Mosaicism

Mosaicism is the presence of two or more genetically distinct cell populations in an individual derived from a single fertilized egg. The timing of the postzygotic mutation determines the proportion and distribution of affected cells. Mosaicism can involve point mutations, chromosomal abnormalities, or structural rearrangements and has significant implications for phenotype, recurrence risk, and genetic testing.

• Somatic mosaicism: The variant is present in some somatic (body) cells but not others. Earlier mutations affect more cells and wider tissue distribution. May cause segmental or patchy phenotypes.
• Germline (gonadal) mosaicism: The variant is present in a proportion of germ cells (egg or sperm) but may be absent from somatic tissues. This explains how apparently unaffected parents can have multiple affected children with a "de novo" dominant condition.
• Somatic + germline mosaicism: Both tissue types are affected. The individual may show mild or segmental features and transmit the full condition to offspring.
• Timing determines severity: A mutation at the 2-cell stage affects ~50% of cells; a mutation at the 16-cell stage affects ~6%. Earlier = more widespread = more clinically significant.
• Segmental mosaicism: Genetic change confined to a body segment, following developmental lineages. Example: segmental neurofibromatosis (NF1 features restricted to one body region).
• Confined placental mosaicism (CPM): Chromosomal abnormality present in placental tissue (cytotrophoblast or mesenchyme) but not in the fetus. Detected via chorionic villus sampling (CVS) and can cause false-positive prenatal results. May lead to intrauterine growth restriction if the abnormal line affects placental function.
• Revertant mosaicism: A second somatic mutation corrects or compensates for the original pathogenic variant in a subset of cells. Documented in epidermolysis bullosa and Wiskott-Aldrich syndrome.

• Germline mosaicism and recurrence risk: A parent with germline mosaicism for a dominant condition may have a recurrence risk of 1-15% for future pregnancies, despite being clinically unaffected and testing negative on blood-based genetic testing. Classic examples include osteogenesis imperfecta (COL1A1/COL1A2) and Duchenne muscular dystrophy.
• McCune-Albright syndrome (GNAS): Somatic activating variants in GNAS are lethal if constitutional. Presents as a mosaic disorder with polyostotic fibrous dysplasia, cafe-au-lait spots with irregular borders, and precocious puberty.
• Pallister-Killian syndrome: Mosaic tetrasomy 12p (isochromosome 12p). Often missed on blood karyotype because the extra chromosome is lost in lymphocytes; detected in skin fibroblasts.
• Prenatal implications: CPM on CVS occurs in ~1-2% of samples. Follow-up amniocentesis is recommended to determine true fetal karyotype. Trisomy 16 CPM is the most common and associated with IUGR.