What is mosaicism in genetics?

Mosaicism is the presence of two or more genetically different cell lines in one person who developed from a single fertilized egg. The second cell line arises after fertilization, from a new gene variant or from a chromosome gained or lost during cell division. The earlier the error happens, the more tissues carry it. Mosaicism does not always cause disease, but it explains patchy or segmental findings and milder forms of chromosomal syndromes.

What is the difference between somatic and germline mosaicism?

In somatic mosaicism, only some body cells carry the change, so the person may have patchy or one-sided findings, such as pigment streaks along Blaschko lines, but cannot pass it on unless egg or sperm cells are also involved. In germline (gonadal) mosaicism, a proportion of eggs or sperm carry the change, so a healthy parent with a normal blood test can have more than one affected child.

What is the difference between mosaicism and chimerism?

Mosaic cells all descend from one zygote; the cell lines differ because of an error after fertilization, usually by a single variant or chromosome. A chimera contains cells from two or more different zygotes, for example after the fusion of two early embryos, so it carries two complete genomes, which can show up as both XX and XY cells or as two DNA profiles. NHGRI draws the line the same way: chimera cells can differ genetically too, but they come from distinct fertilized zygotes.

How can parents with normal genetic tests have two children with the same new mutation?

The usual explanation is germline (gonadal) mosaicism: the variant arose in one parent's germ-cell lineage, so some eggs or sperm carry it while blood cells do not. The parent is healthy and tests negative on blood, yet can pass the condition to more than one child. This is why the recurrence risk after an apparently de novo dominant or X-linked disorder is low but not zero. Reduced penetrance differs because the parent's blood test is positive.

Why can a blood test miss mosaicism?

The abnormal cell line may be absent from blood or present at too low a level to detect. In McCune-Albright syndrome, the GNAS variant is found in about 80% of samples from affected tissue but only 20 to 30% of blood samples with standard sequencing. In hypomelanosis of Ito, a blood karyotype shows the abnormality in up to a third of patients, and testing skin fibroblasts from a lesion finds it in about a quarter more. When mosaicism is suspected, test the affected tissue with sensitive methods.

What is confined placental mosaicism?

Confined placental mosaicism means an abnormal chromosome line is present in the placenta but not in the fetus. It is found in about 1% of chorionic villus sampling (CVS) specimens and can make a prenatal result look abnormal when the fetus is chromosomally normal. Because the cell-free DNA used in prenatal screening comes from placental trophoblast, confined placental mosaicism is a recognized cause of false-positive (and occasionally false-negative) cell-free DNA results, so positive screens and mosaic CVS results need confirmation, sometimes by amniocentesis.

Mosaicism: Somatic vs Germline vs Chimerism Comparison Table

Mosaicism is the presence of two or more genetically different cell lines in one person who developed from a single fertilized egg; the second line comes from a postzygotic error, such as a new gene variant or a chromosome gained or lost during cell division. Timing and location decide the picture: an early error spreads through many tissues, a late one gives patchy or segmental disease (pigment streaks along Blaschko lines, asymmetric growth), and a blood test can miss it. Somatic mosaicism affects the body but is not passed on unless germ cells carry the change; germline (gonadal) mosaicism lets a healthy parent with a normal blood test have more than one affected child. Chimerism is different: cells from two zygotes.

The comparison table: types of mosaicism

Type	Where the second cell line is	Classic clue	Passed to children?	Examples
Somatic mosaicism	Some body tissues, not the germ cells	Patchy, segmental or asymmetric disease; lesion tissue positive, blood often negative	No	McCune-Albright syndrome (GNAS), Proteus syndrome (AKT1), localized mosaic NF1, hypomelanosis of Ito
Germline (gonadal) mosaicism	A fraction of eggs or sperm	Healthy parents with normal blood tests and two or more children with the same "de novo" dominant or X-linked disorder	Yes	Gonadal (or gonadal plus somatic) mosaicism in up to 16% of parents of children with COL1A1/COL1A2 osteogenesis imperfecta
Gonosomal mosaicism (somatic plus germline)	Body tissues and gametes	Parent with mild or localized signs whose child is fully affected	Yes	Adult with mosaic NF1 whose child has typical, generalized NF1
Chromosomal mosaicism	A mix of normal and aneuploid cells (45 or 47 chromosomes beside 46)	Milder or atypical version of a chromosomal syndrome	Only if germ cells carry the abnormal line	Mosaic Turner (45,X/46,XX), mosaic Down syndrome (a small minority of Down syndrome), mosaic trisomy 13 (about 5% of trisomy 13)
Confined placental mosaicism	Placenta only; the fetus is chromosomally normal	Abnormal CVS result (about 1% of samples) that does not match the fetus	No	A recognized cause of false-positive (and occasionally false-negative) cell-free DNA results; a mosaic CVS result may need amniocentesis

The single best exam sentence: mosaicism = one zygote, two (or more) genomes; chimerism = two zygotes in one body.

