Mosaicism
المؤلف:
Cohn, R. D., Scherer, S. W., & Hamosh, A.
المصدر:
Thompson & Thompson Genetics and Genomics in Medicine
الجزء والصفحة:
9th E, P124-125
2025-12-14
64
Although we are used to thinking of ourselves as being composed of cells that all carry the same complement of genes and chromosomes, this is in reality an oversimplified view. Mosaicism is the presence in an individual or a tissue of at least two cell lineages that differ genetically but are derived from a single zygote. Mutations that occur after conception in a single cell in either prenatal or postnatal life can give rise to clones of cells genetically different from the original zygote because, given the nature of DNA replication, the altered allele will per sist in all the clonal descendants of that cell (Fig. 1). Mosaicism for numeric or structural abnormalities of chromosomes is a clinically important phenomenon, and somatic mutation is recognized as the major contributor to most types of cancer.
Fig1. Schematic representation of a mutation occurring after conception, during mitotic cell divisions. Such a mutation can lead to a proportion of cells carrying the mutation – that is, to either somatic or germline mosaicism, depending on the stage of embryonic or postnatal development where the mutation occurred.
Mosaicism can affect any cells or tissue within a devel oping embryo or at any point from after conception to adulthood. It can be a diagnostic dilemma to determine just how widespread the mosaic pattern is. For example, the population of cells that carry a mutation in a mosaic pregnancy might be (a) found only in extraembryonic tissue and not in the embryo proper (confined placental mosaicism), (b) present in some tis sues of the embryo but not in the gametes (pure somatic mosaicism), (c) restricted to the gamete lineage only and nowhere else (pure germline mosaicism), or (d) present in both somatic lineages and the germline. This all depends on whether the mutation occurred before or after the separation of the inner cell mass, the germline cells, and the somatic cells during embryogenesis. Because there are ~30 mitotic divisions in the cells of the germline before meiosis in the female and several hundred in the male, there is ample opportunity for mutation to occur in germline cells after the separation from somatic cells, resulting in pure gonadal mosaicism.
Determining whether mosaicism for a mutation is present only in the germline or only in somatic tissues may be difficult. Failure to find evidence in a subset of cells from a readily accessible somatic tissue (e.g., peripheral white blood cells, skin, or buccal cells) does not ensure that the mutation is not present elsewhere in the body, including the germline.
Segmental Mosaicism
A mutation affecting morphogenesis and occurring during embryonic development might be manifested as a segmental or patchy abnormality, depending on the stage at which the mutation occurred and the lineage of the somatic cell in which it originated. For example, NF1 is sometimes segmental, affecting only one part of the body. Segmental NF1 is caused by somatic mosaicism for the outcome of a mutation that occurred after conception. Although the parents of such an individual would be unaffected and considered not at risk for transmitting the mutated allele, a patient with segmental NF1 could be at risk for having an affected child, whose phenotype would be typical for NF1; that is, not segmental. Whether the individual is at risk for transmitting the defect will depend on whether the mutation occurred before separation of germline cells from the somatic cell line.
Germline Mosaicism
In pedigrees with germline mosaicism, unaffected individuals with no evidence of a given disease-causing mutation in their genome (as evidenced by the failure to find an altered allele the mutation in DNA extracted from their peripheral white blood cells) may still be at risk for having more than one child who inherited the mutation from them (Fig. 2). The existence of germline mosaicism means that geneticists and genetic counselors must be aware that normal examination results and normal gene test results of the parents of a child with an autosomal dominant or X-linked phenotype do not necessarily mean there is no risk of recurrence.
Fig2. Pedigrees demonstrating two affected half-siblings with the autosomal dominant disorder Marfan syndrome (family A) and the X-linked condition Becker muscular dystrophy (family B). In family A, the affected children have the same single nucleotide variant inherited from their father, who is unaffected and does not carry the variant in DNA from examined somatic tissues. He must have been a mosaic for the FBN1 variant in his germline. In family B, the affected children have the same single nucleotide variant inherited from their mother who is unaffected and does not carry the variant in DNA from examined somatic tissues. She must have been a mosaic for the DMD variant in her germline.
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