18. Chromosome breakage syndromes

Question 1

What are chromosome breakage disorders?

Answer 1

Inherited disorders associated with chromosomal instability and breakage either spontaneously or in response to DNA damaging agents.

Question 2

What causes chromosome breakage syndromes?

Answer 2

Defect in DNA repair replication and mechanism responsible for maintaining genomic stability

Question 3

What are the clinical consequence of all CBSs?

Answer 3

Cancer pre-disposition, immunodeficiency

Question 4

What are the 4 common chromosome breakage disorders?

Answer 4

1. Fanconi anaemia
2. Bloom syndrome
3. Ataxia-telangiectasia
4. Nijmegen breakage syndrome

Question 5

What causes Fanconia anaemia?

Answer 5

Mutations in 15 genes involved in recognition and repair of damaged DNA (FANCA, FANCC, FANCG)

Deficient ability to excise UV-induced interstrand cross-links (ICLs) (pyrimidine dimers) –> DSBs

Question 6

What is an interstrand cross link?

Answer 6

Covalent bonding of two nucleotides on opposite strands

Prevent the separation of two DNA strands and therefore replication and transcription

Detected in S phase when replication fork stalls

Question 7

What are the clinical features of Fanconi anaemia?

Answer 7

Bone marrow failure, congenital abnormalities, growth retardation, microcephaly, dev delay, susceptibility to leukaemia and other malignancies

Question 8

How is Fanconi anaemia tested for?

Answer 8

Culturing with a DNA ICL agents e.g. DEB, mitomycin C (MMC) - arrest cells in late S phase of the cell cycle

Shows increased chromosome breakage and radial forms

Examine 80-100 cells due to mosaicism

Sequencing for family follow up

Question 9

What causes Bloom syndrome?

Answer 9

BLM encodes DNA helicase - normally functions as TSG which maintains genomic stability by suppressing inappropriate recombination

Catalyses dissolution of double Holliday junctions at stalled replication forks

Question 10

What are double Holliday junctions?

Answer 10

Intermediate structure formed during homologous recombination repairs of DSBs

Question 11

What three cytogenetic findings are associated with Bloom syndrome?

Answer 11

1. Quadradial configurations (chromosome with four arms, formed by recombination between two chromosomes)
2. Increased sister chromatid exchange
3. Chromatid gaps, breaks, and rearrangements

Question 12

What are the clinical features of Bloom syndrome?

Answer 12

Severe growth deficiency, sun-sensitive skin rash, immunodeficiency, butterfly-shaped patch of reddened skin, predisposition to malignancies

Question 13

What causes A-T?

Answer 13

ATM encodes serine threonine kinase - involved in signalling DSBs, delays G1/S and G2/M transitions in mitosis when DNA is damaged

Ataxia due to defective DNA damage repair in neurones

Question 14

What are the clinical features of ataxia telangiectasia?

Answer 14

Cerebellar ataxia, oculomotor dyspraxia, telangiectasias, immunodeficiency, predisposition to malignancies

Particular sensitivity to ionising radiation

Question 15

What is the mechanism of disease in NBS?

Answer 15

LoF

NBN gene - repairs damaged DNA by forming complex with MRE11A and RAD50

Regulates cell division & proliferation

Question 16

What are the clinical features of Nijmegen breakage syndrome?

Answer 16

Short stature, microcephaly, dev delay, immunodeficiency, increased risk of malignancies (e.g. T and B cell lymphoma)

Question 17

Which rearrangements are commonly seen in CBSs?

Answer 17

Monosomy 7, trisomy 8

5q-, 7q-, 20q-

Often mosaic

Question 18

What is sister chromatid exchange

Answer 18

Takes place at DNA replication

Sister chromatids break and rejoin with one another - exchange regions of the duplicated chromosomes

No information altered during reciprocal interchange by homologous recombination