The panel itself is ambitious in scope. The researchers assembled 564 gene loci linked to Parkinson’s disease, repeat expansion disorders, and other neurodegenerative movement disorders, drawing on established diagnostic panels from the genomics company CeGaT, the International Parkinson and Movement Disorder Society Taskforce, 90 Parkinson’s disease genome-wide association study loci, and the catalog of known repeat expansion genes. Each gene locus was padded with 50 kilobases of flanking sequence on either side, and the mitochondrial genome was added as a separate target. Together the target regions span roughly 113.6 million base pairs, or about 3.44 percent of the GRCh38 human reference genome, comfortably within the 1 to 5 percent fraction recommended for optimal enrichment with adaptive sampling.

The sequencing strategy relies on Oxford Nanopore Technologies’ adaptive sampling, a clever real-time filtering technique built into the MinKNOW operating software. As DNA molecules thread through the protein nanopores, the software maps the first few hundred bases of each read against a predefined BED file of target coordinates. Reads that align to the panel’s genes continue to be sequenced in full, while off-target molecules are ejected from the pore, freeing it to capture another molecule. The result is targeted enrichment without any wet-lab capture step, preserving the native DNA and its long read lengths. In this study, three patient samples were multiplexed per PromethION flow cell and sequenced for 72 hours using R10.4.1 flow cells and super-accuracy base calling with the Dorado basecaller.

The performance metrics are respectable for a first demonstration. Across 18 individuals, the panel achieved a mean on-target coverage of 24X per sample, with a standard deviation of 9X, and a mean on-target read N50 of 21.5 kilobases, a read-length metric considered suitable for detecting structural variants. The average Phred quality score was 19.7. Coverage varied considerably across loci, partly because some genes sit in notoriously difficult genomic terrain: several panel genes lie within or near the highly polymorphic major histocompatibility complex on chromosome 6, and 20 of the 31 genes with mean coverage below 15X are X-linked and therefore less abundant in the ten male participants. The mitochondrial genome, by contrast, reached a mean depth of 1256X.

To test diagnostic utility, the team sequenced 15 positive controls with previously characterized pathogenic variants and 3 negative controls with idiopathic Parkinson’s disease or frontotemporal dementia. The positive controls spanned the full variant spectrum: single-nucleotide variants and small indels in GBA1, LRRK2, PRKN, and RAB32; large deletions in PRKN ranging from 20 to 320 kilobases; a 1.7-megabase triplication encompassing the entire SNCA gene; and repeat expansions in ATXN1, ATXN2, ATXN3, HTT, DAB1, FGF14, C9orf72, and the TAF1-SVA retrotransposon insertion that causes X-linked dystonia-parkinsonism. Of the 20 expected pathogenic variants, 17 were clearly identified, a detection rate of 85 percent with a Clopper-Pearson 95 percent confidence interval of 62 to 97 percent.

The small-variant results were flawless. The EPI2ME human variation workflow, which chains together Minimap2 alignment, the Clair3 deep-learning variant caller, the Sniffles2 structural variant caller, and the Straglr repeat caller, correctly detected all six known single-nucleotide variants and small indels, including the LRRK2 p.G2019S mutation and three PRKN variants. This success reflects years of improvement in nanopore base-calling accuracy, with Q-scores above 20 now routine using R10 chemistry. Structural variants proved harder. Sniffles2 with default parameters caught two large PRKN deletions but missed three others, and no caller detected the SNCA triplication. However, the alternative callers CuteSV and SVIM, run with adjusted size parameters, recovered two of the missed deletions, and visual inspection in the Integrative Genomics Viewer confirmed all PRKN deletions, enabling the team to establish compound heterozygosity through read-based phasing with WhatsHap. The SNCA triplication left a telltale signature even without a formal call: coverage over the SNCA locus was 2.5-fold higher than the panel average, a hint that dedicated copy-number tools for targeted data could convert into a definitive diagnosis.

Repeat expansions showed a mixed picture. Straglr correctly identified pathogenic expansions in ATXN1, ATXN2, ATXN3, and HTT, with repeat numbers closely matching prior results, and the independent Noise Cancelling Repeat Finder tool confirmed them with deviations of only a few repeat units. Expansions in DAB1 and FGF14 were missed by the workflow version of Straglr simply because those genes are absent from its reference catalog, but a standalone version with a custom input file, together with NCRF, detected both. The two failures are instructive. The C9orf72 hexanucleotide expansion, whose GC-rich repeats can form G-quadruplex structures, yielded only six expanded reads despite 43X coverage, too few and too variable to assign a reliable repeat number. The TAF1-SVA insertion is absent from the GRCh38 reference genome entirely, so adaptive sampling discarded some relevant reads as off-target, and the gene’s X-chromosome location further reduced coverage in male samples, leaving only three informative reads. Both cases were classified as inconclusive rather than false negatives, and the authors suggest that reducing the target fraction or increasing coverage could resolve them.

