19.03.22 Origin and significance of markers Flashcards
List 3 names for marker chromsomes
- Small supernumerary marker chromosome (sSMC)
- Extra structurally abnormal chromosome (ESAC)
- Accessory chromosomes
Definition of a marker chromosome
Structurally abnormal chromosome that cannot be identified by conventional banding alone and is equal to or smaller in size than chromosome 20 of the same metaphase spread
- Those bigger than Chr 20 tend to be large enough to identify
- if they are identified, then they are called a derivative chr and not a marker
- Can be derived from any chr but majority come from an acrocentric chromosome
- Can produce a phenotype but more than half do not
- 50% are mosaic (more common in non-acrocentric sSMC)
- Can cause infertility (as they interfere with meiosis)
- 77% are de novo (75% of which have a phenotype)
- 23% are inherited (75% of which have no phenotype) - maternal transmission is twice as common than paternal, due to selection of sperm without sSMC
3 ways a sSMC can appear
1) in addition to a normal karyotype (e.g. 47,XX,+mar)
2) in addition to a numerical abnormality (e.g. Turner syndrome or T21)
3) as part of a structurally abnormal but balanced karyotype (e.g. robertsonian translocation, t(11;22))
Composition of an sSMC
- 70% derived from short arms and pericentromeric regions of acrocentric chromosomes
- Can be inverted duplication chromosomes, small supernumerary ring chromosomes, complex SMC (from unbalanced transmission of balanced rearrangement)
How are markers formed?
- Can occur due to numerical error with subsequent partial trisomy rescue, monosomy rescue, or result from an unbalanced structural rearrangement
- Can be meiotic or mitotic
How to marker chromosomes behave at meiosis?
- Probably form univalent rather than synapsing with chromosome it has been derived from
- Very small markers are prone to loss during cell division
- Familial sSMCs are normally maternally inherited
Phenotype associated with marker chromosomes
- Phenotype can be normal to severely affected
- Phenotype influenced by:
1) size and origin of euchromatin present
2) Level of mosaicism
3) Presence/absence of UPD of sSMCs sister chromosome - There are common marker syndrome
- Unique markers need to be assessed individually for potential phenotype
- Normally small markers, with little euchromatin, have a low risk of causing a phenotype
- Large markers with euchromatin - high risk
- If inherited from a normal parent, likely to have no effect but level of mosaicsm and affected tissue types need to be taken into account
Pallister-Killian syndrome
- isochromosome 12p (so you get tetrasomy 12p)
- Phenotype is severe MR, seizures, characteristic facial features and diaphragmatic hernia
- Detectable in fibroblast tissues, but rarely found in blood
- Almost all cases are mosaic
- Can get false negative results for prenatals (as high as 10% of cases due to varying levels of mosaicism)
Isochromosome 18p syndrome
- get tetrasomy 18p
Phenotype is microcephaly, frontal bossing, strabismus, low set ears, small nose/mouth and MRI abnormalities - Very rare and is often fatal
Emanuel syndrome
- derivative chromsome 22 that causes trisomy for 11q23-qter and 22q11-qter
- Arises from unbalanced 3:1 segregation of recurrent t(11;22)
- Carriers have 10% risk of having an unbalanced baby
- Phenotype is severe ID, miceocephaly, FTT, facial asymmetry, preauricular tags, cleft palate, micrognathia, and renal/heart defects
Cat-eye syndrome
- inv dup(22)
- Get tetrasomy for 22p-q11.2 (can get variable breakpoints)
Phenotype is MR, iris coloboma, downslanting palpebral fissures, anorectal/cardiac/renal malformations - Phenotype can vary a lot, from mild to severe (not linked to size of marker from variable breakpoints)
Idic(15) syndrome
- Inv dup(15)
- Get tetrasomy for 15p-(somewhere between q11 and q14) - due to variable breakpoints
- Phenotype is dev del, autism, epilepsy and minor physical defects
- Phenotype associated with presence of PWS/AS region and is more severe when marker is maternally in origin
- Phenotype normally only seen in 50% of cases but this can be variable
X chromosome derived SMCs
- Ring form is the most common
- 46,X,+SMC is associated with a variant Turner syndrome (can also be in addition to a normal 46,XX or XY cell line)
- Phenotype depends on whether XIST is present or not
- If XIST is absent - more likely to get a phenotype as marker is not inactivated
Y chromosome derived SMCs
- Normally idic/inv dup Y
1) 46,X,+SMC with absence of SRY = get Turner like phenotype but also increased risk of gonadoblastoma
2) 46,X,+SMC with SRY but loss of Yq = get male infertility - If SMC contains any Y material then there is a 30% risk of gonadal tumours
UPD
- See UPD in 5-10% of SMC cases
- Normally due to partial monosomy rescue
- Recommended that if SMC is derived from a chromosome linked to UPD then this should be tested for (i.e. 6, 15, 7, 11 etc)
Testing for sSMCs
- Karyotype - to visualise marker
- FISH - if suggestive of 1 or 2 chromosomes (or needed to provide positional info). Can also identify centromere material (although sometimes not possible for some chromosomes as there are no unique centromeric FISH probes)
- aCGH - if no idea what marker is made up of (if normal then can be more confident that marker is benign). Although array may not pick up low level mosaic markers. SNP arrays are best as they will pick up heterodisomy
Testing strategy for sSMCs
1) karyotype (and parental karyotypes)
2) Assessment of euchromatic content (array, C-banding) - if no euchromatin then low risk, if there is some then carry on testing
3) If acrocentric - do chr 15 FISH or panel of acrocentric probes
- If positive for 15 - confirm with PWS/AS test
- If negative - do alpha-satellite FISH to determine between acrocentrics
4) if not acrocentric then do any FISH that karyotyping suggests, or failing that do array
5) consider UPD testing if required
Recurrence risk for sSMCs
- if de novo, low risk
- if familial, high risk of transmission but is rarely associated with phenotype
- If mosaic in parent, can be mosaic or non-mosaic in child
- if both are mosaic, can still get variable phenotype
