Mosaicism

Mosaicism is the presence of two or more genetically distinct cell populations within an individual who originated from a single fertilized egg. The different cell populations arise from genetic changes that occur after fertilization and during development, leading to a mosaic pattern of tissues with varying genotypes.

Mosaicism is commonly categorized as somatic, germline (gonadal), or gonosomal. Somatic mosaicism affects non-reproductive tissues and is typically limited to certain parts of the body. Germline or gonadal mosaicism involves reproductive cells and can be transmitted to offspring, even when the parent shows no symptoms. Gonosomal mosaicism includes both somatic and germline involvement.

Causes include postzygotic mutations during embryonic development, mitotic nondisjunction producing aneuploid mosaics, and chromosomal rearrangements. Segmental or focal mosaicism affects only a portion of a chromosome or genome within a subset of cells. Mosaicism can thus range from subtle to widespread, and may be tissue-specific.

Notable examples include mosaic trisomy 21, where some cells carry an extra chromosome 21 while others do not, and conditions such as Pallister-Killian syndrome (tetrasomy 12p in a mosaic state) or McCune-Albright syndrome, which results from postzygotic activating mutations in GNAS. Mosaic patterns are also observed in various tumors, contributing to intratumor heterogeneity.

Detection and interpretation rely on sampling multiple tissues. Blood testing may miss mosaicism confined to other organs. Methods include karyotyping, fluorescence in situ hybridization (FISH), microarray analysis, and targeted or whole-genome sequencing, with deep sequencing needed for low-level mosaics.

Clinical significance varies with the proportion and distribution of mosaic cells. It can influence phenotype, diagnostic testing, and recurrence risk, particularly when germline involvement is possible, necessitating careful genetic counseling.