In genetic mapping studies, the phenomenon in which some cells in an organ or tissue have a different genetic constitution from the other cells, is labeled mosaicism.

Mosaicism is the presence in an individual or a tissue of at least two cell lines that differ genetically but are derived from a single zygote.

Although we are used to thinking of ourselves as being composed of cells that all carry exactly the same complement of genes Opens in new window and chromosomes Opens in new window, this is in reality an oversimplified view.

Mosaicism is due to X inactivation Opens in new window that generates two different populations of somatic cells in females, those in which the paternal X is the active chromosome and those in which the maternal X is the active chromosome.

More generally, mutations Opens in new window arising in a single cell in either prenatal or postnatal life can give rise to clones of cells genetically different from the original zygote because once the mutation occurs, it could persist in all the clonal descendants of that cell.

Mosaicism for numerical or structural abnormalities of chromosomes is a clinically important phenomenon, and somatic mutation is recognized as a major contributor to many types of cancer.

Mosaicism for mutations in single genes, in either somatic or germline cells, explains a number of unusual clinical observations, such as segmental neurofibromatosis Opens in new window, in which skin manifestations are not uniform and occur in a patchy distribution, and the recurrence of osteogenesis imperfecta Opens in new window, a highly penetrant autosomal dominant disease, in two or more children born to unaffected parents.

The population of cells that carry a mutation in a mosaic individual could theoretically be present in some tissues of the body but not in the gametes (pure somatic mosaicism), be restricted to the gamete lineage only and nowhere else (pure germline mosaicism), or be present in both somatic lineages and the germline, depending on when the mutation occurred in embryological development.

Whether mosaicism for a mutation involves only somatic tissues, the germline, or both depends on whether during embryogenesis the mutation occurred before or after the separation of germline cells from somatic cells.

If before, both somatic and germline cell lines would be mosaic and the mutation could be transmitted to the offspring as well as being expressed somatically in mosaic form.

A mutation Opens in new window occurring later would be found only in the germline or only in a subset of somatic tissues. Thus, for example, if a mutation were to occur in a germline precursor cell, a proportion of the gametes would carry the mutation.

There are about 30 mitotic divisions in the cells of the germline before meiosis in the female and several hundred in the male, allowing ample opportunity for mutations to occur during the mitotic stages of gamete development.

Determining whether mosaicism for a mutation is present only in the germline or only in somatic tissues may be difficult because failure to find a mutation in a subsets of cells from a readily accessible somatic tissue (such as peripheral white blood cells, skin, or buccal cells) does not ensure that the mutation is not present elsewhere in the body, including the germline.

Characterizing the extent of somatic mosaicism is made more difficult when the mutant allele in a mosaic fetus occurs exclusively in the extraembryonic tissues (i.e., the placenta) and is not present in the fetus itself.

Somatic Mosaicism

Somatic mosaicism occurs in tumor cells—some cells in the body contain an altered chromosome or singe gene mutation, whereas others do not. In somatic mosacism there is no increased risk for affected offspring because the mutation is not in the gonads.

A mutation Opens in new window 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, neurofibromatosis type 1 (NF1) Opens in new window is sometimes segmental, affecting only one part of the body.

Segmental NF1 is caused by mosaicism for a mutation that occurred after conception. In such cases, the patient has normal parents, but if s/he has an affected child, the child’s phenotype is typical for NF1, that is, not segmental. In such cases, the mutation has to be in the patient’s gametes and therefore must have occurred before separation of germline cells from the somatic cell line that carries the mutation.

It is interesting to note that somatic mitochondrial mutations accumulate in all cells with age. It is hypothesized that these mitochondrial mutations play a central role in late-onset degenerative disease, cancer, and aging (Wallace et al., 2007).

Germline Mosaicism

The chance that an autosomal or X-linked disorder caused by a new mutation could occur more than once in a sibship is low because spontaneous mutations are generally rare (on the order of 1 chance in 104 to 106), and having two occur independently in the same gene in the same family is thus very unlikely (less than 1 in 108 to 1012).

After even subtle evidence of the disease had been ruled out in the unaffected parents of a child with an autosomal dominant Opens in new window or X-linked disorder Opens in new window and with negative results of molecular testing for the carrier state, it therefore used to be customary to advise the parents that the disease in their child was the result of a new mutation and that the chance of the same defect in a subsequent child was negligible, equivalent to the population risk.

There are, however, well-documented examples where parents who are phenotypically normal and test negative for being carriers Opens in new window have more than one child affected with a highly penetrant autosomal dominant or X-linked disorder. Such unusual pedigrees Opens in new window can be explained by germline mosaicism.

Germline mosaicism is well documented in as many as 6% of severe, lethal forms of the autosomal dominant disorder osteogenesis imperfecta Opens in new window, in which mutations in type I collagen genes lead to abnormal collagen, brittle bones, and frequent fractures.

Pedigrees Opens in new window that could be explained by germline mosaicism have also been reported for several other well-known disorders, such as hemophilia A Opens in new window, hemophilia B, and Duchenne muscular dystrophy (DMD) Opens in new window, but have only very rarely been seen in other dominant diseases, such as achondroplasia Opens in new window.

Accurate measurement of the frequency of germline mosaicism is difficult, but estimates suggest that the highest incidence is in Duchenne muscular dystrophy (DMD) Opens in new window, in which up to 15% of the mothers of isolated cases show no evidence of the mutation in their somatic tissues and yet carry the mutation in their germline.

Now that the phenomenon of germline mosaicism has been recognized, geneticists and genetic counselors are aware of the potential inaccuracy of predicting that a specific autosomal dominant or X-linked phenotype that appears by every test to be a new mutation must have a negligible recurrence risk in future offspring.

Obviously, in diseases known to show germline mosaicism, phenotypically normal parents of a child whose disease is believed to be due to a new mutation should be informed that the recurrence risk is not negligible.

Furthermore, apparently noncarrier parents of a child with any autosomal dominant Opens in new window or X-linked disorder Opens in new window in which mosaicism is possible but unproven may have a recurrence risk that may be as high as 3% to 4%; these couples should be offered whatever prenatal diagnostic tests are appropriate. The exact recurrence risk is difficult to assess, however, because it depends on what proportion of gametes contains the mutation.

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