19. Mosaicism - origins & clinical significance

Question 1

Define mosiacism

Answer 1

Presence of >2 genetically different cell lineages in an individual, arisen from a single zygote as a result of post-zygotic event

Question 2

What is chimerism?

Answer 2

Arisen from fusion of 2 zygotes, or after BM transplant

Question 3

What factors influence the phenotype associated with mosaicism?

Answer 3

Proportion of affected cells and pattern of distribution

Depend on development time point at which variant occurred, before or after differentiation

Question 4

When would germline mosaicism be suspected?

Answer 4

Variant present in 2 siblings but absent in parents

Question 5

What is the sensitivity of Sanger and NGS to detect mosaicism?

Answer 5

Sanger = 10-20%

NGS = 1% if coverage is 1000x

Question 6

What is the sensitivity of arrays and karyotype/FISH?

Answer 6

SNP array = 5%, sensitivity proportional to probe density in particular region

Karyotype/FISH = count of 30 cells excludes 15% mosaicism at 0.99 confidence

Question 7

What can cause pseudomosaicism? How is this combated?

Answer 7

Culturing cells - cause loss or gain or cell lines

Confirm result with multiple cultures

Question 8

What might explain discrepancy between karyotype/FISH and array?

Answer 8

Array looking at nucleated cells, karyotype/FISH is cultured lymphocytes only

Question 9

What are the two mechanisms that lead to mosaic aneuploidy?

Answer 9

1. Meiotic non-disjunction causes trisomy in zygote. Corrected in early mitosis by anaphase lag –> mosaic for diploid and trisomic cell lines
2. Mitotic non-disjunction –> 1 trisomic + 1 monosomic daughter cell, monosomic cell line disadvantaged to dies out

Question 10

What risk is associated with mosaic aneuploidy due to meiotic non-disjunction?

Answer 10

UPD depending on which chromosome is lost

Particularly important for imprinted chr (6, 7, 11, 14, 15, 20)

Question 11

Give an example of a disorder that is only observed in the mosaic form?

Answer 11

Rett syndrome in males

Otherwise lethal

Question 12

Give examples of mosaic overgrowth disorders

Answer 12

McCune-Albright syndrome (GNAS)

PI3K/AKT/mTOR signalling pathway disorders (GoF mutations):
- PI3K related overgrowth spectrum
- Proteus syndrome (AKT)
- Hemimegalencaphaly (mTOR)

Question 13

What is the role of the PI3K/AKT/mTOR signalling pathway?

Answer 13

Essential role in regulation of normal cell growth, metabolism, and survival

Question 14

What genes negatively regulate PI3K/AKT/mTOR? What is their association with disease?

Answer 14

PTEN and TSC1/2

LoF variants cause Cowden syndrome/tuberous sclerosis complex - mostly germline but can be mosaic

Question 15

How are mosaic overgrowth disorders characterised clinically?

Answer 15

Overgrowth, skin pigmentation abnormalities, blood vessel malformations

Question 16

What type of mutations cause mosaic overgrowth disorders?

Why are they only ever seen in the mosaic state?

Answer 16

Activating/GoGF mutations in signalling pathway genes

Mutations would be lethal in non-mosaic state