Novel Gene and Variant Discovery in Human Genetic Disorders: From Coding and Non-Coding RNA variants

Rapid advances in sequencing technologies have transformed our ability to diagnose human genetic disorders, yet many patients still lack a molecular explanation. Resolving undiagnosed cases and expanding our understanding of human disease mechanisms requires integrated efforts in novel gene discovery, variant interpretation, and rigorous functional validation. While coding variants remain a major contributor, growing evidence highlights the critical role of non-coding RNA variants, including miRNAs, lncRNAs, piRNAs, and other regulatory elements, in disease onset, progression, and phenotypic variability. The pathogenic impact of dysregulated non-coding RNA networks is increasingly recognized but remains underexplored in clinical genomics.

This Research Topic invites contributions that advance gene and variant discovery in human disorders through genome-scale approaches, including genomic sequencing, transcriptomics, systems-level analyses, and experimentally grounded computational work. We especially welcome studies that connect genome function with inter-individual variability and deliver translational insights relevant to precision medicine and clinical practice.

We welcome Original Research, Reviews, Perspectives, and select Case Reports that meet the following criteria:

Case Reports will be considered only when they include rigorous experimental functional validation and generate insights that generalize beyond a single patient.

Appropriate topics include:

• Identification of novel disease-associated genes and variants with demonstrable functional impact • Whole-exome, whole-genome, or long-read sequencing in undiagnosed disorders, with analyses that improve diagnostic yield or variant classification

• Functional characterization of rare coding and non-coding variants, including assays that directly interrogate human alleles/variants in human tissues, primary cells, organoids, or relevant model systems with clear human relevance

• The role of miRNAs, lncRNAs, piRNAs, and other non-coding RNAs in human disease, especially within regulatory networks and multi-omics contexts (e.g., integration of genomics, transcriptomics, epigenomics)

• Systems genomics and regulatory network analyses that elucidate mechanisms of disease and inter-individual variability, and studies that inform clinical decision support or precision-medicine implementation (e.g., ACMG/AMP refinement for non-coding variants)

Methodological expectations and scope safeguards:

• Computational studies must go beyond re-analysis of publicly available datasets and should include new data generation and/or experimental validation; purely in silico manuscripts are out of scope

• Model organism or cell-based assays are welcome when they directly interrogate human variants/alleles or mechanisms clearly relevant to human inter-individual variability

• Mendelian randomization submissions (if applicable) must adhere to current best practices, including robust instrument selection, pleiotropy assessment, and sensitivity analyses

• Submissions should provide detailed background, reproducible methods, and insightful discussion connecting functional genomics to clinical utility, precision medicine, and disease prevention

This collection aims to deliver cutting-edge, clinically relevant insights into both coding and non-coding contributors to human genetic disorders, highlighting emerging molecular mechanisms with diagnostic and therapeutic potential.