Origin and significance of marker chromosomes Flashcards
What terms are used to describe marker chromosomes?
ESACs- Extra structurally abnormal chromosome
Accesrroy chromosome
small supernumary chromosome
what is the definition of a marker chromosome?
small structurally abnormal chromosome which cannot be identified by G-banding, smaller than chromosome 20
if they are larger than chromosome 20 they can usually be identified by banding pattern and are termed derivatives
What is the prevalence of markers?
present in less than 1% of the population
- more common in infertile and ID populations
What percentage of markers are de novo and inherited?
~75% de novo- 75% of these are associated with phenotype but this value is skewed by ascertainment bias
remaining are inherited and ~75% are not associated with clinical phenotype
- most are maternally transmitted suggesting that they could be excluded in spermatogenesis
What percentage of markers are mosaic?
up to 50% of markers are mosaic
- more common in non-acrocentric markers
- some are always mosaic e.g. i(12p)
what chromosomes are markers derived from?
~70% majority of markers are derived from the short arm and pericentromeric region of the acrocentric chromosomes.
What are the different types of marker chromosomes?
inverted up
ring
centric
neocentric
what is the proposed mechanism of marker formation?
markers may arise as a result of a numerical error with partial trisomy or monosomy rescue or as a result of an unbalanced structural rearrangement. Can be mitotic or meiotic
Proposed mechanisms for isochromosome / inv dup marker / neocentric marker formation;
- centric fission / U type exchange (Figure 1) / centromere misdivision
how to markers behave at meiosis?
Probably form a univalent rather than pairing with their homologous chromosome
- prone to loss resulting in mosaicism
what chromosome are the most common markers derived from?
chr15- test for this first
What should be considered when interpreting the phenotypic consequence of a marker?
- size
- genetic content- the less euchromatin present in general the lower risk of phenotype
- level of mosaicism
- de novo / inherited- if inherited from a normal parent generally considers benign but need to consider the level of mosaicism and tissue distribution
- Presence of UPD for the markers sister chromosome.
what features are associated with iso9p
- very rare
- prenatal diagnosis is uncommon as marker is cmore common in blood and can be absent from skin, CVS and AF due to somatic mosaicism
- bulbous nose. cleft palat, micrognathia
What fetaures are associated with i(8p) tetrasomy8p?
- agenesis of the corpus callosum
- enlarged ventricles
- facial dysmorphism
- MR
what is the incidence, marker and phenotype of pallister Killian syndrome?
i(12p)- 4 copies of 12p
diaphragmatic hernia
MR
seizures
characteristic facial features
detectable in skin but rarely in blood. May be missed in CVS/AF prenatally due to high level of mosaicism
what is the incidence, marker and phenotype of iso(18p) syndrome?
i(18p)- tetrasomy 18p
microcephaly frontal bossing low set ears MRI abnormalities small mouth/jaw
what is the incidence, marker and phenotype of Emmanuel syndrome?
der(22)t(11;22)(q23;q11)
- trisomy for 11qter and 22qter
Due to 3:1 unbalanced inheritance of balanced parental rearrangement. carriers have 10% risk of offspring with Emmanuel syndrome
MR microcephaly failure to thirve cleft palate micrognathia renal/cardiac abn
what is the incidence, marker and phenotype of Cat eye syndrome?
invdup(22) = Tetrasomy for 22p->22q11.1
iris coloboma
downslanting palpebral fissures
anorectal and cardiac malformation
Highly variable phenotype depending from normal to severe and not associated with marker size
what is the incidence, marker and phenotype idic(15)?
invdup(15) = tetrasomy for 15p->15q11-q14 (variable bp)
DD
autism
epilepsy
minor physical defects
phenotype is associated with the presence of the PWS/AS region when maternally inherited. Phenotype seen in 50% of cases but is variable
what is the impact of X chromosome derived markers?
Most commonly ring X
may be found with a 45,X cell line in variant turner or in addition to a XX/XY cell line
phenotype is depending on Xist- if it is absent it will be more severe
what is the impact of Y chromosome derived markers?
Usually an idic/inv dup Y
46,X + Y marker without SRY will result in a turners like phenotype with increased risk of gonadal blastoma so important to test for Y in these cases
46,X+ Y marker with SRY present is associated with male infertility
What is the consideration for UPD when a marker is detected?
UPD should be considered if a marker contain a chromosome involved in UPD and phenotype is suggestive
seen in 5-10% of cases and likely to result from monosomy rescue
How are markers investigated?
Often detected by array as this has become the first line test and can be karyotyped to confirm if the additional material is a marker
array can be useful for determining genetic content and clinical consequence and is less labor intensive than the possibility of sequential FISH
arrayCGH will miss low level mosaic markers
SNP array may detect UPD associated with markers
FISH cannot identify all acrocentric centromeric markers as there are no unique centromeric probes
if acrocentric best first FISH is for chr15
what is the recurrence risk of marker chromosome?
de novo have a low recurrence risk
familial markers have a high recurrence risk - up to 50%
if parent carried a mosaic marker the child may have it in the mosaic or non-mosaic form. There may be significant phenotype difference depending on level and distribution of mosaicism