Beyond confirming known variants, the panel surfaced five additional findings in five patients that had not been previously reported for those individuals: potentially pathogenic variants in STXBP2, AP4S1, RARS2, and ALS2, and a CCTG repeat expansion of 137 units in CNBP, the gene associated with myotonic dystrophy type 2. All were validated by Sanger sequencing or PCR and gel electrophoresis. Notably, none of the affected patients showed clinical features of the corresponding conditions, which are mostly recessive, so the team interprets these as incidental findings demanding cautious counseling rather than new diagnoses. Intriguingly, 13 patients also carried benign AAAAG expansions in RFC1, below the pathogenic threshold of 250 repeats, illustrating how comprehensively long reads expose the repetitive landscape of the genome.

The economics are part of the appeal. With three samples multiplexed per flow cell, the sequencing cost per patient, roughly 330 to 830 euros, matches a whole-genome nanopore run for a single individual, and validation steps would bring the total to roughly 500 to 1000 euros as a first-line test. Because the panel is defined by a simple text file of genomic coordinates, it can be updated overnight as new Parkinson’s risk loci and repeat motifs are discovered. The authors envision it as either a first-line combined test ordered by an experienced clinician or a second-line assay after negative short-read sequencing. Limitations remain real: the cohort was small, four samples came from induced pluripotent stem cells rather than blood, which is unsuitable for clinical diagnostics because reprogramming can introduce somatic variants, and most variant callers are still optimized for whole-genome rather than targeted long-read data. Manual inspection of difficult variants, about 30 minutes per sample, is not scalable. Still, as specialized tools mature and larger validation cohorts accumulate, the vision of a single, flexible, cost-effective test that reads out point mutations, massive rearrangements, and sprawling repeat expansions in one pass is coming sharply into focus.

Subject of Research: A targeted long-read nanopore sequencing gene panel for the combined genetic diagnosis of Parkinson's disease and repeat expansion disorders

Article Title: Unified long-read panel for Parkinson’s and repeat expansion disorders

Article References: Fienemann, A., Prietzsche, J. C., Laβ, J., Much, C., Schaake, S., Lüth, T., Gabbert, C., Zimprich, A., Stögmann, E., König, T., Ganos, C., Gül-Demirkale, T., Başak, A. N., Jamora, R. D. G., Rosales, R. L., Saranza, G., Diesta, C. C. E., Möller, M., Borsche, M., … Trinh, J. (2026). Unified long-read panel for Parkinson’s and repeat expansion disorders. npj Parkinson's Disease, 12(1), Article 233. https://doi.org/10.1038/s41531-026-01585-4

Image Credits: AI Generated

DOI: 10.1038/s41531-026-01585-4

Keywords: Parkinson's disease, long-read sequencing, Oxford Nanopore, adaptive sampling, repeat expansion disorders, genetic diagnostics, structural variants, LRRK2, PRKN, SNCA, C9orf72, gene panel

Carrier screening is based on a simple biological premise. Many severe genetic disorders, including thalassemias, metabolic conditions, and neuromuscular diseases, follow an autosomal recessive inheritance pattern, meaning a child is affected only when both parents carry a pathogenic variant in the same gene. Carriers themselves are typically completely healthy, with no symptoms and often no family history, which is precisely why untargeted testing has historically missed so many at-risk couples. When both members of a couple are carriers of variants in the same gene, each pregnancy carries a 25 percent chance of being affected. Knowing this risk in advance opens a range of reproductive options, from preimplantation genetic testing during in vitro fertilization to prenatal diagnosis, informed family planning, and preparation for the medical care an affected child might need.

What distinguishes the Singapore program is its deliberate tailoring to Asian genetic diversity. Rather than adopting a panel built around variants common in European populations, the team designed a customized 112-gene panel targeting recessive diseases that are population-specific to the major ancestral groups represented in the country, including Chinese, Malay, Indian, and other Asian communities. This approach reflects a growing recognition in genomics that variant databases and screening panels calibrated on European data perform poorly elsewhere, both missing genuine carriers and generating confusing results from variants that behave differently across ancestries. Singapore, with its compact geography and well-characterized multiethnic population, provides an ideal setting to demonstrate how precision medicine can be adapted to Asian diversity rather than imported wholesale from Western frameworks.

