Origin and significance of marker chromosomes

Question 1

What terms are used to describe marker chromosomes?

Answer 1

ESACs- Extra structurally abnormal chromosome

Accesrroy chromosome

small supernumary chromosome

Question 2

what is the definition of a marker chromosome?

Answer 2

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

Question 3

What is the prevalence of markers?

Answer 3

present in less than 1% of the population

- more common in infertile and ID populations

Question 4

What percentage of markers are de novo and inherited?

Answer 4

~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

Question 5

What percentage of markers are mosaic?

Answer 5

up to 50% of markers are mosaic

• more common in non-acrocentric markers
• some are always mosaic e.g. i(12p)

Question 6

what chromosomes are markers derived from?

Answer 6

~70% majority of markers are derived from the short arm and pericentromeric region of the acrocentric chromosomes.

Question 7

What are the different types of marker chromosomes?

Answer 7

inverted up
ring
centric
neocentric

Question 8

what is the proposed mechanism of marker formation?

Answer 8

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

Question 9

how to markers behave at meiosis?

Answer 9

Probably form a univalent rather than pairing with their homologous chromosome
- prone to loss resulting in mosaicism

Question 10

what chromosome are the most common markers derived from?

Answer 10

chr15- test for this first

Question 11

What should be considered when interpreting the phenotypic consequence of a marker?

Answer 11

• 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.

Question 12

what features are associated with iso9p

Answer 12

• 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

Question 13

What fetaures are associated with i(8p) tetrasomy8p?

Answer 13

• agenesis of the corpus callosum
• enlarged ventricles
• facial dysmorphism
• MR

Question 14

what is the incidence, marker and phenotype of pallister Killian syndrome?

Answer 14

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

Question 15

what is the incidence, marker and phenotype of iso(18p) syndrome?

Answer 15

i(18p)- tetrasomy 18p

 microcephaly
frontal bossing
low set ears
MRI abnormalities
small mouth/jaw

Question 16

what is the incidence, marker and phenotype of Emmanuel syndrome?

Answer 16

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

Question 17

what is the incidence, marker and phenotype of Cat eye syndrome?

Answer 17

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

Question 18

what is the incidence, marker and phenotype idic(15)?

Answer 18

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

Question 19

what is the impact of X chromosome derived markers?

Answer 19

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

Question 20

what is the impact of Y chromosome derived markers?

Answer 20

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

Question 21

What is the consideration for UPD when a marker is detected?

Answer 21

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

Question 22

How are markers investigated?

Answer 22

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

Question 23

what is the recurrence risk of marker chromosome?

Answer 23

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