Chromosome breakage disorders Flashcards
What are the characteristic features of chromosome breakage disorders?
- AR inheritance
- Due to mutations in genes involved in repair of damaged DNA and defects result in chromosome breakage and instability
- Associated with an increased risk of malignancy (except cockayne syndrome)
- FA and BLM show somatic mosaicism and can acquire a WT and double mutant due to high levels of recombination
What is the incidence of FA?
most common breakage disorder ~1 in 35,000
What are the clinical features of FA?
IUGR Postnatal growth retardation skeletal abnormalities (radial defects, hypoplastic or absent thumbs DD microcephaly increased risk of malignancy pancytopenia, anemia, progressive bone marrow failure genital abn in males
what malignancies is FA associated with?
Increased risk of AML and MDS with poor prognisis
what are the causative genes in FA? What is there role?
Due to mutations in genes in the fanconi complementation group
involved in recognition and repair of DNA damage incl DSBs
FANCA is most common (2/3) cases
FANCC and FANCG next most common ~ 10% each
Are there phenotype- genotype correlations in FA?
homozygous null mutations result in more severe pheno than missense
Somatic mosaicism in FA- why and implications?
Somatic mosaicism is common (10-25%) due to the high level of recombination and a somatic cell reverting back to WT
- so need to analyse sufficient cells (80-100 in BPG)
- recommended to average chromosome breaks across all cells analysed as well as calculate absolute breaks per cell
- may test another tissue e.g. skin if -ve result but FA still suspected
What is the hypersensitivity/ moelcular mechanism in FA?
Cells are sensitive to UV induced pyrimidine dimers and can’t excise them
sensitive to cross-linking agents and oxidative damage. - results in the formation of DSBs in S-phase
How is FA tested for?
FA patients show high levels of breakage (SCE) following culturing with a DNA crosslinking agent (clastogen) e.g. mitomycin C or DEB
- cannot detect carriers
- mutation testing also performed to allow for family follow-up
what are the FA BPG?
No specific BPG but mentioned in general guidelines
- analsye sufficient cells to exclude mosaicism
- include a control to show that the clastogen has worked- control should also show increased sister chromatid exchange compared to untreated control
what are the clinical features of Bloom syndrome
- more common in males- unclear why
- characteristic butterfly shaped reddened skin across face
- sun sensitivity
- immunodeficiency- resulting in recurrent infections due to reduced IgG and IgA
- hypo and hyper pigmented skin
- males are infertile and women may struggle to conceive
- increased risk of malignancy- leukemia, lymphoma, adenocarcinoma
What is the causative gene in BLM?
BLM gene- RecQ family helicase
normally functions as a tumour supressor and maintains genome stability by preventing inappropriate recombination
Mosaicism in BLM- cause and considerations for testing
High levels of somatic mosaicism due to high levels of recombination- intragenic recombination in an individual with 2 different BLM mutations can result in the generation of a WT allele and double mutant allele.
If not detected in peripheral blood should consider testing another tissue e.g. skin
examination of 20 harlequin metaphases recommended in case of mosaicism
What is the characteristic cyto feature in BLM?
Quadriradial configuration
4 armed figure consisting of 2 homologous chromosome and caused by chromosome breaks and rearrangements
Also see high levels of SCE
what are the clinical features of AT (ataxia telengiecstasia)
- ataxia- become wheelchair bound at 10-15yrs
- telegiecstasias (spider veins)
- eye abnormalities
- hypogonadism
- increased risk of malignancy - leukemias and lymphomas predominantly
- death in childhood due to pulmonary disease
- immunodeficiency due to low levels of low levels of IgA and IgE
