18.03.18 Chromosome breakage disorders Flashcards Preview

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Flashcards in 18.03.18 Chromosome breakage disorders Deck (42)
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1
Q

Give three examples of chromosome breakage disorders.

A
  1. Fanconi anaemia
  2. Ataxia telangectasia
  3. Bloom syndrome
  4. Nijmegen breakage syndrome
  5. Xeroderma pigmentosum
  6. Cockayne syndrome
  7. Trichothiodystrophy
2
Q

What is the incidence of Fanconi anaemia?

A

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.

3
Q

Is there a difference of incidence between males and females?

A

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

4
Q

What are the clinical features of Fanconi anaemia?

A

Physical abnormalities, present in approximately 75% of affected individuals, include one or more of the following:

  1. short stature
  2. abnormal skin pigmentation
  3. skeletal malformations of the upper and lower limbs
  4. microcephaly
  5. 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.
  6. The incidence of acute myeloid leukemia is 13% by age 50 years.
  7. Solid tumors – particularly of the head and neck, skin, gastrointestinal tract, and genitourinary tract – are more common in individuals with FA.
5
Q

Which genes are involved in the pathophysiology of Fanconi anaemia.

A

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.

6
Q

Which gene is the most common cause of FA cases?

A

FANCA is the most common cause, accounting for around two thirds of cases

7
Q

Other than FANCA, which genes have been associated with FA?

A

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)
8
Q

Describe the cytogenetic testing strategy for Fanconi anaemia.

A

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).

9
Q

What are the common cytogenetic abnormalities seen in FA?

A

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.

10
Q

Give an example of genotype-phenotype correlation in FA.

A

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.

11
Q

What proportion of FA patients show somatic cell mutation?

A

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.

12
Q

What is the incidence of Bloom syndrome?

A

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

13
Q

What are the clinical features of Bloom syndrome?

A
  1. Growth deficiency
  2. Characteristic facies (triangular shaped face, dolicocephaly (long narrow head), narrow cranium, malar (cheekbone) hypoplasia, nasal prominence, small mandible and prominent ears)
  3. sun-sensitive skin rash,
  4. telangiectatic
  5. hypo- and hyperpigmented skin
  6. immunodeficiency, marked predisposition to malignancy.

Also typical is a butterfly-shaped patch of reddened skin across the nose and cheeks.

  1. Recurrent GI and respiratory tract problems occur in infancy.
  2. Males are invariably infertile, whilst females may find it difficult but not impossible to conceive.
  3. 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.

14
Q

What gene is associated with Bloom syndrome?

A

BLM (15q26.1)

15
Q

What is the function of the BLM protein?

A

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.

16
Q

What is a typical cytogenetic finding in Bloom syndrome?

A
  1. 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.
  2. 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.
17
Q

How many harlequin stained cells should be analysed?

A

As some affected individuals have a population of cells with a normal SCE frequency, examination of 20 harlequin-stained metaphases is advisable. The laboratory should have a record of the SCE frequencies found when the same methods are applied to a range of normal control samples. Sequencing of the BLM gene is also available.

18
Q

What causes mosaicism in Bloom syndrome?

A

Mosaicism can occur due to the increased rate of chromosome recombination causing an intragenic recombination event in an individual with two different mutations of the BLM gene creating a functionally normal copy along with a double mutant copy.

Therefore if diagnosis of Bloom Syndrome is still suspected following a normal result on a peripheral blood sample it may be wise to also test a second sample type such a skin fibroblasts.

19
Q

What is the incidence of Ataxia telangectasia?

A

Frequency: ~ 1 case per 40,000-100,000 live births worldwide. The frequency of carriers is approx. 1 in 300.

20
Q

What are the clinical features of AT?

A

Also known as Louis-Bar syndrome.
Early onset autosomal recessive disorder characterized by cerebellar ataxia, truncal ataxia (jerky movements) progressing to peripheral ataxia, ocularmotor apraxia (inability to follow an object across visual fields), telangiectasias, immunodeficiency, hypogonadism, and predisposition to neoplasias.

Symptoms initially present in childhood between 1-4 years of age.

Patients are particularly sensitive to ionizing radiation and radiomimetic compounds. Patients become wheelchair-bound by age 10-15 years. Severely affected patients usually do not survive childhood. No cure.

21
Q

What is the leading cause of death in AT patients?

A

Pulmonary disease

22
Q

Which gene is associated with AT?

A

Caused by mutations in ATM (ataxia telangiectasia mutated) gene located at 11q22.3

~600 unique mutations identified in ATM gene (approx. 14 large scale deletions).

Most result in lack of protein for ATM.

No hotspots of mutations known.

23
Q

What are the diagnostic strategies for AT patients?

A
  1. Diagnosis by sequencing - detects about 90% of mutations.

Patients are usually compound heterozygotes, with different mutations in the 2 alleles of ATM. However, some ATM mutations, especially missense mutations, produce a dominant negative effect (in which a mutation in only 1 of the 2 alleles of the gene results in the disease phenotype).

