Mosaicism and Disease Flashcards
1
Q
Discuss the clinical significance and origins of mosaicism in Human disease and describe diagnostic tests used to detect mosaicism.
A
- Introduction
- Significance, definition and types of mosaicism
- Normal mosaicism
- X-inactivation, loss of X/Y with age
- Commonly seen mosaic abnormalities
- Aneuploidies
- Sub-chromosomal copy number
- SNVs/indels/STRs
- Epigenetic mosaicism
- Prenatal mosaicism
- Chimerism (tech not mosaicism)
- Origins of mosaicism
- Methods for detection of mosaicism
2
Q
Define mosaicism and describe it’s clinical significance
A
- Mosaicism is defined as
- the presence of two or more genetically different cell lineages within one individual that have arisen post-zygotically within a single organism
- Emerging studies show that mosaicism is common: individuals are complex mosaics of genetically distinct cells, to such an extent that no two somatic cells are likely to have the exact same genome
- Post-zygotic variation
- has diverse physiological roles and pathological consequences
- is an important confounder in medical genetic testing
3
Q
Describe the types mosaicism
A
- “Somatic” Mosaicism
- “Germline mosaicism” (Gonadal)
- “Somatic gonadal” mosaicism
4
Q
Describe somatic mosaicism
A
- Mosaicism that occurs only in a somatic cell population of a given organism; therefore, there is no risk of passing on the mosaic genotype to offspring.
- The earlier in embryogenesis that these mitotic errors occur, the greater the likelihood of a substantial fraction of the soma being chromosomally abnormal, leading to increasing departure from the normal phenotype i.e. an increase in the percentage of abnormal cells usually leads to an increased phenotypic abnormalities.
5
Q
Describe germline mosaicism
A
- If an abnormality arises during the formation of a germ cell prior to the onset of meiosis, an abnormal cell line can be established and occupy a part of the gonad or gonads.
- Cells destined to give rise to gametocytes originate in the yolk sac in early embryogenesis and migrate to the gonadal ridge on the dorsal wall of the abdominal cavity where, along with the supporting cells, they come to comprise the tissue of the gonad. In doing so, gametocytes must replicate many times, going through about 30 cell divisions. The potential for error exists at each cell division contributing to this population.
6
Q
Describe somatic-gonadal mosaicism
A
- When an abnormality arises in embryogenesis prior to differentiation of the germ cell line, somatic tissue may also be involved generating somatic gonadal mosaicism
7
Q
Describe non-pathogenic forms of mosaicism
A
- X Chromosome Inactivation
- All females are mosaic due to X chromosome inactivation, usually a random process (see X-inactivation notes for further details). However, it is possible for X inactivation to become skewed with one X chromosome being preferentially inactivated.
- Age Related Sex Chromosome Aneuploidy in blood
- Loss of an X, or Y to give an occasional 45,X cell is a normal characteristic of ageing (see 5+6 for further info)
- Normal loss of X chromosome (in females) by cytogenetic analysis of blood: ≤1% at 30yrs; 2% at 40yrs; 3% at 50yrs; 5% at 65yrs
- Normal loss of Y typcially seen in much older males >70 years
- If levels of loss are more significant then this can be causitive of disease
8
Q
Describe why aneuploidies are commonly seen in mosaic form
A
- For most of the autosomes, full trisomy is lethal with foetal loss occurring early in pregnancy.
- When the trisomy occurs in mosaic form, however, the phenotypic effects can be ameliorated and the pregnancy may proceed to term.
- Liveborns have been reported with mosaic trisomies for most of the autosomes including
- 1, 8, 9, 16, 17, and 22 (as well as 13, 18, 21)
9
Q
Describe a few notible mosaic aneuploidies
A
- Chromosome 13 – Patau Syndrome
- mosaicism seen in ~5% cases; range of clinical severity of mosaic T13 probably likely due to varying proportion of T13 cells and distribution within the body.
- Chromosome 16
- 1% clinically recognized pregnancies; most commonly occurring trisomy; always mosaic; very rarely found in multiple tissues, typically confined to skin or lung; not detected in PB; no obvious syndrome, but IUGR and cardiac defects common; UPD16 tend to be smaller at birth than those with biparental inheritance; however, T16 in placenta seems to have adverse effect on growth even without UPD.
- Chromosome 18 – Edward Syndrome;
- mosaicism seen in <5% cases. Phenotype in mosaic cases highly variable ranging from complete trisomy 18 phenotype to apparently phenotypically normal adults; no apparent correlation between the percentage of trisomy 18 cells seen in either blood cells or skin fibroblasts and the severity of clinical manifestations.
