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A genomic view of mosaicism and human disease

Key Points

  • Mosaicism refers to the presence of genetically distinct cells within an organism that result from postzygotic mutational events.

  • There are several different types of mosaicism at the organismal level that are categorized by the tissue distribution of the variant cells, including germline mosaicism and somatic mosaicism.

  • Many different molecular types of genetic lesions — from single-nucleotide changes to large-scale chromosomal alterations — can be present in a mosaic form.

  • Mosaicism can be generated not only by mutations resulting in variant genotypes but also by the reversion or rescue of abnormal genotypes.

  • Mosaicism can lead to a diverse range of phenotypes, from overt to occult. It can also allow the clinical expression of mutations that would otherwise be lethal in the non-mosaic state, thus providing a broader assessment of genotype–phenotype correlations than do germline-inherited disorders.

  • Modern genomic technologies have allowed the considerable frequency of mosaicism in humans to be increasingly recognized. For example, the frequency of chromosome aberrations in the early embryo has now been estimated as close to 70%.

  • The complexity of the genetic causes and phenotypic consequences of mosaicism pose challenging dilemmas for the diagnosis, prognosis and mechanistic understanding of mosaic diseases in affected individuals.


Genomic technologies, including next-generation sequencing (NGS) and single-nucleotide polymorphism (SNP) microarrays, have provided unprecedented opportunities to assess genomic variation among, and increasingly within, individuals. It has long been known that cancer is a mosaic genetic disorder, but mosaicism is now apparent in a diverse range of other clinical disorders, as indicated by their tissue distributions and inheritance patterns. Recent technical advances have uncovered the causative mosaic variant underlying many of these conditions and have provided insight into the pervasiveness of mosaicism in normal individuals. Here, we discuss the clinical and molecular classes of mosaicism, their detection and the biological insights gained from these studies.

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Figure 1: Types of mosaicism and patterns of cutaneous mosaicism.
Figure 2: Detection of mosaicism.
Figure 3: Mosaicism for isochromosome 12p in two patients with Pallister–Killian syndrome.
Figure 4: Mechanisms of whole-chromosome uniparental disomy.
Figure 5: Segmental uniparental disomy for 11p in two tissues from one patient.


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L.G.B. is funded by the Intramural Research Program of the US National Human Genome Research Institute of the National Institutes of Health. He is an uncompensated consultant to the Illumina Corporation and receives an honorarium from the Wiley–Blackwell Corporation for editing activities. N.B.S. is funded by the US National Institute of Diabetes and Digestive and Kidney Diseases, the US National Human Genome Research Institute, the Ring14 Association and is supported by the Fred and Suzanne Biesecker Liver Center in the Research Institute at the Children's Hospital of Philadelphia. She is grateful, as always, to L. Conlin, both for scientific discussion and for the generation of the drafts of figures included in this work.

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Corresponding author

Correspondence to Leslie G. Biesecker.

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Competing interests

Leslie G. Biesecker is an uncompensated consultant to the Illumina Corporation. He receives honoraria from the Wiley–Blackwell Corporation for editing activities. Nancy B. Spinner declares no competing financial interests.

PowerPoint slides


Germline mosaicism

The diploid germ cell precursors in the gonad are heterogeneous: some have a mutation and some do not.

Somatic mosaicism

The non-germ cells of the body are heterogeneous: some have a mutation and some do not.

Lines of Blaschko

Streaky lines visible on the skin that radiate inferolaterally from the area over the dorsal spine. They are the consequence of the migration of neuroectodermal cells from the closure of the neural tube.

Heterochromia irides

Describes an individual with irises that are of distinctly different colours.


A human cell with other than a multiple of 23 chromosomes.

Structural alterations

Describes genomic changes that can be balanced, large-scale rearrangements without copy number changes (such as translocations and inversions) or large deletions and duplications that result in copy number changes.


A dermatological condition consisting of a thickening of the keratin-rich layer of the epidermis.


A condition of tissue volume loss due to disuse or lack of trophic stimulation.


All cells of the body other than the germ cells.


The degree to which a trait manifests in an individual who has some recognizable manifestation of the disorder.

Segmental mosaicism

This is a subtype of somatic mosaicism: an anatomically recognizable portion of the body has cells that have a mutation that is not present in other parts of the body.

Hereditary haemorrhagic telangiectasia

A disorder of vessel dysplasia that can be caused by mutations in a number of genes.

Darier–White disease

A disorder of heterogeneous skin lesions, which can include warty papules, plaques, and seborrhoea, caused by mutations in ATP2A2.


The proportion of individuals with a specific phenotype among carriers of a particular genotype.

Discordant monozygotic twins

Twins that result from the fission of a single fertilized inner cell mass but who have a distinct phenotypic difference between them.

Bony hyperostoses

Focal overgrowths of bone and osteoid (partially calcified bone matrix).

Café-au-lait spots

Light brown macules of the skin that are a common manifestation of neurofibromatosis, McCune–Albright syndrome and several of other disorders.

Proteus syndrome

A disorder of mosaic, progressive overgrowth caused by mutation in AKT1.

Nevus sebaceous

A skin lesion characterized by overgrowth of sebaceous glands.

Pallister–Killian syndrome

A disorder of dysmorphic features and intellectual disability caused by mosaic tetrasomy of chromosome 12p.

Osteogenesis imperfecta type II

A disorder of bone fragility and short stature caused by mutations in COL1A1 or COL1A2.


A disorder of short stature and dysmorphic features, generally less severe than achondroplasia, caused by mutations in COMP.


A disorder with severe short stature and dysmorphic features caused by mutations in FGFR3.


The failure of chromosomes to segregate normally during cell division, resulting in the mis-segregation of chromosomes into daughter cells. Nondisjunction at meiosis I results in products with additional or missing chromosomes that are genetically distinct (homologues), whereas nondisjunction at meiosis II results in missing or extra sister chromatids.

Cat eye syndrome

A syndrome of dysmorphic features and intellectual disability caused by duplication of a segment of chromosome 22q.


Extra copies of either a whole chromosome or of a chromosome segment that contains a centromere.

Loss of heterozygosity

Describes that status of a cell or tissue that was originally heterozygous at a genetic locus but owing to somatic alterations is subsequently homozygous or hemizygous.

Uniparental disomy

(UPD). When both chromosomes of a homologous pair are inherited from the same parent. When these chromosomes are different, this is uniparental heterodisomy. When these chromosomes are identical through duplication, this is uniparental isodisomy.


A descriptor for a brain that has substantial asymmetry, with one side being abnormally large and commonly malformed.

Fibroadipose overgrowth

A manifestation of overgrowth that includes excess fatty tissue with fibrous strands caused by somatic mutation of PIK3CA.

Waldenström macroglobulinaemia

A malignant B cell neoplasm with lymphoplasmacytic infiltration of bone marrow and excess monoclonal immunoglobulin M.


An enlarged tissue caused by an increased number of cells.


An enlarged tissue caused by enlarged cells.

Beckwith–Wiedemann syndrome

An overgrowth and tumour susceptibility syndrome caused by imprinting defects of 11p15.

Costello syndrome

A syndrome of dysmorphic features, intellectual disability and tumour predisposition caused by mutations in the HRAS gene. A member of the rasopathy family of phenotypes.

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Biesecker, L., Spinner, N. A genomic view of mosaicism and human disease. Nat Rev Genet 14, 307–320 (2013).

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