Building Equity Into Rare Disease Research Through Biobanking: Lessons From PIK3CA-Related Overgrowth Spectrum Disorders.

Rare diseases collectively affect hundreds of millions of individuals worldwide, yet the majority remain underdiagnosed, undercharacterized, and underrepresented in biomedical research. Although individually rare, these conditions impose a significant global health burden, often associated with prolonged diagnostic delays, fragmented care pathways, and limited therapeutic options. Advances in genomic technologies have transformed the understanding of many rare diseases by enabling identification of disease-causing variants and molecular pathways that can be targeted therapeutically. However, these advances have not been distributed equitably across global populations. In many regions, particularly low- and middle-income countries (LMICs), limited access to genomic diagnostics and research infrastructure continues to impede accurate diagnosis and participation in therapeutic discovery. Biobanking represents a critical but underutilized component of the rare disease research ecosystem. Biobanks provide foundational infrastructure for translational research, biomarker discovery and clinical trial development by systematically collecting and preserving biospecimens linked to clinical and phenotypic data. When aligned with international standards and integrated with interoperable data systems, biobanks enable large-scale collaborative research even for extremely rare conditions. This opinion article argues that biobanking should be recognized as core infrastructure within rare disease strategies rather than as a secondary research activity. Using PIK3CA-Related Overgrowth Spectrum (PROS) disorders as an illustrative example, we examine how integrating biospecimen repositories with clinical and genomic data can improve diagnostic accuracy, facilitate genotype:phenotype correlations, and accelerate development of pathway-targeted therapies. We further discuss how establishing locally anchored but globally interoperable biobanks may help address persistent inequities in rare disease research by ensuring that diverse populations contribute to and benefit from advances in precision medicine. The importance of representative biobanking and inclusive rare disease datasets is particularly acute when considering how clinical presentations vary across populations. Individuals with darker skin tones frequently present with dermatologic and vascular manifestations of PROS disorders in ways that may differ from presentations documented in existing clinical atlases and training datasets. Such differences can contribute to delayed recognition, misclassification, and prolonged diagnostic odysseys. Racial and ethnically underrepresented populations with rare diseases thus face compounded disadvantages: limited genomic characterization within reference datasets, underrepresentation in biospecimen repositories, and reduced access to diagnostic tools calibrated primarily on non-diverse cohorts. Ensuring that diverse populations are systematically represented in biospecimen collections, imaging datasets, genomic repositories, and longitudinal clinical annotation is therefore not simply an equity consideration but a scientific and clinical necessity for improving diagnostic accuracy and therapeutic development across all populations.