- Chromosome 21 – Down syndrome
- mosaicism seen in ~2% cases. Features often similar to T21 but usually milder depending on level and distribution of trisomic cells; low levels of T21 have been detected in phenotypically normal adults tested due to recurrent pregnancy loss/trisomic pregnancy.
10
Q
Describe a few notible sex chromosome mosaic aneuploidies
A
- Turner’s Syndrome, (45,X)
- At least 15% of cases are mosaic.
- Turner’s syndrome has been proposed as a form of aneuploidy that exists only as mosaics. It is suggested that conceptuses with a 45,X chromosome constitution probably survive to term only when a 46,XX or 46,XY cell line is present somewhere in the organism
- More than 98% of conceptuses that are identified as 45,X are spontaneously lost, and probably represent those embryos that are non-mosaic.
- Numerical, e.g. 45,X/46,XY or 45,X/46,XX/47,XXX
- Important to identify mosaic karyotypes as can have implications for an affected individual’s development (particularly where a diagnosis is made in infancy)
- Numerical mosaic Turner’s may have a milder phenotype: generally taller; may enter puberty spontaneously; are likely to have secondary amenorrhea/premature menopause; may be fertile.
- Klinefelter’s Syndrome (47,XXY)
- Most often referred with infertility/azoospermia, gynaecomastia (30-50%) or a Klinefelter’s “habitus”
- Karyotype analysis shows that there is often a mosaic 47,XXY/46,XY chromosome complement and these men may be fertile
11
Q
Describe notible mosaic structural chromosomal abnormalities
A
- Turner’s Syndrome, (45,X)
- Structural, e.g. 45,X/46,X,i(X)(q10) or 45,X/46,X, +mar, 45,X/46,X,r(X) etc.
- Turner’s with structurally abnormal X chromosome or marker chromosome may feature fewer of the Turner stigmata, perhaps only short stature/gonadal dysgenesis.
- Marker chromosome must be investigated to determine if the marker is of X or Y derivation.
- If Y material is present in a phenotypic female there may be an elevated risk of gonadoblastoma.
- If Xist is absent on a derived X marker, there may be a more severe phenotype due to functional partial X disomy.
- Severity of phenotype will be dependent on the genes present. In fact, small markers without Xist may not affect phenotype at all.
- 12p Pallister Killian syndrome always present in a mosaic form
- significant levels in fibroblast, AF, CVS and BM samples but are extremely rare in dividing lymphocytes. This is due to the instability of the i(12)p at mitosis and the additional chromosome being lost from the lymphocytes due to the huge turnover rate of these cells.
12
Q
Describe the clinical significance of mosaic copy number variants
A
- aCGH has identified mosaic CNVs in between 0.5-2% of paediatric developmental delay cases
- A recent large study showed identified mosaic structural variation in 0.9% of a cohort of children with developmental delay
- This was significantly higher than the level seen in controls
13
Q
Describe some notible examples of disease caused by mosaic SNVs/indels
A
- McCune Albright Syndrome
- Mosaic gain of function mutations in GNAS1 gene
- Disorder is only seen in mosaic form
- Phenotype: bony hyperostosis, café-au-lait spots and endocrine dysfunction
- Osteogenesis Imperfecta type II
- Parents typically unaffected but carry dominant germline mosaic point mutations in Collagen COL1A1 or COL1A2
- Severe congenital connective tissue disorder characterized by brittle bones
- Gives an initial appearance of AR inheritance.
- Proteus Syndrome
- Characterised by multiple overgrowths of the skin, bone, connective and other tissues,
- caused by a dominant somatic mutation in the gene AKT1.
- It has never been reported to be recurrent in a family or to be heritable across generations, which is consistent with its incompatibility with survival
- The multiple lesions of Proteus syndrome contain between 1 and 50% mutant cells
- Neurofibromatosis type 1 (NF1)
- Some patients have segmental NF1 (also referred to as mosaic/localised). Clinical manifestation of NF1 limited to only single portion of their body
- Result from post zygotic NF1 point mutations or CNVs during organogenesis.
- Can be limited to somatic cells or include germline.
14
Q
Describe a disease caused by mosaic STRs and methylation mosaicism
A
- Fragile X syndrome
- 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 STR mosaics
- All cells have a full mutation, but the methylation pattern may not be the same in all cells / tissues - aka “methylation mosaicism”
15
Q
Describe the types of mosaicism detected in a prenatal diagnostic setting
A
- True fetal mosaicism
- Confined placental mosaicism
- Pseudomosaicism
