19.01.19 Origin of mosaicism

Question 1

What is the definition of mosaicism?

Answer 1

The presence of two or more genetically different cell lineages within one individual that have arisen in a single zygote

Question 2

What is the definition of chimerism?

Answer 2

The presence of two or more genetically different cell lineages within one individual that have arisen from different zygotes, e.g. aggregations of fraternal twins

• can arise in several ways
• May be present in dizygotic twins due to twin-twin transfusion
• Individual may also become chimeric after an allogenic bone marrow transfusion.

Question 3

What determined pattern of mosaicism?

Answer 3

• Normal embyro development (cell replication, migration and apoptosis) and by the timing and pathophysiological effects of the abnormalities

Question 4

Name two types of mosaicism

Answer 4

Somatic and germline

Question 5

What is somatic mosaicism?

Answer 5

• Mosaicism that occurs in a somatic cell population - no risk of recurrence in next generation - Earlier in embryogenisis that mitotic error occurs, the greater fraction of cells contain the abnormality (and more severe phenotype)

Question 6

What is germline mosaicism?

Answer 6

• Abnormality arises during formation of a germ cell prior to the onset of meiosis - therefore have an abnormal cell line in the gonads - Cells originate in the yolk sac and then migrate to the gonadal ridge on the dorsal wall of the abdominal cavity - they then comprise the tissue of the gonads - These gametocytes must replicate around 30 times, so there is potential for errors to exist at each cell division

Question 7

What is somatic gonadal mosaicism?

Answer 7

• When an abnormality arises in embryogenesis prior to differentiation of the germ cell line, somatic tissue may also be involved generating somatic gonadal mosaicism

Question 8

List two types of mosaic chromosomal abnormalities?

Answer 8

Mosaic trisomies and sex chromosome mosaicism

Question 9

Mosaic trisomies - what ones are more common?

Answer 9

1) 13 - 5% of Patau cases are mosaic 2) 16 - Found in <1% of pregnancies - most commonly occuring trisomy. It is always mosaic and normally confined to skin or lung (not in blood). Get IUGR, cardiac defects 3) 18 - <5% Edward cases are mosaic. No link between level of mosaicism and phenotype severity 4) - 21 - Mosaicism in 2% of cases.

Question 10

Sex chromosome mosaicism - Turner syndrome

Answer 10

• 15% mosaic - can be numerical (e.g. 45,X/46,XX) or structural (e.g. 45,X/46,X,+mar) mosaicism. - Numerical tend to have milder phenotype, may enter puberty and may be fertile. - If marker present, must test to see if X or Y due to gonadoblastoma risk with Y material, and also XIST is present (yes - may get stronger phenotype, no - may not be affected.

Question 11

Sex chromosome mosaicism - Klinefelter syndrome

Answer 11

• Most often referred due to infertility, gynaecomastia (30-50%) or a Klinefelter’s “habitus” - Often a mosaic complement (e.g. 47,XXY/46,XY) and these men may have some fertility

Question 12

Give an example of a mosaic iso chromosome

Answer 12

• 12p Pallister Killian syndrome - Always present in a mosaic form - and shows tissue specific mosaicism - Get normal diploid karyotype in blood, abnormal cells normally found in fibroblats, amino fluid, CVS and bone marrow. - Rare to find them in dividing lymphocytes due to huge turnover rate of the cells - Normally test buccal smears

Question 13

Do mosaic CNVs occur?

Answer 13

• Can occur but are rare - seen on ~1% of CNVs in dev del cases

Question 14

Do mosaic point mutations occur? Give 2 examples

Answer 14

Yes 1) McCune Albright syndrome - mosaic GoF variants in GNAS1 - only seen in mosaic form - get bony hyperostosis (excessive bone growth) and endocrine dysfunction 2) NF1 - Some patients have segmental NF1 (also called mosaic). Clinical phenotype limited to only a single portion of body - Occurs due to post zygotic NF1 PM or CNV during organogenesis

Question 15

What is the main mechanism that causes mosaic aneuploidy?