  1. Linkage analysis may also identify carriers.
  2. Cytogenetic analysis: Chromosome gaps, breaks, and interchanges between nonhomologous chromosomes are a result of the defective DNA damage repair.
24
Q

What is the function of ATM protein?

A

ATM gene codes for a large serine-threonine kinase, involved in signalling the existence of dsDNA breaks.

It delays G1 to S and G2 to M stages of mitosis in the presence of DNA damage.

The role of the ATM protein is similar to the BRCA genes. Telomeres degrade faster is AT patients. Ataxia develops due to brain cells dying due to defective DNA damage repair of neurons caused by processes such as oxidative stress.

25
Q

What is observed in cytogenetic analysis of AT patients?

A

Cytogenetic analysis for chromosome breakage in dividing cells exposed to irradiation may be used to identify heterozygotes and chromosome aberrations in patients.

Karyotyping is performed on peripheral blood.

Lymphopenia and a decreased response to phytohemagglutinin hinder chromosome analysis, but 20-40% of chromosome breakage is observed in vitro.

AT patients frequently have abnormalities involving chromosome 14, particularly a 7;14 chromosome translocation, which is seen in 5-15% of peripheral lymphocytes from patients that are stimulated with phytohemagglutinin and harvested at 72 hours. The chromosome breakpoints are typically 14q11 (T-cell receptor-alpha locus) and 14q32 (B-cell receptor locus).

26
Q

What proportion of AT patients develop cancer?

A

Predisposition to malignancy (particularly ALL and lymphoma) – with ~35% of AT patients developing cancer. Susceptible to X-ray radiation, 1000 times more likely to get cancer, particularly lymphoma and leukaemia.

Carriers of ATM mutations have an increased risk of cancer – 4-fold increased risk of breast cancer.

27
Q

Give an overview of Nijmegen breakage syndrome, including incidence.

A

Also known as Berlin Breakage syndrome or Ataxia Telangiectasia variant 1

  1. Incidence estimated at 1:100,000 (most common in Slavic populations)
  2. Characterized by short stature, microcephaly, distinctive “bird-like” facial features (sloping forehead, prominent nose, large ears, small jaw, upslanting palpebral fissures), developmental delay, recurrent respiratory tract infections, intellectual disability, and other health problems.
  3. Slow growth during infancy and early childhood.
  4. Immunodeficiency - abnormally low levels of immunoglobulin G (IgG) and immunoglobulin A (IgA)
  5. shortage of T cells (many have rearrangements
  6. The immune system abnormalities increase susceptibility to recurrent infections.
  7. Increased risk of non-Hodgkin lymphoma, usually by age 15, rhabdomyosarcoma, Burkitts lymphoma and brain tumours
28
Q

What are the most frequently observed breakpoints in NBS?

A

7p13
7q35
14q11
4q32

which are the sites of the Tcell receptor genes and the human immunoglobulin heavy chain gene (IGH)).

29
Q

What gene is associated with NBS? What is the common mutation?

A

Caused by mutations in the NBN1 gene (8q21) – Nibrin protein - involved in repairing damaged DNA. Typically truncating mutations.

The majority of NBS patients identified are homozygous for a 5bp deletion (c.657_661del5) in exon 6

30
Q

What is the role on NBN1 protein?

A

Nibrin regulates cell division and proliferation, thus mutations lead to immunodeficiency - a lack of functional nibrin results in less immune cell proliferation

31
Q

What are the cytogenetic indications of NBS?

A

Cytogenetically, can observe spontaneous open chromatid and chromosome breaks, aneuploidies, marker chromosomes, and partial endoreduplication. In addition to characteristic translocations, lymphocyte chromosomes frequently show end-to-end fusions indicating telomere dysfunction (also seen in AT)

32
Q

Give an overview of Xeroderma pigmentosum, including incidence.

A

Incidence – 1:450,000 (northern European) but more common in Japan, North Africa and Middle East (1 in 50,000).

Extreme sensitivity to ultra-violet (UV) radiation including UVA and UVB. Exposure to even a very small amount of UV radiation leads to severe sunburn and blistering, beginning at a very young age.

The sensitivity to UV radiation results in increased freckling, areas of hypo skin pigmentation and very dry skin. There is a high risk of squamous cell and basal cell skin cancers and melanoma.

XP patients have eye problems, especially with the eyelids and eyes are also very sensitive to light, with a slightly increased risk of cancer of the eye.

Cancers of the lips, mouth, and the tip of the tongue have also been reported. 30% develop progressive neurological problems including developmental disabilities, mental handicap, and high-frequency hearing loss that leads to deafness.

Xeroderma = dry skin; pigmentosum = changes in pigmentation

33
Q

Which genes are associated with Xeroderma pigmentosum?

