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 ICLs (pyrimidine dimers) - leads to 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, growth restriction, microcephaly, dev delay

Susceptibility to leukaemia and other malignancies, immunodeficiency

Question 8

How is Fanconi anaemia tested for?

Answer 8

Culturing with a DNA ICL agents e.g. mitomycin C, cisplatin - 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 (AR)

TSG that 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. Significantly 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, sensitivity to sun, butterfly-shaped patch of reddened skin

Predisposition to malignancies, immunodeficiency

Question 13

What causes A-T?

Answer 13

ATM (AR)

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

Question 14

What are the clinical features of ataxia telangiectasia?

Answer 14

Cerebellar ataxia, telangiectasias

Predisposition to malignancies, immunodeficiency

Question 15

What causes NBS?

Answer 15

LoF variants in NBN (AR)

Regulates cell division & proliferation

Question 16

What are the clinical features of Nijmegen breakage syndrome?

Answer 16

Short stature, microcephaly, dev delay

Increased risk of malignancies (e.g. T and B cell lymphoma), immunodeficiency

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 and how is it tested for?

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

Cells treated with BrdU during 2 cell cycles followed by Giesma staining –> differentially stained sister chromatid