The program operates nationwide, and its pilot phase began in September 2024. Participants receive culturally tailored online education about the screening program before providing samples, and results are returned with genetic counseling and a full discussion of reproductive options. The numbers reported so far illustrate both the appetite for such testing and the practical realities of implementation. Since the pilot began, 1,619 couples have registered interest in the program, and 60 percent of those deemed eligible went on to participate. Among the 550 couples who had received their results at the time of reporting, six couples, or 1.0 percent, were identified as being at increased risk of having a child affected by a recessive genetic condition. That figure, while small in absolute terms, represents couples who now have the knowledge to make fully informed reproductive decisions, something that would otherwise have remained invisible to them.

Beyond the laboratory and clinic, the research team invested heavily in understanding how the wider community views genetic screening, recognizing that a program’s success depends as much on social acceptance as on scientific accuracy. The researchers surveyed 1,002 community members, including both couples who had participated in the program and members of the general public. The results showed that interest in carrier screening was high, with 59 percent of respondents expressing interest across the cohort. However, the survey also revealed important fault lines: awareness of carrier screening, intent to participate, and understanding of the implications for reproductive options differed significantly by sociodemographic factors such as ancestry and religion. These findings underscore that a one-size-fits-all communication strategy would leave parts of the population behind, potentially exacerbating existing health inequities rather than reducing them.

Religious and cultural sensitivity emerged as a central theme of the implementation effort. The team engaged directly with religious leaders, whose support for the program was indicated through the engagement process, a step that reflects the realities of implementing reproductive genetics in a society where religious beliefs can shape attitudes toward prenatal testing and reproductive choice. By building these relationships before scaling up, the program aimed to ensure that its messaging and services would be culturally appropriate and that communities would not feel targeted or stigmatized by screening offers. This kind of groundwork is often overlooked in genomic medicine programs, which tend to emphasize technical validation over social license, but the Singapore experience suggests the two are inseparable.

The healthcare professional perspective revealed a different set of challenges. Among 113 healthcare professional respondents, there was broad acknowledgment that carrier screening will become routine in medical care, a consensus that mirrors international trends as sequencing costs fall and professional guidelines expand. Yet the same respondents reported limited confidence and limited resources for delivering this service. This gap between expected demand and workforce readiness is a familiar problem in genomics. Genetic counseling capacity is scarce in most countries, and frontline physicians in obstetrics, general practice, and family medicine often receive little training in interpreting carrier screening results or communicating residual risk. The Singapore findings suggest that any country contemplating population screening must budget as much for professional education and counseling infrastructure as for the genetic tests themselves.

The program sits within a broader national strategy. It forms part of Singapore’s National Precision Medicine initiative, a multi-phase government effort to build genomic infrastructure tailored to Asian populations, supported by the National Research Foundation and the Ministry of Health. Funding for the carrier screening program itself came through the Temasek Foundation and strategic academic funds, with the community questionnaire study supported by Singapore’s Social Science Research Council. This layered funding model, combining philanthropy, national research investment, and health system integration, may prove instructive for other countries weighing how to finance genomic screening programs that are expected to run for decades rather than years.

The technical architecture of the program also merits attention. The 112-gene panel was developed with contributions from the hospital’s DNA Diagnostic and Research Laboratory and the national diagnostics manufacturing hub, with a dedicated reporting system built at the National Heart Centre Singapore. Variant classification follows established frameworks from the American College of Medical Genetics and Genomics, and population frequency data drawn from resources such as the Genome Aggregation Database inform the interpretation of variants in the local context. Ethics approval was obtained from the SingHealth Centralised Institutional Review Board, and the program’s design incorporated input from clinical geneticists, genetic counselors, and genetics nurses who reviewed the educational content delivered to participants. The result is an end-to-end system in which education, testing, reporting, and counseling are integrated rather than bolted together.

The authors conclude that these early outcomes and community engagement findings are now guiding the expansion of population-based carrier screening in Singapore, but they are explicit that this expansion is contingent on addressing practical challenges through equitable outreach and professional training. The study’s significance extends well beyond the island nation. Most of the world’s population lives in Asia, yet genomic screening programs have been designed and validated overwhelmingly in Europe, North America, and Australia. Singapore’s experience demonstrates that population-specific panels, culturally grounded engagement, and honest assessment of healthcare workforce limitations can be combined into a workable national program. As other Asian countries develop their own precision medicine strategies, the Singapore model offers both a technical template and a cautionary lesson: the genetics may be the easy part, and the harder work lies in earning the trust of diverse communities and preparing clinicians to translate genomic knowledge into genuinely useful reproductive choices.

