Mosaicism

A mosaic in the biological sense, also known as a genetic mosaic or somatic mosaicism, refers to an individual whose cells have different genetic material. New methods of genome analysis, in particular the high-throughput sequencing method "next generation sequencing" (NGS) introduced in 2005, have enormously improved the detection of mosaics and thus the understanding of mosaic diseases.

Genetic mosaics result from new mutations that only occur after fertilization (postzygotic). They have thus emerged from a homogeneous zygote (genetically different cell populations are referred to as chimeras). In principle, any monogenic disease can also occur as a mosaic and then be associated with a milder or atypical course than a mutation that affects all body cells.

Genetic mosaics have been described in recent years as the cause of a large number of diseases. These are mainly neurocutaneous diseases and syndromic developmental disorders with a characteristic phenotype. In some cases there is a tumor predisposition.

A genetic mosaic can affect all organs. If the skin is affected, such a mutation can lead to visible changes. A cutaneous m osaic is macromorphologically recognizable by a characteristic pattern (see below Blaschko lines/Bae T et al. 2018).

Mosaics with a chromosomal aberration are not uncommon in the sex chromosomes as a result of the loss of an X chromosome (e.g. Turner syndrome with the karyotype 45,XO/46,XX).

As a result of X chromosome inactivation, women have a functional mosaic, whereby the maternal and paternal X chromosomes are partly active in the cells. Many mosaic mutations are not detectable in the blood, but only in the affected tissue.

The detection of a postzygotic mosaic often means relief for parents of an affected child, as there is usually no increased risk of recurrence for further children. The child can only pass the mutation on to the next generation if the germ cells (egg or sperm cells) are also affected by the mosaic. In the case of inheritance, however, a continuous mutation rather than a mosaic occurs in the offspring.

The severity and clinical symptoms of postzygotic mosaics depend on the time of the mutation event, the cell type in which the mutation occurs, the expansion of cells with mutation, the mutated gene and the type of mutation (Moog U et al. 2020). The later mosaics occur in embryonic development, the more limited the symptoms. For example, certain hamartomas of the skin are caused by localized mosaics in skin cells (Happle R 2016).

Mosaics for lethal mutations lead to clinical pictures that only exist in mosaic form, such as Proteus syndrome, Sturge-Weber syndrome or McCune-Albright syndrome. These diseases can therefore not be passed on from affected individuals to their own children, as the mutation would be present throughout and would be lethal if inherited.

Correct classification is important as molecular therapeutic approaches are already available for some mosaic diseases, for example for "PIK3CA-related overgrowth spectrum" (PROS) with a PIK3CA inhibitor.

Evidence of mosaic disease may be visible, persistent changes in the skin that are punctate, disseminated, segmental or linear. The most common distribution pattern of postzygotic mosaics are the Blaschko lines, a system of lines in the skin that corresponds to the migration of cells during embryogenesis. For example, pigment mosaics in chromosomal disorders and isolated or syndromal epidermal hamartomas can follow the Blaschko lines. The skin is probably a frequent organ of manifestation of mosaics because cutaneous changes are easily accessible and can then be used diagnostically. Various of the mosaic diseases listed below are also associated with skin changes (Moog U et al. 2020).

The detection of a mosaic disease can be therapeutically relevant, but requires a specific suspicion and a suitable choice of method in genetic diagnostics, as detection is usually not possible in the blood. In the case of cutaneous mosaics, it is possible to detect a mutation from lesional skin.

1. Bae T et al. (2018) Different mutational rates and mechanisms in human cells at pregastrulation and neurogenesis. Science 359: 550-555
2. Lim YH et al (2017) Mosaicism in cutaneous disorders. Annu Rev Genet 51: 123-141
3. Moog U et al (2020) Diseases caused by genetic mosaics. Dtsch Ärztebl Int 117: 119-125
4. Happle R (2016) The categories of cutaneous mosaicism: a proposed classification. Am J Med Genet A 170A: 452-459