20.05.15 Marker chromosome at PND - strategy and management Flashcards
What is a marker chromosome
- Extra chromosomal piece found during karyotyping that are usually derived from a structural rearrangement.
- Present in addition to normal chromosome complement
- Also called supernumerary marker chromosome (SMC)
Criteria for a marker chromosome
- Structurally abnormal, smaller or equal to the size of chromosome 20 on the same metaphase spreads.
- Cannot be identified/characterised by conventional banding cytogenetics.
Review of marker chromosome
- Found in individuals with normal and abnormal clinical phenotypes.
- Effect on phenotypes depends on: size, gene content, level of mosaicism, eu/heterochromatic, UPD.
- Result in copy number gain of affected genomic sequence
Which chromosome are marker chromosomes most frequently derived
Chromosome 15 (30-50%)
What percentage of marker chromosomes are inherited
30%
How many syndromes are associated with marker chromosomes
- 8
- e.g. Cat eye syndrome, Emanuel syndrome
Which 4 groups of patients are marker chromosomes generally identified
- Prenatally (with and without abnormal scan)
- Adults with fertility issues
- Children/adults with unexplained developmental delay or dysmorphism
- Incidental findings when cytogenetic analysis is performed for other reasons.
Incidence of marker chromosomes in live births
0.04%
Incidence of marker chromosomes in intellectual disability
0.28%
Incidence of marker chromosomes in infertility
0.125%
Problem with best practice guidelines for investigating marker chromosomes in prenatal setting
- Published in 2009 and is focused on marker chromosomes found by prenatal karyotyping
- Doesn’t reflect current practices which are testing by arrayCGH as a front line test for samples with abnormal scans
Reasons to characterise a marker chromosome
- Determine gene content.
- Allows better understanding of phenotypic consequence and recurrence
Methods of characterising a marker chromosome
-Banding, FISH, array CGH to identify chromosomal origin, breakpoints, gene content.
2 reasons why array isn’t as good at detecting marker chromosomes compared to banding cytogenetics and FISH
- array would miss low level mosaicism (<20%)
- Array would miss marker chromosomes that contain only heterochromatin
What considerations should be made regarding characterisation of a marker chromosome
- Is it de novo or inherited, could UPD be involved (if derived from an imprinted chromosome)
- What is the chromosomal origin, size and gene content
- Is euchromatic material involved
- Is there mosaicism
Pros and cons of using cytogenetic banding to investigate a marker chromosome
- Pro: can provide information regarding structure of marker, may reveal mosaicism
- Cons: limited resolution (analysis of small markers is difficult), limited power to identify origin of marker
- C banding can be used to establish absence/presence of heterochromatin (C+ve) or euchromatin (C-ve). If mainly heterochromatin then less risk as little active gene content.
- Silver staining: identifies NORs (nucleolar organisation regions). Distributed across short arms of 5 acrocentric chromosomes (13, 14, 15, 21, 22)
Pros and cons of using FISH to investigate a marker chromosome
- Pros: can determine chromosome origin, e.g. X chromosome (markers in 7-16% of Turner syndrome cases), chr15 (56-60% of markers)
- Cons: limited accuracy and resolution, costly and inefficiency to do sequential testing.
What two types of chromosome 15-derived supernumerary marker chromosomes (SMCs) are there
- Small sSMC(15)s: without euchromatic material. Do NOT contain Prader-Willi/Angelman critical region. Usually no phenotype
- Large SMC(15)s: acrocentric chromosomes containing copies of PWS critical region, so associated with abnormal phenotypes.
If origin of marker not determined, should cell cultures be kept
Yes, you can keep for FISH or DNA extraction (array and UPD studies)
Benefit to using array over FISH
- FISH can only confirm presence of regions covered by probes, unlike array.
- arrayCGH can detect chromosome imbalance
- Array can detect complex markers, where material is derived from multiple chromosomes.
- Limitations of array: may miss mosaics, won’t detect heterochromatic material.
Do ring marker chromosomes have higher or lower risk than non-ring marker
Higher risk, due to instability at meiosis, may manifest features of ring syndrome.
