Open research questions in Genomics and Rare Diseases

What the literature leaves open

• Limited number of cases reported with Keipert syndrome. Variable expressivity of the disorder. Lack of understanding of the genetic basis of Keipert syndrome.

  Keipert syndrome beyond classical features: novel GPC4 variant associated with epilepsy but preserved cognition · 2026 · DOI

• The diagnosis of monogenic diabetes remains a challenge due to the multitude of molecular causes. There is a need for more precise diagnosis and treatment selection for MD. The study identifies the gap in the diagnosis of MD in Polish patients.

  Search for the most precise diagnosis of monogenic diabetes - the usefulness of short-read NGS method in molecular testing in Polish patients · 2026 · DOI

• The diagnosis of Kondo-Fu syndrome can be challenging due to its similarity to other genetic disorders. The management of the syndrome is limited by the lack of therapies that target the cause. The study of the syndrome is hindered by its ultra-rare nature and the limited number of patients.

  Novel MBTPS1 variant associated with Kondo-Fu syndrome with expanded skeletal manifestations and a distinctive biochemical profile · 2026 · DOI

• Rare diseases are often difficult to diagnose and lacking effective targeted therapeutics. The clinical courses of rare diseases are frequently chronic, progressive, and debilitating, often leading to severe disability or premature death. There is a need to optimize critical care management, resource allocation, and healthcare policy development for rare pediatric diseases.

  Admission patterns and clinical management of rare diseases in 46 pediatric intensive care units across China: a multicenter survey · 2026 · DOI

• There is a lack of empirical data on the admission status of pediatric patients with rare diseases in pediatric intensive care units across China. There is a need to optimize critical care management, resource allocation, and healthcare policy development for rare pediatric diseases.

  Admission patterns and clinical management of rare diseases in 46 pediatric intensive care units across China: a multicenter survey · 2026 · DOI

• Evaluating dense granules via light microscopy of a peripheral blood smear is not a validated method for diagnosing δ-granule deficiency. The patient's unusual clinical phenotype presented a challenge for diagnosis. The need for multidisciplinary long-term monitoring of patients with HPS-1 poses a challenge for healthcare providers.

  Case Report: Hermansky-Pudlak syndrome type 1 in the Russian Federation presenting with genotype-phenotype discordance · 2026 · DOI

• Navigating disparate sources of variant information is time-consuming and complex. The need for a computational framework to facilitate the process of identifying the functional consequences of genetic variants. The lack of efficient methods to gather and understand knowledge about variants.

  Text Mining to Understand Disease-Causing Gene Variants · 2024 · DOI

• While the influence of neighboring nucleotides is well known and accounted for in mutation models, the effective range of these flanking influences and the extent of their higher-order interactions remain insufficiently understood.

  Exploring the role of local sequence context on patterns of germline mutation · 2026 · DOI

• Premature termination codons (PTCs) usually trigger nonsense-mediated decay (NMD), but PTCs in the final exon or within 50 base pairs of the last exon-exon junction escape surveillance and can yield stable truncated or altered proteins whose disease mechanisms remain poorly defined.

  Phase Separation Contributes to Pathogenicity for Nonsense Mediated Decay-Escaping Variant Alleles · 2026 · DOI

• However, it remains unclear how well known structural features and predicted functional scores explain the heterogeneous effects of protein coding variants on human complex traits.

  Functional architecture of rare protein coding variation across 786,871 exomes · 2026 · DOI

• Although inherited variants have been reported in a small number of dominant developmental disorder genes, their contribution remains poorly understood.

  Incompletely penetrant protein-truncating variants confer developmental disorder risk through partial reductions in gene expression · 2026 · DOI

• Parent/patient-reported datasets provide ready access to phenotypic data for monogenic neurodevelopmental disorders yet their concordance with clinical data is unclear.

  How do clinician and parent-reported data differ? An analysis of similarity and difference in the datasets from a cross-syndrome genetics cohort study (GenROC) · 2026 · DOI

• However, direct comparisons between parent-reported and clinician-reported data at the individual level have been limited, leaving a gap in understanding the reliability and granularity of these data sources.

  How do clinician and parent-reported data differ? An analysis of similarity and difference in the datasets from a cross-syndrome genetics cohort study (GenROC) · 2026 · DOI

• These results highlight that a large proportion of P/LP variation is either absent or has conflicting evidence for pathogenicity in ClinVar, emphasising the importance of periodic reassessment, discrepancy resolution and updates to ensure completeness and accuracy of public databases.

  Clinically significant DNA variation from the GENCOV and HostSeq COVID-19 genome sequencing studies · 2026 · DOI

• Short-read data suggested the SV was an Alu element insertion within the RNase IIIa domain of DICER1, but read length was insufficient for conclusive characterisation.

  The SINEs were there: identification of a pathogenic Alu insertion in a patient with DICER1-related tumour predisposition · 2026 · DOI

• The optimal disease spectrum for carrier screening (CS) remains debated.

  Expanded carrier screening in a Southwestern Chinese population indicates East Asian specific low-frequency pathogenic variants account for nearly half of the at-risk couple rate · 2026 · DOI

• Although FFPE-based molecular analytical methods are maturing, a unified workflow for multilayered and comprehensive pathological investigations, from FFPE sample preparation to NGS-based molecular analyses, has not been established.