Subject of Research: Implementation of population-based reproductive carrier screening for diverse Asian populations in Singapore

Article Title: Implementing reproductive carrier screening to include diverse Asian populations: insights from Singapore

Article References: Bylstra, Y., Juann, M. Y., Teo, J. X., Goh, J., Choi, C., Chan, S., Song, C., Yin Goh, J. C., Siew Chai, N. B., Lieviant, J. A., Toh, H. J., Chan, S. H., Blythe, R., Menezes, M., Yang, C., Hodgson, J., Graves, N., Sng, J., Lim, W. W., … Jamuar, S. S. (2026). Implementing reproductive carrier screening to include diverse Asian populations: insights from Singapore. BMC Medicine. https://doi.org/10.1186/s12916-026-05286-w

Image Credits: AI Generated

DOI: 10.1186/s12916-026-05286-w

Keywords: reproductive carrier screening, genetic testing, precision medicine, Singapore, Asian populations, autosomal recessive disease, genetic counseling, population screening, community engagement, healthcare professionals, gene panel, thalassemia

Myopathies — diseases that primarily affect skeletal muscle — represent one of the most heterogeneous diagnostic challenges in clinical genetics. They can arise from defects in hundreds of different genes, spanning structural muscle proteins, ion channels, metabolic enzymes, mitochondrial machinery and RNA-processing factors. Clinical presentations overlap heavily: a patient with progressive weakness may ultimately turn out to have a dystrophinopathy, a metabolic myopathy, a congenital myopathy or an inflammatory condition with a genetic underpinning. This heterogeneity has long forced diagnostic laboratories to choose between narrowly targeted gene panels, which are cheap but blind to anything outside their curated gene list, and exome sequencing, which captures the protein-coding portion of the genome but systematically misses variants buried in introns, regulatory regions and structural rearrangements.

The study was conducted within PFMG2025, a national program piloted by the French Genomic Medicine Initiative to bring genome sequencing into routine clinical practice for rare diseases. Between July 2020 and October 2024, patients with myopathies who remained genetically undiagnosed after prior testing underwent genome sequencing at two designated clinical laboratories: SeqOIA in Paris and AURAGEN in Lyon. The retrospective analysis drew on clinical, paraclinical and genetic data collected across these platforms, making it one of the largest real-world assessments of genome sequencing for muscle disease conducted at a national scale. Crucially, the sequencing was performed as part of ordinary clinical care, not as a research protocol, which means the results reflect what health systems can realistically achieve rather than what is possible only under ideal laboratory conditions.

The headline result is deceptively simple: among 265 families, genome sequencing produced a conclusive molecular diagnosis — variants classified as likely pathogenic or pathogenic under American College of Medical Genetics and Genomics criteria — in 68 cases, a diagnostic yield of 26 percent. That figure might appear modest until it is placed in context. Every one of these patients had already passed through the existing diagnostic cascade, including, for many, gene panels and exome sequencing specifically designed to catch myopathy genes. A 26 percent yield in this heavily pre-tested population demonstrates that genome sequencing is not merely a marginal upgrade over existing methods; it reaches diagnostic territory that those methods structurally cannot access.

The technical reasons for this advantage lie in the fundamental differences between sequencing strategies. Gene panels and exome approaches rely on capture-based enrichment, which selectively amplifies exons — the roughly one to two percent of the genome that encodes proteins — before sequencing. Deep intronic regions, where pathogenic variants can disrupt splicing by creating cryptic exon insertion sites, are largely invisible to these methods unless specifically probed. Copy-number variants, complex rearrangements and variants in poorly captured exons are also systematically underdetected. Whole-genome sequencing, by contrast, reads across the entire genome uniformly, without capture bias, allowing laboratories to detect deep intronic splice-altering variants, exon-level deletions and duplications, and other non-coding pathogenic mechanisms in a single assay. This breadth proved decisive in the French cohort: the authors report that genome sequencing was necessary for the resolution of 20.5 percent of all cases with conclusive or candidate findings, because the responsible variants would not have been detectable using other established techniques.

Beyond the confirmed diagnoses, the study highlights the more nuanced contribution of variants of uncertain significance. When the researchers considered candidate VUS findings that nonetheless raised a strong diagnostic hypothesis — for example, variants in genes consistent with the patient’s clinical presentation, or variants whose pathogenicity is supported by emerging functional evidence but which do not yet meet formal ACMG criteria for pathogenicity — the effective diagnostic yield rose to 44 percent. In clinical practice, such findings are not endpoint diagnoses, but they can reshape patient management, guide surveillance for known complications, inform reproductive counseling, and direct families toward research studies and, increasingly, toward gene-specific clinical trials. As gene-specific therapies for neuromuscular diseases multiply, the difference between a confirmed diagnosis and a strong hypothesis is shrinking in practical importance, because both can determine eligibility for intervention.

