anomalies. BMC Pediatrics. https://doi.org/10.1186/s12887-026-07633-5

Image Credits: AI Generated

DOI: 10.1186/s12887-026-07633-5

Keywords: small for gestational age, trio whole-exome sequencing, failed catch-up growth, multisystem anomalies, molecular diagnosis, copy-number variants, genetic counselling, pediatrics, next-generation sequencing, rare variants, clinical genetics, Clinical

The clinical problem the team set out to address is well known in genomic medicine. Molecular diagnosis of rare disease currently plateaus at roughly fifty percent of patients, even after whole exome or whole genome sequencing. A substantial share of those unresolved cases involves variants that alter splicing, the process by which RNA transcripts are cut and re-joined to produce mature messenger RNA. Predicting whether a DNA change actually disrupts splicing in a patient’s tissues remains notoriously difficult, and variants of uncertain significance accumulate in reports without a practical way to test their effects directly.

Short-read RNA sequencing, which fragments transcripts into small pieces before reading them, often cannot show how exons connect across a whole transcript. Long-read platforms from Oxford Nanopore Technologies solve this by reading RNA-derived molecules end to end, revealing full isoform structures. Until now, however, long-read RNA approaches have typically demanded large control cohorts, complex bioinformatics and tissue samples that are hard to obtain, keeping them confined to specialist research laboratories rather than routine diagnostics.

RAPID, short for RNA Analysis Pipeline for Integrated Diagnostics, was designed from the outset to be diagnostically deployable. It is fully modular, covering the entire sample-to-answer journey, from primer design targeting genes of interest through nanopore sequencing to reproducible single-sample interpretation. Cases entered the workflow after exome or genome sequencing and multidisciplinary team review had narrowed the search to five or fewer candidate genes, meaning the sequencing effort could be focused and fast. Crucially, the method relies on accessible tissues such as blood and does not require large control datasets for interpretation.

The study applied the workflow to six probands with suspected monogenic neurometabolic disease, and the outcomes illustrate three distinct diagnostic scenarios. In two cases, targeted long-read RNA sequencing confirmed pathogenic splice disruption at the transcript level, converting uncertainty into a resolved molecular diagnosis. In one case, the RNA evidence argued against a candidate gene, prompting its exclusion and redirecting the diagnostic search. In the remaining three cases, transcript-level findings prioritised further DNA investigation, refining how the variants of uncertain significance should be weighed.

Technically, the workflow captured amplicons spanning the relevant exons and splice junctions of each candidate gene, generating reads long enough to assemble near-full-length isoform structures. The team demonstrated reproducibility by showing consistent isoform composition for a control gene across commercial blood RNA samples and an independent public long-read dataset, and they characterised the minimum read depth needed to detect transcripts at low fractional abundance. Quality control metrics, including read length and depth, were achieved using standard long-read sequencing infrastructure within a clinically relevant timeframe.

The authors also mapped their RNA results onto the established variant interpretation framework used by clinical scientists, in which aberrant splicing leading to frameshifts or premature stop codons, particularly in transcripts subject to nonsense-mediated decay, can support pathogenic classifications. By providing direct, mechanism-level evidence rather than in silico predictions, the workflow strengthens this evidence hierarchy and gives diagnostic laboratories a practical route to resolving variants that would otherwise remain reportable only as uncertain.

The significance for patients and families is considerable. A definitive molecular diagnosis can end a diagnostic odyssey that sometimes lasts decades, inform prognosis, guide surveillance and treatment, enable accurate genetic counselling, and open doors to targeted therapies and clinical trials. For a field in which half of patients still leave the sequencing process without answers, a rapid, cost-effective test that interrogates RNA directly addresses one of the largest remaining diagnostic gaps.

The researchers argue that RAPID shows long-read RNA sequencing can be implemented within existing diagnostic infrastructure, offering a scalable path to routine transcript-level assessment in clinical genomics. As nanopore sequencing becomes more widespread in NHS and hospital laboratories, workflows of this kind could shift splicing variant interpretation from probabilistic prediction to direct functional measurement. Supported by funding from the charity Sparks and conducted with appropriate ethical approvals and participant consent, the study points toward a future in which reading the transcript itself becomes a standard step in solving rare disease.

The biological importance of splicing in human disease provides useful context for why this approach matters. Introns interrupt most human genes, and their precise removal depends on short sequence signals at exon boundaries that are frequently disrupted by single-nucleotide changes lying well outside protein-coding regions. Because such variants often sit in positions that protein-prediction tools ignore, they can be classified as benign or left as uncertain even when they silently abolish a transcript. Deep intronic changes can also activate cryptic exon inclusion, an effect essentially invisible to standard exome analysis, which is one reason splice-altering variation has been described as a substantial hidden burden within the undiagnosed fraction of rare disease cohorts.