  Elucidating disease pathogenesis using formalin-fixed paraffin-embedded samples: Integrating genomics, spatial transcriptomics, and histology – A focus on vascular anomalies · 2026 · DOI

• It remains poorly understood how many RET VUSs are returned in clinical practice, how many are ultimately reclassified, and which patient populations are affected most.

  RET Variant Reclassification across Demographic Sub-Groups in a Large-Scale Clinical Population · 2026 · DOI

• Individual UK laboratories have developed local approaches to standardise somatic variant interpretation, often based on different sets of published guidelines, but a comprehensive national standardised framework is lacking.

  Association for Clinical Genomic Science (ACGS) guidelines for the classification of oncogenicity of somatic variants in cancer: recommendations by the UK somatic variant interpretation group (SVIG-UK) · 2025 · DOI

• Further analysis of intronic and regulatory regions of genes, - Investigation of changes in the mitochondrial genome, - Collection of complete clinical data for all…

  Search for the most precise diagnosis of monogenic diabetes - the usefulness of short-read NGS method in molecular testing in Polish patients · 2026 · DOI

• Further investigation of the genetic etiology of Kondo-Fu syndrome, - Study of the functional impact of the variant on mRNA processing, - Investigation of the expression of the MBTPS1 gene in other patients with Kondo-Fu…

  Novel MBTPS1 variant associated with Kondo-Fu syndrome with expanded skeletal manifestations and a distinctive biochemical profile · 2026 · DOI

• Further studies on the clinical variability of HPS-1, - Investigation of the genetic and molecular mechanisms underlying the syndrome, - Research on the long-term outcomes of patients…

  Case Report: Hermansky-Pudlak syndrome type 1 in the Russian Federation presenting with genotype-phenotype discordance · 2026 · DOI

• Development of digital twins for simulating therapy before administration - Use of AI to integrate diverse datasets and reduce bias - Global validation of AI tools to ensure equitable…

  Tailored Therapeutic Strategies for Fetuses, Neonates, Pediatrics, Geriatrics, Athletes, and Critical Cases in the Era of Personalized Medicine · 2025 · DOI

• Developing selective treatments to modulate pathway activities for various medical conditions - Investigating the effects of genetic variants on protein function and development…

  Text Mining to Understand Disease-Causing Gene Variants · 2024 · DOI

• Healthcare systems struggle with insufficient knowledge and resources, hindering effective care.

  Lived Experiences of Patients With Rare Diseases and Healthcare System Barriers: A Phenomenological Study · 2026 · DOI

Most-cited papers in Genomics and Rare Diseases

• Initial sequencing and analysis of the human genome · Nature · 2001 · 18,687 citations
• A global reference for human genetic variation · Nature · 2015 · 18,026 citations
• The mutational constraint spectrum quantified from variation in 141,456 humans · Nature · 2020 · 9,307 citations
• Analysis of protein-coding genetic variation in 60,706 humans · Nature · 2016 · 9,096 citations
• An integrated map of genetic variation from 1,092 human genomes · Nature · 2012 · 7,028 citations
• A map of human genome variation from population-scale sequencing · Nature · 2010 · 6,817 citations
• The International HapMap Project · Nature · 2003 · 4,928 citations
• Clinical Whole-Exome Sequencing for the Diagnosis of Mendelian Disorders · New England Journal of Medicine · 2013 · 1,698 citations
• Molecular Findings Among Patients Referred for Clinical Whole-Exome Sequencing · JAMA · 2014 · 1,198 citations
• Clinical Exome Sequencing for Genetic Identification of Rare Mendelian Disorders · JAMA · 2014 · 812 citations

Most recent work

• International guideline on genetic testing of children with short stature · European Journal of Endocrinology · 2026
• Detection of clonal hematopoiesis of indeterminate potential via genome or exome sequencing underestimates disease associations · Journal of Clinical Investigation · 2026
• Points to consider for the reporting of variants of uncertain significance in germline genetic and genomic testing: A statement of the American College of Medical Genetics and Genomics (ACMG) · Genetics in Medicine · 2026
• European Reference Networks – a flagship activity of the EU in the field of rare and complex diseases: from 2017 to 2025 · Orphanet Journal of Rare Diseases · 2026
• Harnessing artificial intelligence for genomic variant prediction: advances, challenges, and future directions · GigaScience · 2026
• Molecular genotype-phenotype correlation in ACTB- and ACTG1-related non-muscle actinopathies · The American Journal of Human Genetics · 2026
• Return of genome-informed risk-assessment results for common conditions to 23,840 adults and children: An eMERGE network study · The American Journal of Human Genetics · 2026
• Systematic analysis of snRNA genes reveals frequent RNU2-2 variants in dominant and recessive developmental and epileptic encephalopathies · Nature Genetics · 2026
• Genome-wide methylation detection and episignature analysis using PacBio long-read sequencing · Genome Medicine · 2026
• Long-read genome sequencing enhances diagnostics of pediatric neurological disorders · Genome Medicine · 2026

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