Systematic Approaches to Biomarker Discovery for Early Detection

The field of genomic medicine has experienced tremendous progress with the advent of next-generation sequencing (NGS), which has revolutionized our ability to interrogate the human genome at unprecedented depth and scale. NGS technologies, particularly whole exome sequencing (WES), have enabled significant advancements in detecting genetic variants across a variety of diseases, especially those with complex or rare presentations.

Despite these advances, challenges persist in the discovery and interpretation of clinically relevant genomic variants, particularly in cases of rare diseases associated with developmental disabilities. Critical questions remain regarding the best strategies for leveraging trio and quad analyses to identify de novo and inherited mutations, and how assumptions about variant frequency, inheritance patterns, and genetic heterogeneity affect our understanding of disease mechanisms. While recent studies have demonstrated the power of parent-child trio and quad WES analyses in detecting single nucleotide variants (SNVs) and small insertions or deletions (indels), there is still debate about their clinical utility, the biases inherent to these study designs, and the limitations in current annotation methods.

This Research Topic aims to provide a comprehensive overview of systematic approaches to biomarker discovery for the early detection of rare and complex genetic diseases. It seeks to address the methodological challenges and innovative strategies in applying NGS, particularly for conditions where the underlying genetic basis remains elusive. The main objectives are to shed light on refined analyses of rare disease cohorts, improve variant interpretation frameworks, explore the implications of de novo versus inherited mutations, and evaluate how advancements in sequencing technology can directly benefit individuals with developmental disabilities. This initiative further aims to bridge the existing gap between technological innovation and practical, clinical application, fundamentally enhancing early diagnosis and intervention opportunities.

The scope of this Research Topic encompasses the integration of cutting-edge sequencing approaches, novel analytical frameworks, and clinical perspectives in the context of early biomarker discovery for rare diseases. While the focus is on NGS, especially trio/quad WES, contributions addressing related technologies and their functional interpretation will be considered. To facilitate a comprehensive dialogue, we welcome articles addressing, but not limited to, the following themes:

· Systematic approaches to exome and genome sequencing in biomarker discovery
· Novel analytical and computational methods for variant detection and interpretation
· Clinical case studies leveraging trio/quad analyses in rare disease cohorts
· Challenges in annotation, inheritance modeling, and genetic heterogeneity
· Strategies for translating sequencing discoveries into clinical practice
· Ethical, social, and practical considerations in the context of disability and rare disease detection

We invite submissions of original research articles, systematic reviews, methods papers, and perspective pieces addressing these and related topics.

Topic Editor Prashanth N. Suravajhala is the founder of Bioclues.org, a not-for-profit professional society supporting mentor–mentee initiatives. Ashish Kumar is part of a pre-seed deep-tech startup and holds equity interest in the company, which is developing point-of-care diagnostics for molecular biomarker detection. All other Topic Editors declare no competing interests with regard to the Research Topic subject.

Article types and fees

This Research Topic accepts the following article types, unless otherwise specified in the Research Topic description:

• Brief Research Report
• Case Report
• Clinical Trial
• Community Case Study
• Data Report
• Editorial
• FAIR² Data
• FAIR² DATA Direct Submission
• General Commentary
• ... View all formats

Articles that are accepted for publication by our external editors following rigorous peer review incur a publishing fee charged to Authors, institutions, or funders.

Article types

This Research Topic accepts the following article types, unless otherwise specified in the Research Topic description:

• Brief Research Report
• Case Report
• Clinical Trial
• Community Case Study
• Data Report
• Editorial
• FAIR² Data
• FAIR² DATA Direct Submission
• General Commentary
• Hypothesis and Theory
• Methods
• Mini Review
• Opinion
• Original Research
• Perspective
• Policy and Practice Reviews
• Policy Brief
• Review
• Systematic Review
• Technology and Code

Keywords: genomic medicine, next-generation sequencing, whole exome sequencing, rare diseases, biomarker discovery, trio/quad analysis, variant interpretation

Important note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.