From curiosity to clinical relevance: Rethinking genetic mosaicism

ABSTRACT

A recent international case involving a sperm donor who unknowingly transmitted a pathogenic TP53 variant to numerous offspring has renewed attention to germline mosaicism and its clinical implications. This column traces the evolution of mosaicism from early clinical observations of segmental and asymmetric phenotypes to its current recognition as a common biological phenomenon. Advances in genetic technologies, including ultra-deep next-generation sequencing, have transformed the detection of mosaicism and helped clarify its biological and clinical significance. These insights have prompted important shifts in clinical thinking, as mosaicism challenges traditional assumptions about genotype–phenotype relationships, contributes to variable expressivity across disorders, and complicates genetic testing and counseling. This column also provides a foundation for a companion article in this issue, which presents clinically focused case studies illustrating different forms of mosaicism and offering practical guidance for nurse practitioners in applying these principles to patient care.