Mosaicism arises when a postzygotic mutational event — occurring after fertilization — creates a subpopulation of cells carrying a genetic alteration distinct from the original zygote. The earlier the mutation occurs during development, the larger the proportion of affected cells and the more widespread its distribution across tissues. Mutations arising in the first few cell divisions can affect all three germ layers; those occurring later are more restricted. The mutation can be a chromosomal non-disjunction, structural rearrangement, single nucleotide variant, copy number variant, or epigenetic change.

Chromosomal mosaicism results from mitotic errors that generate cell lines with abnormal chromosome number or structure alongside a normal diploid line. Phenotypic consequences depend on which chromosome is involved, the proportion of abnormal cells, and the tissue distribution at critical periods of organogenesis. Mosaicism typically produces a milder phenotype than the constitutional aneuploidy, but phenotypic prediction from a karyotype alone is unreliable because blood karyotype may not reflect brain or gonadal cell populations.

Somatic mosaicism is increasingly recognized as a cause of conditions previously thought to be purely de novo or even sporadic. Brain somatic mosaicism — mutations arising in neural progenitor cells during cortical neurogenesis — is now understood to be a major cause of focal cortical dysplasia, hemimegalencephaly, and certain epilepsy syndromes. Because the mutation is present only in a fraction of brain cells (and often absent in blood), standard germline sequencing misses these variants, requiring high-depth sequencing of affected tissue.

Germline (gonadal) mosaicism occurs when a postzygotic mutation is confined to — or substantially enriched in — germ cells, leaving somatic cells largely unaffected. The clinically normal parent can be an unsuspected carrier whose germ cells harbor a pathogenic variant, allowing transmission to multiple children. This is the critical concept that explains why a second affected child can be born to apparently unaffected parents of a child with a supposedly de novo condition. Germline mosaicism has been documented for many autosomal dominant disorders including osteogenesis imperfecta, DMD, Rett syndrome, and rasopathies.

Detecting mosaicism requires understanding the sensitivity limits of each diagnostic platform and selecting the appropriate tissue source. Standard clinical sequencing (NGS panels, exome, genome) at typical depths (50–100×) can detect variants present in >10–15% of cells; lower VAF requires specialized approaches. Tissue selection is paramount — testing blood may miss variants confined to brain or skin, and testing buccal cells may miss blood-specific mosaicism.