Answer 15

• Post-zygotic mitotic (somatic) non-disjunction - Non-disjunction can cause mosaicism for trisomic and monosomic cells lines
• growth of the monosomic cell line is normally severely disadvantaged so often dies out and leaves normal cell lines and trisomic one

Question 16

Discuss the process of trisomy rescue

Answer 16

• Mosaicism normally arises due to a non-disjunction error during a mitotic cell division or during meiosis, followed by a postzygotic correction of the aneuploidy (i.e. trisomy rescue)
• Trisomy rescue normally occurs due to anaphase lag
• A homologue is lost due to delayed movement of the chromsoome during anaphase of mitosis - so it fails to connect to the spindle or is drawn to the pole at too late a stage to be included in the reformation of the nuclear membrane
• Then forms a micronucleus which is lost
• Most mosaic disomy/trisomy 13, 18, 21 and 45,X arise through this mechanism
• Trisomy rescue is one mechanism that can give rise to UPD

Question 17

Mosaicism in neoplasia

Answer 17

• Example of somatic mosaicism
• LOH by mitotic recombination has been described in many tumours

Question 18

X chromosome inactivation

Answer 18

• all females are mosaic due to X chromosome inactivation (random process)
• Can get skewed X inactivation

Abnormal X chromosome inactivated - asymptomatic carrier

Normal X chromosome inactivated - may present with phenotypic features (e.g. DMD)

Question 19

Age related sex chromosome aneuploidy

Answer 19

• Normal ageing process to lose an X or Y to give occasional 45,X cell line
• Over 44 years of age - 14% of women have 1/15-30 cells with gain of X
• Over 44 years of age - 21% of women have 1/15-30 cells with loss of X
• Normal range = <1% at 30 yrs, 2% at 40 yrs, 3% at 50 yrs, 5% at 65 yrs
• Significant loss = 6% at 30 yrs, 9% at 40 yrs, 13% at 50 yrs, 17% at 60 yrs
• Freq to Y loss is greater in older men

Question 20

Hypomelanosis of Ito (HI)

Answer 20

• rare birth defect that causes streaked, whirled, or mottled patches of light-colored skin following Blaschko’s lines
• range of conditions known as ‘pigmentary mosaicism’

Question 21

UPD mosaicism

Answer 21

• Occurs as a consequence of meiotically originating trisomies - mitotic loss of one copy of the duplicated chromosome (trisomy rescue)
• Leaves risk of UPD for the diploid cell line

Question 22

What is dynamic mosaicism?

Answer 22

• A feature of ring chromosomes
• Cell division becomes disrupted as rings become entangled, broken or doubled fowlloing sister chromatid exchange
• Therefore daughter cells would be partially or totally aneuploid for the ring
• If cells survive they remain in mosaic state

Question 23

What is mutational mosaicism?

Answer 23

• E.g. FRAX
• the coexistence of the full mutation and the premutation due to somatic instability of the triploid repeat (up to 20% of fragile X males mutational mosaics).

Question 24

What is methylation mosaicism?

Answer 24

• e.g. FRAX
• All cells have a full mutation, but the methylation pattern may not be the same in all cells / tissues.

Question 25

What is diploid/triploid mosaicism?

Answer 25

• Some cells which are triploid,
• Triploid line reflects either digyny (diploid ovum becoming fertilized by a monoploid sperm) or diandry (normal ovum by either a diploid sperm (MI or MII error) or by two sperm (dispermy))
• Get a variable phenotype including skin pigmentary changes (lines of Blaschko), growth & mental retardation, truncal obesity hemihypertrophy and clino- / camptodactyly

Question 26

What is a vanishing twin?

Answer 26

• Two cell lines identified at CVS but only one at amniocentesis due to one of the co-conceptus having died and only fibrotic placental tissue remaining.

Question 27

What is a pseudomosaicism?

Answer 27

• Mosaicism that arises in culture and is not true mosaicism

Question 28

What is a confined placental mosaicism?

Answer 28

• mosaicism restricted to the placenta and does not reflect the true fetal genotype
• Even if fetus is diploid, can still gte IUGR etc due to placenta not working and developing properly

Question 29

What methods detect mosaicism?

Answer 29

1. Karyotype and FISH- 30 cell screen excludes 15% risk at 0.99 confidence. Although limited by resolution and number fo cells that can be analysed. Interphase FISH can exclude mosaicism at a lower level as cells at all stages of cycle can be counted
2. Microarray - aCGH detects >10% level of mosaicism for aneuploidy and around 30% for mosaic CNVs. SNP arrays can detect around 5% mosaicism
3. MLPA - can detect 30-40% mosaicism (dups harder than dels)
4. Sanger - 10-20% mosaicism (dups harder to detect)
5. NGS - ~1% mosaicism (BUT need 5000X coverage to get this)