The interpretation framework applied in the study reflects a broader international movement toward using RNA evidence in clinical classification. Guidelines from professional bodies now allow aberrant splicing demonstrated at the transcript level to contribute to pathogenic classifications, provided the altered transcript is shown to escape nonsense-mediated decay or to produce a clearly deleterious product. This matters because a large proportion of loss-of-function variants predicted to trigger nonsense-mediated decay are already treated as pathogenic by default; demonstrating experimentally that a variant of uncertain significance produces the same consequence effectively moves it into that well-established category. Conversely, showing that a candidate variant leaves splicing intact can be equally decisive, as the gene-exclusion case in this cohort illustrates.

Tissue choice is a central consideration for any transcript-based diagnostic test. Genes are not expressed uniformly across the body, and the reference resources that underpin transcript interpretation, such as population-scale tissue atlases, show that many disease-relevant genes have their highest expression in tissues that cannot ethically or practically be sampled. Blood, however, is accessible, and the workflow’s reliance on peripheral blood RNA, collected in standard preservation tubes and stored frozen, means the logistics resemble those of routine clinical phlebotomy rather than specialist tissue procurement. The supplementary analyses showing that isoform composition of a control gene is consistent across commercial RNA references and public datasets speak to the reproducibility that regulators and accreditation bodies would expect of a deployable assay.

The depth requirements characterised by the team address a practical question that any diagnostic laboratory must answer before adopting such a test: how much sequencing is enough. Because a deleterious transcript may represent only a small fraction of all transcripts from a given gene, particularly when nonsense-mediated decay degrades the abnormal product rapidly, sensitivity at low fractional abundance is essential. Mapping the relationship between transcript rarity and required read depth gives laboratories a principled basis for setting sequencing targets and quality thresholds rather than relying on ad hoc criteria.

The study also sits within a distinctive UK genomic infrastructure. Several participating families had previously been sequenced through national genome programmes, and the ethical frameworks governing those programmes permit recontact of participants for follow-up sampling, a mechanism that allowed the researchers to obtain fresh RNA from already-investigated patients. This recontact pathway, coordinated through clinical interpretation partnerships, represents a model for how long-read RNA follow-up could be layered onto existing genomic medicine services without requiring patients to restart the consent and recruitment process from scratch.

From a health-systems perspective, the economics of the approach deserve emphasis. Whole genome sequencing has become affordable at scale, but the interpretation bottleneck, not the sequencing itself, now limits diagnosis. A targeted assay that sequences only a handful of genes consumes modest sequencing capacity on instruments that many hospital laboratories already operate or can readily access, and the modular design means primer sets can be redesigned quickly for each new case. The near-full-length isoform output also reduces interpretive ambiguity, because the analyst sees the complete exon connectivity of each transcript rather than inferring it from fragmented short reads.

The neurometabolic focus of the cohort is itself informative. Leukodystrophies and related neurodegenerative conditions of childhood often present with nonspecific imaging findings and progressive symptoms, and several of the genes implicated in these disorders are known to harbour splice-disrupting variants that confound standard pipelines. For families facing such progressive conditions, the speed of the workflow is not merely convenient; an earlier molecular answer can determine eligibility for emerging therapies, some of which are most effective when started before irreversible neurological damage accumulates.

Looking forward, the study suggests a tiered model of genomic diagnosis in which short-read sequencing remains the first-line discovery tool, while targeted long-read RNA analysis serves as a rapid functional triage step for the subset of cases with splice-relevant candidates. The authors’ demonstration that results can be obtained within a clinically relevant timeframe, using standard infrastructure and single-sample interpretation without large control cohorts, positions transcript-level evidence to become a routine component of multidisciplinary review rather than a research exception reserved for specially funded projects.

Subject of Research: A targeted long-read RNA sequencing workflow for functionally resolving splicing variants in rare disease diagnosis

Article Title: RAPID: a targeted long-read RNA workflow for functional resolution of splicing variants in rare disease

Article References: Montgomery, K.-A., Macpherson, H., Anderson, C., Wade, C., Gustavsson, E. K., Lynch, D. S., Wilson, L. C., Davison, J., Wakeling, E., Tuschl, K., Houlden, H., Clement, E., Mills, P. B., & Ryten, M. (2026). RAPID: a targeted long-read RNA workflow for functional resolution of splicing variants in rare disease. Genome Medicine. https://doi.org/10.1186/s13073-026-01754-3

Image Credits: AI Generated

DOI: 10.1186/s13073-026-01754-3

Keywords: long-read RNA sequencing, Oxford Nanopore Technologies, splicing variants, rare disease diagnostics, variants of uncertain significance, neurometabolic disease, transcriptomics, molecular diagnosis, clinical genomics, whole exome sequencing, RNA splicing, diagnostic workflow