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Open research questions in Genomics and Rare Diseases

260 unresolved questions extracted from the limitations and future-work sections of 560 Genomics and Rare Diseases papers in our library. Each links back to the study that raised it.

What the literature leaves open

  • CBIcall operates as a validation and execution layer above existing workflow backends, - its performance is best evaluated through realistic end-to-end analyses, - the study used a limited number of datasets

    CBIcall: a configuration-driven framework for variant calling in large sequencing cohorts · 2026 · DOI

  • MPSA datasets had design limitations preventing detection of some aberrant splice events, - assay scores generated by five of seven MPSAs were unable to differentiate aberrant from natural splicing events, - the study was limited to evaluating splicing assay datasets from MPSAs and traditional minigene RT-PCR assays

    Evidence-based recommendations for application of construct-based splicing data in clinical variant classification · 2026 · DOI

  • further evaluation of splicing assay datasets from MPSAs and traditional minigene RT-PCR assays is needed, - development of new methods to improve the detection of aberrant splice events is required, - investigation of the clinical relevance of gene variants in different population groups is necessary

    Evidence-based recommendations for application of construct-based splicing data in clinical variant classification · 2026 · DOI

  • The paper identifies a gap in the discussion of ethical issues in the clinical use of diagnostic technologies for rare causes of psychosis. The authors highlight the need for a multidisciplinary perspective to address the challenges and consequences of using such technologies.

    Ethical issues in the clinical use of diagnostic technologies for rare causes of psychosis · 2026 · DOI

  • Reduced performance of EpiPred on the holdout set, - Small subset of conflicting variants where EpiPred predictions did not match the known class, - Limited to STXBP1 gene, - Requires further validation and clinical reevaluation

    Gene-specific machine learning model EpiPred identifies likely pathogenic variants in the epilepsy-related gene STXBP1 · 2026 · DOI

  • Further validation of EpiPred predictions, - Clinical reevaluation of possibly misdiagnosed variants, - Exploration of variant effect and complex interaction of protein features, - Expansion to other clinically actionable Mendelian disease genes

    Gene-specific machine learning model EpiPred identifies likely pathogenic variants in the epilepsy-related gene STXBP1 · 2026 · DOI

  • The lack of understanding of the specific functional variants contributing to interindividual differences in human cortical structure. The need for a genome-scale functional framework to understand the influence of noncoding variation on cortical structure.

    Massively parallel assessment of gene regulatory activity at human cortical-structure-associated variants · 2026 · DOI

  • integrating additional workflow engines, - extending the framework to support other types of genomic analyses

    CBIcall: a configuration-driven framework for variant calling in large sequencing cohorts · 2026 · DOI

  • Accurate prediction of single-nucleotide variant (SNV) tolerability across the entire human genome remains a fundamental challenge in computational genomics, particularly for non-coding regions where the regulatory landscape is vast and poorly understood.

    PHACTn enables training-free, context-independent inference of nucleotide variant tolerance across the genome · 2026 · DOI

  • While some subtypes involve impaired DNA damage responses, the molecular basis of PD remains incompletely defined.

    NSMCE2 / MMS21 structural variant causes chromosome breakage syndrome with primordial dwarfism and severe lung disease · 2026 · DOI

  • Critically, these regions remain underrepresented in genetic research, resulting in insufficient data to inform NBS panel design.

    Globalizing newborn screening: bridging gaps in genetic diagnosis and treatment · 2025 · DOI

  • Background: TUBGCP2 variants are associated with the LIS spectrum disorders, but its pathogenesis remains unclear.

    TUBGCP2 variants cause lissencephaly spectrum disorders: a case report and literature review · 2025 · DOI

  • Objective De novo variants in MAST4 are increasingly implicated in neurodevelopmental disorders (NDDs), but the associated phenotypic spectrum remains incompletely characterized.

    Genetic and clinical insights into MAST4-related neurodevelopmental disorders · 2025 · DOI

  • Blood RNA sequencing (RNA-seq) complements DNA-level diagnosis by revealing the functional impact of variants on gene expression and splicing, but to what extent RNA-driven approaches offer diagnostic benefits across different scenarios-with and without pre-existing candidate variants-remains uncertain.

    Blood RNA-seq in rare disease diagnostics: a comparative study of cases with and without candidate variants · 2025 · DOI

  • Little is known about how often NGS insurance claims are denied and what factors are associated with these denials.

    Claim Denials for Cancer-Related Next-Generation Sequencing in Medicare · 2025 · DOI

  • Despite their rarity, around 70% of these diseases afflict children, yet limited research has focused on their experiences.

    A qualitative exploration of children's lives with rare diseases · 2024 · DOI

  • Health care disparities are unfortunately widespread in the US health care system, but disparities in the utilization of genetic testing for neurologic conditions have not been studied.

    Disparities in Genetic Testing for Neurologic Disorders · 2024 · DOI

  • Systems that integrate clinical and genetic data from multiple sources are scarce due to their distinct data types, interoperability, security and data ownership issues.

    A framework for sharing of clinical and genetic data for precision medicine applications · 2024 · DOI

  • However, the relationship between genotype and phenotype is not yet fully understood.

    Case report of kabuki syndrome in a newborn caused by KMT2D gene mutation · 2024 · DOI

  • Importance: The diagnosis of rare diseases and other genetic conditions can be daunting due to vague or poorly defined clinical features that are not recognized even by experienced clinicians.

    Cost-Effectiveness of Whole-Genome vs Whole-Exome Sequencing Among Children With Suspected Genetic Disorders · 2024 · DOI

  • Importance: The lack of standardized genetics training in pediatrics residencies, along with a shortage of medical geneticists, necessitates innovative educational approaches.

    Recognition of Genetic Conditions After Learning With Images Created Using Generative Artificial Intelligence · 2024 · DOI

  • The Gaddi dog breed is adapted to extreme environments, which poses a challenge for its conservation and breeding. The breed is facing genetic dilution due to the lack of dedicated breeding programs.

    Whole-genome resequencing and functional annotation of genetic variants in the Gaddi dog from the Western Himalayas · 2026 · DOI

  • Limited genomic studies have been conducted on indigenous breeds, particularly those adapted to extreme environments. There is a lack of dedicated breeding programs for the Gaddi dog breed.

    Whole-genome resequencing and functional annotation of genetic variants in the Gaddi dog from the Western Himalayas · 2026 · DOI

  • The study identifies a gap in the understanding of the functional and structural effects of nsSNPs in the GH1 gene. The study highlights the need for further research into the role of nsSNPs in growth hormone-related disorders.

    Identification and in-silico analysis of non-synonymous single nucleotide polymorphism (nsSNPs) in the human GH1 gene · 2026 · DOI

  • The interpretation of genomic data is challenging due to the complexity of the data. The implementation of WGS in clinical practice is challenging due to the need for specialized expertise and equipment. The analysis of complex paralogous regions is challenging using short-read WGS.

    The genomic medicine center Karolinska 10-year report on genome sequencing for rare diseases and a strategy for stepwise clinical implementation · 2026 · DOI

Most-cited papers in Genomics and Rare Diseases

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260 open questions have been extracted from the limitations and future-work passages of 560 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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