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Open research questions in Genomics and Rare Diseases

79 unresolved questions extracted from the limitations and future-work sections of 355 Genomics and Rare Diseases papers in our library. Each links back to the study that raised it.

What the literature leaves open

  • BackgroundClear guidance is lacking regarding how truthset variants should be used for clinical validation of functional assays, namely determining the allocatable evidence points (EPs) towards clinical classification.

    Clinical validation of large-scale functional assays: insights from 2,120 gene-truthset-assay evaluations · 2026 · DOI

  • ResultsThe EPs from clinical validation of each assay varied widely according to which truthset was used across 2,120 permutations of gene-truthset-assay combinations.

    Clinical validation of large-scale functional assays: insights from 2,120 gene-truthset-assay evaluations · 2026 · DOI

  • While NGP has been widely integrated into differential diagnosis workflows, its application in variant reclassification within the ACMG framework remains underexplored.

    Leveraging Next-Generation Phenotyping in Dysmorphology to Support Variant Interpretation in Mowat-Wilson Syndrome · 2026 · DOI

  • Alzheimer's disease and related dementias (ADRD) and Parkinson's disease and related disorders (PDRD) have substantial genetic contributions, yet the role of rare damaging coding variants remains incompletely characterized at population scale.

    Population-scale burden analysis of rare damaging coding variants identifies novel risk genes for Alzheimer's disease and related dementias and Parkinson's disease and related disorders · 2026 · DOI

  • Abstract The genetic variants that cause inherited myopathies vary widely in type, size and sequence context, encompassing small sequence variants, large structural variants, repeat expansions, and more complex events, such as the D4Z4 macrosatellite contraction and hypomethylation that causes facioscapulohumeral muscular dystrophy.

    Targeted long-read sequencing enables comprehensive analysis of the genetic and epigenetic landscape of inherited myopathies · 2026 · DOI

  • What remains uncertain, however, is which specific cases they may help to solve, given the rarity, disperse distribution, and, in some cases, underdiagnosis or neglect of these conditions [38].

    A global survey of systems biology-based predictions of gene-rare disease associations to enhance new diagnoses · 2026 · DOI

  • As shown by recent landscape analyses, PEG lists vary widely in methodology, evidence definition, nomenclature, provenance tracking, and data structure, limiting interoperability, benchmarking, reuse, and adherence to FAIR principles.

    Predicted Effector Gene Aggregation, Standards and Unified Schema (PEGASUS): A Community Framework for Effector Gene Reporting · 2026 · DOI

  • As an example of discovery in an understudied phenotype, we highlight pityriasis versicolor, a superficial fungal infection with 34 loci in EstBB-FinnGen meta-analysis, including a rare Estonian-enriched splice-disrupting TNFSF15 variant.

    Leveraging nationwide health care records in Estonia to identify the genetic background of understudied disease phenotypes · 2026 · DOI

  • Rare disease research and diagnosis rely on the integration of genomic and phenotypic data generated across diverse clinical sites; however, the absence of widely adopted standards for representing genomic data and associated metadata has limited data interoperability, reuse, and cross-study analysis.

    Building an Interoperable Rare Disease Multi-omic Resource: The GREGoR Data Model and Dataset · 2026 · DOI

  • The severity metrics generated here provide a foundation for systematically ranking human phenotypes by their impact on health and quality of life, enabling more principled prioritisation of targets for therapeutic intervention, particularly in the context of rare diseases where evidence is sparse and resources for curation are limited.

    Using GPT-4 to annotate the severity of all phenotypic abnormalities within the human phenotype ontology · 2026 · DOI

  • The broader application of long-read sequencing (LRS) for repeat expansion characterization in myotonic dystrophy type 2 (DM2) and other repeat expansion disorders (REDs) remains limited by the lack of systematic validation and benchmarking of sequencing results and bioinformatic workflows.

    Long-read cross-platform validation reveals novel repeat features in myotonic dystrophy type 2 · 2026 · DOI

  • Despite the insights provided by this systematic review, several limitations must be acknowledged. Only six studies met the inclusion criteria, reflecting the scarcity of research on the psychosocial experiences of RD families. While this highlights the importance of the review in addressing a gap in the literature, the small number of studies limits the generalisability of the findings. As most included studies were qualitative, the review interpretivist epistemological paradigm. followed an Although this reduces generalisability, it allowed for a deeper exploration of lived experiences. The inclusion of one mixed-methods study introduced a post-positivist perspective, partially enhancing generalisability, thus compensating for the rest of the data which lied within a interpretive epistemological paradigm. The predominance of qualitative approaches is appropriate given the complexity of psychosocial experiences. However, the absence of longitudinal studies limits understanding of how emotional distress and coping strategies evolve over time and restricts causal inference. Despite these limitations, this review offers important strengths. It synthesises evidence that provides meaningful insights into the psychosocial burden experienced by children with RDs and their caregivers, emphasising the need for improved support systems. Key themes, including emotional distress, caregiver burden, and communication challenges, were identified, offering a foundation to inform future research, interventions, and policy development.

    Mental health challenges and psychosocial impact of rare diseases in children and adolescents -a systematic review · 2026 · DOI

  • Conclusion The research investigation evaluated machine learning technologies used for genomic analysis with a special focus on individual medical solutions. Available research confirms how advanced deep learning approaches combined with tree-based models increase accuracy levels of predicting diseases while improving pharmaceutical advancement methods. CNNs surpassed traditional ML methods through their performance which yielded a 95.3% success rate in disease classification tasks. SHAP-based analyses feature determined the fundamental genetic variants responsible for disease predisposition which added to the models' interpretability capabilities. The application of Graph Neural Networks in drug discovery showed better results when predicting drug- target interactions because they generated MSE results at 0.012 which surpassed traditional docking algorithms. The results demonstrate AI methodology potential to research while enhancing quicken pharmaceutical targeted medical treatments. Reliable implementation of ML within genomic medicine remains conditional upon solving current data heterogeneity standards together with model understanding requirements and privacy privacy requirements.

