mosaicism

Mosaicism occurs when a mutation or nondisjunction event happens during mitosis after the zygote has already formed, resulting in an individual with two or more genetically distinct cell lines derived from one fertilized egg. This contrasts with germline mutations, which affect all cells, and with chimerism, where two genetically different zygotes fuse to form one organism.

Key clinical examples include: - Mosaic Turner syndrome (45,X/46,XX): individuals may have a milder phenotype than classic 45,X Turner syndrome depending on the proportion and distribution of normal vs. abnormal cell lines. - Mosaic Down syndrome: due to postzygotic nondisjunction, producing a mixture of trisomy 21 and normal cell lines; phenotype severity can vary. - McCune-Albright syndrome: caused by a somatic activating mutation in GNAS1, leading to a mosaic distribution of affected tissues, resulting in polyostotic fibrous dysplasia, café-au-lait spots (irregular "coast of Maine" borders), and endocrine abnormalities (e.g., precocious puberty). - Gonadal mosaicism: mutation confined to germ cells (sperm or egg precursors), which can explain unexpected recurrence of autosomal dominant conditions (e.g., osteogenesis imperfecta, achondroplasia) in offspring of unaffected parents.

The clinical phenotype in mosaicism depends on the timing of the mutational event (earlier = more cells affected), the tissue distribution of the mutant cell line, and the specific gene or chromosome involved. Diagnosis often requires testing multiple tissue types (e.g., skin fibroblasts vs. blood lymphocytes) since a mutation may not be detectable in all cell lineages.

Mosaicism is an important concept for genetics questions on the USMLE, particularly in distinguishing it from chimerism, understanding variable expressivity/phenotype severity, and explaining recurrence risk in genetic counseling scenarios (especially gonadal mosaicism).