The identification of deep intronic variants deserves particular emphasis, because these discoveries are rewriting the known architecture of neuromuscular disease. Pathogenic changes located thousands of base pairs away from the nearest exon were long considered unfindable at diagnostic scale, yet they are now recognized as substantial contributors to myopathies — most famously in dystrophinopathies, where deep intronic pseud exon activation accounts for a meaningful fraction of patients who previously tested negative on exons-focused assays. In the French cohort, the ability of genome sequencing to elucidate these complex variants, and to uncover previously undescribed pathogenic mechanisms, accounted for a large share of the diagnoses that panel and exome sequencing had missed. The authors argue that this capacity underscores the complex nature of neuromuscular genetic disorders and demonstrates how genome sequencing can deliver a genetic diagnosis within routine clinical practice rather than in specialized research settings.

The PFMG2025 program itself is a case study in how to operationalize genomic medicine at national scale. Funded by the French government through the National Research Agency under the Programme d’Investissements d’Avenir, the initiative connects a dense network of neuromuscular reference centers — spanning hospitals from Paris to Marseille, Lyon, Bordeaux, Grenoble and beyond — with centralized sequencing and analysis platforms. Clinicians across the FILNEMUS network prescribed genome sequencing for patients with suggestive phenotypes, encoded clinical information in standardized HPO terms, and returned findings through structured counseling pathways. This architecture allowed the study to capture the full diversity of myopathy subtypes and patient ages, from infants with congenital presentations to adults with slowly progressive weakness, and to measure performance in the messy reality of clinical medicine rather than in a curated cohort.

For patients and families, the practical consequences of a molecular diagnosis are difficult to overstate. A confirmed genetic cause ends the diagnostic odyssey — often a decade or more of investigations — and replaces uncertainty with a named condition that carries a defined natural history, evidence-based surveillance recommendations and, increasingly, targeted treatment options. Genetic diagnoses also ripple across families, enabling cascade testing of relatives, precise reproductive risk assessment and prenatal or preimplantation diagnostic options. In neuromuscular medicine specifically, the therapeutic landscape is changing rapidly: therapies for spinal muscular atrophy have transformed that disease’s trajectory, and gene-targeted approaches for Duchenne muscular dystrophy, limb-girdle muscular dystrophies and metabolic myopathies are advancing through trials. Every one of these interventions depends on knowing the exact gene involved — which makes the diagnostic yield of genome sequencing a direct determinant of who can access emerging treatments.

The French results add to a growing international consensus that the era of sequential, gene-limited testing is ending. Health systems that still route patients through panels first, then exomes, then genomes only after years of delay, are paying for repeated negative tests while withholding the one assay capable of detecting the full spectrum of pathogenic variation. The PFMG2025 findings — a 26 percent conclusive yield in a pre-tested myopathy population, rising to 44 percent with strong candidate findings, and more than one in five resolved cases achievable only through genome sequencing — make a data-driven argument for moving genome sequencing forward in the diagnostic pathway for muscle disease. As sequencing costs continue to fall and analysis pipelines for non-coding and structural variants mature, the question facing clinicians and payers is shifting from whether to adopt genome sequencing to how quickly the diagnostic cascade can be reorganized around it.

Subject of Research: Diagnostic yield of whole-genome sequencing compared with gene-panel and exome sequencing in genetically unresolved myopathies

Article Title: Genome sequencing improves diagnostic outcomes over panel and exome sequencings in myopathies: findings from the French PFMG2025 initiative

Article References: Verebi, C., Maino, A., Metay, C., Nectoux, J., Leturcq, F., Michel, L., Menassa, R., Pion, E., Cossee, M., Gorokhova, S., Krahn, M., Ramond, F., Fauré, J., Hersent, C., Malfatti, E., FILNEMUS PFMG2025 Consortium, Audic, F., Authier, F.-J., Barnerias, C., … Stojkovic, T. (2026). Genome sequencing improves diagnostic outcomes over panel and exome sequencings in myopathies: findings from the French PFMG2025 initiative. Genome Medicine. https://doi.org/10.1186/s13073-026-01769-w

Image Credits: AI Generated

DOI: 10.1186/s13073-026-01769-w

Keywords: genome sequencing, myopathy, diagnostic yield, PFMG2025, exome sequencing, gene panel, neuromuscular disorders, deep intronic variants, genomic medicine, France, rare disease diagnosis, variants of uncertain significance