Mosaicism vs the look-alike concepts

Concept	What it is	How to tell it from mosaicism
Chimerism	Cells from two or more zygotes in one person	Two whole genomes (for example, XX and XY cells, or two DNA profiles); mosaic cell lines come from one zygote and usually differ by a single variant or chromosome
Heteroplasmy	A mix of mutant and normal mitochondrial DNA within each cell	About mtDNA copies, not nuclear cell lines; passed on only by the mother; disease appears above a threshold level, and levels differ between tissues and between siblings
Uniparental disomy (UPD)	Both copies of a chromosome (or part of one) come from one parent	Chromosome number is normal; the classic consequences come through imprinted genes, as in Prader-Willi syndrome (maternal UPD 15) and Angelman syndrome (paternal UPD 15)
Variable expressivity	The same constitutional variant causes different severity in different people	The variant is in every cell, so blood testing finds it (Marfan syndrome: tall and slender in one relative, aortic disease in another)
X-inactivation (lyonization)	Random silencing of one X chromosome in each female cell	DNA is identical in every cell (a functional, not genetic, mosaic); the patchy expression needs two X chromosomes, so it is a female pattern

More on these contrasts: uniparental disomy, penetrance vs expressivity and the X-linked disorders flowchart.

Rule 1: timing decides how much of the body is involved

Early postzygotic error: many tissues carry it, so disease can be widespread and can reach the germ cells. GeneReviews puts it plainly for McCune-Albright syndrome: variants that occur early in development cause widespread disease, and later ones cause limited disease.
Late error: one lineage or body segment only, giving patchy, linear or one-sided findings that are not transmitted.
Only germ cells count for the next generation. A variant confined to skin or bone cannot be passed on; one present in egg or sperm precursors can, even if the parent looks normal.

Rule 2: a normal blood test does not rule it out

Test the affected tissue. In McCune-Albright syndrome, the GNAS variant is found in about 80% of lesional tissue samples but only 20-30% of blood samples with standard sequencing methods. In hypomelanosis of Ito, a blood karyotype shows the mosaic abnormality in up to 33% of patients, and skin fibroblasts find it in about 25% more.
Use sensitive methods. A low-level mosaic line can slip past standard testing, so labs test the lesion itself and use more sensitive methods, such as deep sequencing.
Clues that should make you think of it: pigment streaks or whorls along the lines of Blaschko (the paths of skin-cell migration in the embryo), hemihypertrophy or other asymmetry, café-au-lait spots or neurofibromas limited to one segment, and a milder-than-expected chromosomal syndrome.

Somatic mosaic disorders to know

Disorder	Postzygotic change	Classic findings
McCune-Albright syndrome	Activating GNAS variant (Gs alpha keeps adenylate cyclase switched on)	Polyostotic fibrous dysplasia; café-au-lait spots with jagged "coast of Maine" borders; endocrine hyperfunction such as precocious puberty, hyperthyroidism, growth hormone excess or Cushing syndrome. Never inherited: a germline variant in every cell is thought to be lethal
Proteus syndrome	AKT1 variant that drives abnormal cell growth	Asymmetric overgrowth of bone, skin and other tissues, usually apparent at 6-18 months; cerebriform connective tissue nevus on the soles; not inherited
Localized mosaic NF1 (older term: segmental NF1)	NF1 loss-of-function variant in part of the body	NF1 features limited to one or more body segments, usually milder than typical NF1; affected adults can have children with typical NF1
Hypomelanosis of Ito	Chromosomal mosaicism (sometimes a mosaic single-gene variant)	Hypopigmented whorls and streaks along Blaschko lines; intellectual disability, seizures, hemihypertrophy

Germline mosaicism and recurrence risk

The pedigree: two children with the same dominant or X-linked disorder, healthy parents, and a negative parental blood test. A proportion of one parent's eggs or sperm carry the variant (MedlinePlus).
Recurrence is low but not zero after an apparently de novo dominant or X-linked condition, because a normal parental blood test cannot exclude germline mosaicism. Example: GeneReviews puts the overall rate of mosaicism at up to 16% in parents of children with COL1A1/COL1A2 osteogenesis imperfecta (review the osteogenesis imperfecta breakdown).
Do not confuse it with reduced penetrance: a nonpenetrant parent carries the variant in every cell, so the parent's blood test is positive.