A

At least 8 inherited forms – XP A-G plus a variant type XP V (some more likely than others to cause neurological problems)

Inherited mutations in at least eight genes have been found to cause XP. >50% result from mutations in the XPC, ERCC2, or POLH genes. Diagnostic testing by sequencing.

All known XP genes are involved in DNA damage repair – most in nucleotide excision repair (NER)

34
Q

What is the pathophysiology of xeroderma pigmentosum?

A

All known XP genes are involved in DNA damage repair – most in nucleotide excision repair (NER)

The major features of XP result from a build-up of unrepaired DNA damage. When UV rays damage genes that control cell growth and division, cells can either die or grow too fast and in an uncontrolled way. Unregulated cell growth can lead to the development of cancerous tumours. Neurological abnormalities are also thought to result from an accumulation of DNA damage

35
Q

What is the incidence of Cockayne syndrome?

A

The minimum incidence of CS has been estimated at 2.7 per million births in western Europe.

36
Q

What are the clinical features of Cockayne syndrome?

A

Characterized by;

  1. microcephaly
  2. failure to thrive leading to very short stature, premature aging (progeria)
  3. delayed development.

The signs and symptoms of this condition are usually apparent from infancy, and they worsen over time.

Most affected individuals have an increased photosensitivity, and in some cases even a small amount of sun exposure can cause a sunburn or blistering of the skin.

Other signs and symptoms often include hearing loss, vision loss, severe tooth decay, bone abnormalities, hands and feet that are cold all the time, and changes in the brain that can be seen on brain scans.

37
Q

How many types of Cockayne syndrome are there? What are they?

A

Classified into 3 types (based on the severity and age of onset of symptoms):

CS type I (classic or moderate form), CS type I, the “classic” or “moderate” form;

CS type II, a more severe form with symptoms present at birth; this form overlaps with cerebrooculofacioskeletal syndrome (COFS) or Pena-Shokeir syndrome type II;

CS type III, a milder form; Xeroderma pigmentosum-Cockayne syndrome (XP-CS).

38
Q

How is classic cockayne syndrome diagnosed?

A

Classic CS is diagnosed by clinical findings including postnatal growth failure and progressive neurologic dysfunction along with other minor criteria. Molecular genetic testing or a specific DNA repair assay on fibroblasts can confirm the diagnosis. The two genes in which mutations are known to cause CS are ERCC6 (65% of individuals) and ERCC8 (35% of individuals).

Unlike the other chromosome breakage syndromes, CS is not associated with a predisposition to cancer.

39
Q

Give an overview of Trichothiodystrophy (TTD).

A

TTD is an autosomal recessive group of disorders characterized by short, brittle hair with low-sulphur content (due to an abnormal synthesis of the sulphur containing keratins), often combined with growth retardation and intellectual deficit, congenital ichthyosis and nail abnormalities.

The abnormalities are usually obvious at birth, with variable clinical expression.

About half of the patients with TTD exhibit marked photosensitivity, due to abnormalities in excision repair of ultraviolet (UV)-damaged DNA. In most cases, the deficiency in DNA excision repair is indistinguishable from that observed in Xeroderma Pigmentosum type D.

40
Q

How many types of TTD are there, what are they?

A

TTD can be sub classified into 4 syndromes: BIDS, PBIDS, IBIDS and PIBIDS:

BIDS Syndrome is an acronym for brittle hair-ichthyosis-decreased fertility-short stature syndrome. It is also called Amish brittle hair syndrome and hair brain syndrome. Characterised by brittle hair, ichthyosis, decreased fertility and short stature. Patients with BIDS syndrome are not photosensitive.

PBIDS Syndrome is an acronym for photosensitivity-brittle hair-ichthyosis-decreased fertility-short stature syndrome. It is basically a photosensitive form of BIDS syndrome.

IBIDS Syndrome is an acronym for intellectual impairment-brittle hair-ichthyosis-decreased fertility-short stature syndrome. It is also called Tay syndrome because it was first described by D-Tay in 1971 and sulphur-deficient brittle hair syndrome. It is a congenital disease, characterised by intellectual impairment, brittle hair, ichthyosis, decreased fertility, short stature and non-photosensitivity.

PIBIDS syndrome is the photosensitive form of IBIDS syndrome.

41
Q

Of the photosensitive TTD cases, what proportion are due to mutations in XPD (ERCC2)? Which genes are the remaining cases caused by?

A

95% (ERCC2/XPD, 19q13.2-13.3)

The remaining cases are caused by mutations within the XPB and GTF2H5 genes. These genes encode the DNA-dependent ATPase/helicase subunits of TFIIH (transcription factor).

42
Q

Which gene has been associated with the non-photosensitive form of TTD?

A

Mutations in at least one gene, MPLKIP, have been reported to cause a non-photosensitive form of TTD.

Mutations in this gene account for fewer than 20 percent of all cases of non-photosensitive TTD.

Little is known about the protein produced from the MPLKIP gene, although it does not appear to be involved in DNA repair.

It is unclear how mutations in the MPLKIP gene lead to the varied features of TTD.