18.03.18 Chromosome breakage disorders Flashcards
Give three examples of chromosome breakage disorders.
- Fanconi anaemia
- Ataxia telangectasia
- Bloom syndrome
- Nijmegen breakage syndrome
- Xeroderma pigmentosum
- Cockayne syndrome
- Trichothiodystrophy
What is the incidence of Fanconi anaemia?
1 in 350,000 births
Fanconi anemia (FA) is the most common genetic cause of aplastic anemia and one of the most common genetic causes of hematologic malignancy.
The ratio of males to females is 1.2:1
Carrier frequency was 1:181 in North Americans and 1:93 in Israel.
Specific populations have founder variants with increased carrier frequencies (<1:100), including Ashkenazi Jews (FANCC, BRCA2), northern Europeans (FANCC), Afrikaners (FANCA), sub-Saharan Blacks (FANCG), Spanish Gypsies (FANCA), and others.
Is there a difference of incidence between males and females?
The ratio of males to females is 1.2:1
Males and females appear to be affected in equal numbers for the autosomal recessive forms of FA.
However, about 32% of males have abnormal genitalia compared with 3% of females.
For the X-linked complementation group of FA (FANCB), males are affected and females are unaffected carriers
What are the clinical features of Fanconi anaemia?
Physical abnormalities, present in approximately 75% of affected individuals, include one or more of the following:
- short stature
- abnormal skin pigmentation
- skeletal malformations of the upper and lower limbs
- microcephaly
- ophthalmic and genitourinary tract anomalies. 6. 6. Progressive bone marrow failure with pancytopenia typically presents in the first decade, often initially with thrombocytopenia or leukopenia.
- The incidence of acute myeloid leukemia is 13% by age 50 years.
- Solid tumors – particularly of the head and neck, skin, gastrointestinal tract, and genitourinary tract – are more common in individuals with FA.
Which genes are involved in the pathophysiology of Fanconi anaemia.
FA is a genetically heterogeneous disease with 15 different complementation groups.
These genes are involved in the recognition and repair of damaged DNA and thus individuals with FA are susceptible to haematological malignancy.
Mutated cells have deficient ability to excise UV-induced pyrimidine dimers from the cellular DNA, they are sensitive to small concentrations of DNA crosslinking agents or lesions arising from oxidative damage.
The defect may be in any of the proteins involved in DNA interstrand crosslink repair, it leads to double-strand breaks in the S phase of the cell cycle and accumulation of cells in G2 biallelic mutation leads to a particularly severe form of FA with a very high cancer risk.
Which gene is the most common cause of FA cases?
FANCA is the most common cause, accounting for around two thirds of cases
Other than FANCA, which genes have been associated with FA?
FANCC - 10%
FANCG - 10%
All other genes (AR) 12% combined BRACA2 FANCD2 FANCE FANCF FANCI BRIP1 FANCL FANCM PALB2 RAD51C SLX4 FANCB (only XL gene)
Describe the cytogenetic testing strategy for Fanconi anaemia.
Alkylating agent sensitivity:
Patient and control PHA stimulated cultures treated with DiEpoxyButane (DEB) and the chromosome damage compared in 80 cells
SCEs for DEB control
Follow up: VB use MECOM FISH for dup 3q & del 7q interphases plus in BM standard clone analysis
DEB arrest cells in late S phase of the cell cycle. This increased breakage occurs even in the absence of other symptoms. Cytogenetic analysis can aid in a diagnosis of FA but it does not identify heterozygotes (carriers).
What are the common cytogenetic abnormalities seen in FA?
Common cytogenetic abnormalities are:
monosomy 7;
deletions of the long arms of chromosomes 5, 7, and 20 (5q−, 7q−, 20q−)
; trisomy 8;
translocations and rearrangements of chromosomes 1 and 3.
Patients may have 2 or more cell lines, one of which may be normal. The normal cell line is thought to arise from back mutation, gene conversion, and selective loss of the abnormal cell line.
Give an example of genotype-phenotype correlation in FA.
Genotype-phenotype correlations exist for the various complementation groups:
e.g. in FANCA, patients homozygous for null mutations had an earlier onset of anaemia and a higher incidence of leukaemia than those with mutations producing an altered protein.
FA group G patients and patients homozygous for null mutations in FANCA are high-risk groups with a poor hematologic outcome and should be considered as candidates both for frequent monitoring and early therapeutic intervention.
What proportion of FA patients show somatic cell mutation?
10-25% of FA patients, often due to a somatic cell reverting to wild type (sometimes due to mitotic recombination between chromosomes carrying different Fanconi mutations) therefore it is recommended to count average breaks per cell across all cells analysed as well as the absolute number of breaks per cell, in order to increase the likelihood of detecting mosaic cases.
If a diagnosis of FA is still suspected following a negative result on peripheral blood then it is advised that a second tissue type such as skin fibroblasts are tested.
What is the incidence of Bloom syndrome?
Incidence: 1/160,000 in the UK population. Higher prevalence amongst Askenazi Jews of around 1/50,000 and other ethnic groups where it occurs at around 1 per million
What are the clinical features of Bloom syndrome?
- Growth deficiency
- Characteristic facies (triangular shaped face, dolicocephaly (long narrow head), narrow cranium, malar (cheekbone) hypoplasia, nasal prominence, small mandible and prominent ears)
- sun-sensitive skin rash,
- telangiectatic
- hypo- and hyperpigmented skin
- immunodeficiency, marked predisposition to malignancy.
Also typical is a butterfly-shaped patch of reddened skin across the nose and cheeks.
- Recurrent GI and respiratory tract problems occur in infancy.
- Males are invariably infertile, whilst females may find it difficult but not impossible to conceive.
- Predisposition to malignancy: leukaemias develop at an average of around 22 years of age, whilst other solid tumours, particularly of the breast and gastro-intestinal tract occur by 35 years of age.
Prevalence slightly higher in males but cause unknown.
What gene is associated with Bloom syndrome?
BLM (15q26.1)
What is the function of the BLM protein?
Encodes a DNA helicase ‘RecQ protein-like-3’ at 15q26.1. The gene product is DNA helicase RecQ–like 3, one of 5 members of the RecQ helicase family.
The normal protein functions as a caretaker tumor suppressor gene; it is essential for the maintenance of genome stability because it suppresses inappropriate recombination. BLM forms part of a multienzyme complex including topoisomerase III alpha (Top3a), replication protein A (RPA), and BLAP75/RMI1 to catalyze dissolution of double Holliday junctions at stalled replication forks. BLM interacts with DNA damage response proteins 53BP1, H2AX, FEN1, and colocalizes with the Fanconi anemia pathway protein FACND2. BLM complexes with TRF2 and has a role in telomere maintenance.
Lack of BLM results in hyper-recombination and telomere association, to genomic instability and cancer predisposition.
What is a typical cytogenetic finding in Bloom syndrome?
- Quadriradial configuration, which is produced by chromatid rearrangements. The 4-armed figure consists of 2 homologous chromosomes caused by chromosome breaks and rearrangements. Quadriradials also may be seen in some heterozygous males’ sperm.
- Sharply increased SCE level. A normal level of SCEs in a cell is around 6-10. In Bloom Syndrome it is greater than 50. Prenatal diagnosis can be carried out on chorionic villus cells although SCEs should really be used in combination with detection for a known mutation or linked polymorphic markers.