Chromosomal and placental mosaicism

Chromosomal mosaicism comes from a cell-division error in cells other than eggs and sperm: some cells end up with 45 or 47 chromosomes, others with 46 (MedlinePlus).
Mosaic Turner syndrome: some cells are 45,X, missing one X chromosome, while others have the usual number. Compare the Turner syndrome breakdown.
Mosaic Down syndrome: a very small percentage of Down syndrome; a random event during cell division early in fetal development, not inherited.
Mosaic trisomy 13: about 5% of cases, with milder features and longer survival possible, though severity does not reliably track the percentage of trisomic cells (see Patau syndrome).
Confined placental mosaicism: an abnormal line in the placenta but not the fetus, found in about 1% of CVS specimens. Cell-free "fetal" DNA comes from placental trophoblast, so confined placental mosaicism is a recognized cause of false-positive (and occasionally false-negative) cell-free DNA screening results. A positive screen must be confirmed with diagnostic testing.

Practice question

A 3-year-old boy is evaluated for developmental delay and seizures that began at 8 months of age. Since infancy he has had hypopigmented whorls and streaks that follow the lines of Blaschko on his trunk and left leg, and his left leg is longer and wider than the right. His parents and sister are healthy. A peripheral blood karyotype is 46,XY. Karyotyping of cultured fibroblasts from a hypopigmented streak shows two cell lines: one 46,XY and one with an extra chromosome.

Which of the following best explains his findings?

A. A constitutional (germline) variant with variable expressivity
B. Somatic mosaicism from a postzygotic error
C. Complete trisomy from maternal meiotic nondisjunction
D. Uniparental disomy affecting an imprinted region
E. Chimerism from the fusion of two zygotes
F. Random X-inactivation (lyonization)

Answer: B. Two karyotypes in one tissue, a normal blood karyotype, Blaschko-line pigmentation and one-sided overgrowth add up to somatic chromosomal mosaicism: the two cell lines arose after fertilization (most simply, a cell-division error in an early progenitor whose descendants populate part of the skin, leg and brain). This is the pattern of hypomelanosis of Ito.

A: a constitutional variant sits in every cell, including blood, and gives a body-wide rather than streaky pattern. Variable expressivity describes different severity between people with the same variant, not two genotypes inside one person.
C: meiotic nondisjunction puts the extra chromosome in every cell, so the blood karyotype would be abnormal and the findings systemic.
D: UPD leaves the chromosome count normal; its effects come from parent-of-origin imprinting (Prader-Willi, Angelman), not from a trisomic cell line in streaks of skin.
E: chimeras carry two complete genomes from two zygotes; here the two lines differ by a single chromosome, which points to one zygote.
F: lyonization silences one of two X chromosomes without changing the DNA, so it cannot create a second karyotype, and his 46,XY cells have only one X. Patchy X-linked disease is a female pattern.

Key takeaways

Mosaicism = one zygote, two or more genomes, from a postzygotic error; chimerism = two zygotes.
Earlier error, more tissues; later error, patchy or segmental disease.
Somatic mosaicism is not transmitted; germline mosaicism explains "de novo" disorders that recur in siblings despite normal parental blood tests.
Test the affected tissue with sensitive methods: blood is often normal (GNAS found in about 80% of lesions vs 20-30% of blood samples).
Classic somatic mosaic disorders: McCune-Albright (GNAS), Proteus (AKT1), localized mosaic NF1, hypomelanosis of Ito.
Chromosomal mosaicism gives milder variants (mosaic Turner, mosaic Down, mosaic trisomy 13 at about 5%); confined placental mosaicism (about 1% of CVS samples) can make cell-free DNA or CVS results look abnormal when the fetus is not.
Different concepts: heteroplasmy (mtDNA mix within each cell), UPD (parent of origin), variable expressivity (same variant, different severity) and lyonization (a functional mosaic of X expression with the same DNA in every cell).