    Exploring Machine Learning Applications for Genomic Data Analysis in Personalized Medicine · 2026 · DOI

  • Researchers should unite their efforts to integrate Federated Learning system for private genomic analysis across distributed databases. The development of XAI thus methods helps generating trust in clinical applications. 5.

    Exploring Machine Learning Applications for Genomic Data Analysis in Personalized Medicine · 2026 · DOI

  • Registry-based cohort study designs widely used for drugs and devices are generally ill-suited to genome-scale genomic approaches in rare Mendelian disorders; alternative study designs specifically tailored to WGS evaluation must be developed and validated across populations with varying phenotypic overlap and clinical presentation patterns.

    Clinical Validity and Utility of Whole-Genome Sequencing In Rare Mendelian Disorders: Lessons for Population Screening and Policy · 2026 · DOI

  • Psycho-social and economic cost–utility data remain absent for WGS-based diagnostic services in rare Mendelian disorders; these health economic evaluations are needed to inform adoption decisions across different healthcare delivery systems with varying access to clinical specialists.

    Clinical Validity and Utility of Whole-Genome Sequencing In Rare Mendelian Disorders: Lessons for Population Screening and Policy · 2026 · DOI

  • Clinical studies of WGS in rare Mendelian disorders must explicitly report both specimen-collection/analytical stages AND variant-interpretation stages, as current epidemiological and genomic studies restrict analysis and reporting to only the analytical component, limiting comprehensive assessment of diagnostic utility.

    Clinical Validity and Utility of Whole-Genome Sequencing In Rare Mendelian Disorders: Lessons for Population Screening and Policy · 2026 · DOI

  • Alternative approaches to systematic literature reviews and meta-analyses are needed for assessing clinical validity and utility of WGS in rare Mendelian disorders, as traditional comparative-effectiveness research methodologies cannot accommodate the heterogeneity in disease prevalence, inheritance patterns, pathophysiological mechanisms, and limited literature per condition.

    Clinical Validity and Utility of Whole-Genome Sequencing In Rare Mendelian Disorders: Lessons for Population Screening and Policy · 2026 · DOI

  • Guidelines are needed to clarify how rare Mendelian conditions should be prioritized and communicated from a policy perspective for large-scale WGS screening deployment, particularly regarding demarcation of genomic technologies (whole-exome sequencing, gene-panel technologies, WGS) and the maximum time window for trial commencement based on population characteristics.

    Clinical Validity and Utility of Whole-Genome Sequencing In Rare Mendelian Disorders: Lessons for Population Screening and Policy · 2026 · DOI

  • Patient and specimen registries with longitudinal follow-up data are needed to study clinical progression and treatment outcomes for rare Mendelian disorders evaluated with WGS, yet current frameworks for formal assessment of genomic test clinical effectiveness vary significantly across countries, requiring harmonization to support population-wide trials.

    Clinical Validity and Utility of Whole-Genome Sequencing In Rare Mendelian Disorders: Lessons for Population Screening and Policy · 2026 · DOI

  • Cohort studies and observational approaches must be designed to accommodate the low prevalence of many rare Mendelian disorders and multiple genomic alterations associated with specific conditions, with particular attention to how epidemiological, health-system, and social contexts differ across countries and regions for WGS implementation planning.

    Clinical Validity and Utility of Whole-Genome Sequencing In Rare Mendelian Disorders: Lessons for Population Screening and Policy · 2026 · DOI

  • Real-world implementation studies are urgently needed to evaluate whole-genome sequencing across diverse populations, specifically examining operational feasibility, public health implications, and performance of emerging genomic technologies in resource- and access-limited settings targeting a subset of rare Mendelian conditions with known prevalence or clear public health value.

    Clinical Validity and Utility of Whole-Genome Sequencing In Rare Mendelian Disorders: Lessons for Population Screening and Policy · 2026 · DOI

  • Unrestricted transfers of individual-level exome data between institutions across country borders pose privacy risks and raise informed consent questions that undermine anonymization principles; alternative data governance approaches using federated architectures for biobanks must be empirically evaluated for effectiveness in protecting participant privacy while enabling collaborative WES research.

    Ethical, Legal, and Social Implications of Whole-Exome Sequencing in Biobank Initiatives: Consent, Governance, and Trust Methods, Challenges, and Future Directions · 2026 · DOI

  • Ethical guidance documents emphasize that dynamic consent must incorporate transparent information on privacy, fairness, and individual rights within biobank initiatives; however, concrete implementation frameworks for integrating electronic health records and web-based data sharing platforms with dynamic consent in WES biobanks have not been operationalized.

    Ethical, Legal, and Social Implications of Whole-Exome Sequencing in Biobank Initiatives: Consent, Governance, and Trust Methods, Challenges, and Future Directions · 2026 · DOI

  • The ability to contact participants and validate original consent provisions is compromised by frequent changes in research landscapes and evolving sociopolitical contexts; biobanks require mechanisms to systematically re-evaluate and update negotiated obligations for WES data use, but protocols for managing this continuous consent re-evaluation remain underdeveloped.

    Ethical, Legal, and Social Implications of Whole-Exome Sequencing in Biobank Initiatives: Consent, Governance, and Trust Methods, Challenges, and Future Directions · 2026 · DOI

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79 open questions have been extracted from the limitations and future-work passages of 355 Genomics and Rare Diseases papers in our library. Each one below links back to the study that raised it, so you can read the original claim in context.

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