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GiM > Multifactorial disease, familial cancer, chromosomal inheritance > Flashcards

Multifactorial disease, familial cancer, chromosomal inheritance Flashcards

1
Q

Mendelian definition

A

Obey’s Mendel’s laws of segregation (dominant, recessive, X-L)

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2
Q

Complex definition

A

Vaguely used to describe something inherited with non-Mendelian component

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3
Q

Polygenic definition

A

The result of multiple genes

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4
Q

Multifactorial definition

A

Multiple factors - genetic + environmental

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5
Q

Multifactorial diseases seen in:

A 
Familial clustering
Twin studies (DZvsMZ)
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6
Q

Problems with using MZ twins

A

Large differences in birth weights ie differences in prenatal environment
Variation in the time of splitting of the early embryo
Diamniotic monozygotics survive more than monochorionic

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7
Q

DZ twins can share more than half their genes - why?

A

1 in 10 undergo blood transfusion during pregnancy

Can be chimeras - mixture of cells from two genetically distinct individuals

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8
Q

Prevention of NTDs

A

Neural tube defects

50-70% are prevented by maternal folic acid supplementation one month after conception to 3months after conception

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9
Q

Population Association study

A

High frequency in population with relatively low morbidity

Most disease bearing chromosomes are descended from a few ancestral chromosomes.
New stretches are added to ancestral chromosomes by recombination

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10
Q

Functional study

A

Low frequency in population and low morbidity

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11
Q

Linkage analysis

A

Low frequency in population but high magnitude in effect

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12
Q

Genetics of alzheimers

A

variants in polymorphic locus has large effect on age of onset. ApoE implicated in heart disease. Three haplotypes of ApoE: ApoE*E2, E3, E4

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13
Q

ApoE*E4

A

Increases susceptibility to Alzheimer’s

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14
Q

Apo*E2

A

Protective effect to Alzheimer’s

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15
Q

Age-related macular degeneration (AMD)

A

Leading cause of irreversible central visual disfunction caused by degeneration of the macula.
Characterised by early deposition of drusen

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16
Q

AMD multifactorial factors

A

Genetics (CFH), ARMS2
Major effect = smoking
Intermediate effect = smoking (70 fold increase)

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17
Q

Main examples of polygenic disease

A

Schizophrenia, T2DM, Alzheimers, AMD

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18
Q

Two types of genes involved in familial cancer

A

Caretaker genes - DNA repair, carcinogen metabolism

Gatekeeper genes - cell cycle control, apoptosis

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19
Q

Two groups of environmental factors affecting cancer formation

A

Macro - chemicals, viruses, radiation, physical agents

Mirco - oxyradicals, hormones, growth factors

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20
Q

Multi-stage carcinogenesis

A

Series of genetic changes occur within cells leading to increasingly cancerous activity

Normal epi -> hyperproliferative epi -> early adenoma -> intermediate adenoma -> late adenoma -> carcinoma -> metastasis

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21
Q

Penetrance definition

A

% with a gene change who develop the condition

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22
Q

Landscaper genes

A

Control surrounding stromal environment

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23
Q

Tumour supressor genes

A

Protects cell from cancer

Loss of function increase cancer e.g. APC, BRCA1/2, TP53, Rb

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24
Q

Oncogenes

A

Regulate cell growth and differentiation
Gain of function/activating mutations increase the risk of cancer
e.g. Growth and signal transduction factors, RET gene

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25
Q

Knudson’s two hits hypothesis

A

In order to cause cancer, both tumour suppressors genes need to be knocked, if one of the chromosomes from family already has one knocked out, cancer more likely.

Dominant inhertiance yet recessive in activity in cell.

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26
Q

Is cancer AR or AD?

A

AD

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27
Q

AR inheritance patterns examples

A

MYH associated polyposis, Fanconi anaemia, ataxia telangiectasia

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28
Q

Sporadic vs familial cancer

A

Familial = older age onset +
Multiple primary cancers +
Other family affected +
Same type/genetically-related cancers

Some cancers are rarely genetic: cervix + lung

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29
Q

Retinoblastoma

A 
Childhood ocular cancer - yellow eye instead of redeye
1 in 15-30k
30-50 children
Knudson 2-hit hypothesis
Rb1 gene (retblast)
30
Q

Familial adenomatous polyposis (FAP)

A

100s of bowel polyps from teen onwards
1% of bowel cancers
Up to 100% of bowel cancer
APC tumour suppressor gene

31
Q

Herditary non-polyposis colorectal cancer (NHPCC)

A 
2-3% of bowel cancers
Polyps common but not polyposis
Other cancer risks
Mismatch repair genes
MLH1 (50%), MSH2 (40%), MSH6 (10%)
AD
32
Q

BRCA1 and BRCA2 genes

A 
Involved in DNA repair
10% of breast cancers
Jewish populations
AD
Risk of breast cancer 80%
Ovarian (BRCA1) - 40%
Ovarian (BRCA2) - 10-20%
33
Q

Li Fraumeni Syndrome

A

P53 mutations - rare
AD
50% have cancer by age 40, close to 100% lifetime
Breast, sarcoma, brain, adrenocortical, leukaemia
Avoid radiotherapy (more cancer risk)
Poor prognosis
Value of genetic testing here

34
Q

Cytogenetics definition

A

Study of chromosomes

35
Q

Conventional cytogenetics

A

Metaphase chromosome analysis - G-banding

36
Q

Molecular cytogenetics

A

Cytogenetic analysis at the molecular resolution at all stages of cell cycle via DNA or in situ

FISH, microarray CGH, next gen sequencing, MLPA, QF-PCR, qPCR

37
Q

Chromosome bands

A

Above centromere = p banding
Below centromere = q banding
Numbered in bands from centromere outwards

38
Q

How do cytogenetic abrnormalities produce an abnormal phenotype?

A

Dosage effect
Disruption of gene (breakpoint)
Effect due to the parental origin (genomic imprinting)
Position effect (new chromosomal environment)
Unmasking recessive disorder

39
Q

Phenotypic severity in cytogenetic abnormalities

A

Many lethal in utero
Survivable imbalances inc: organ malformation, facial dysmorphism, compromised mental function

Sex chromosome imbalance possible and more severe than autosomal

40
Q

Aneuploidy meaning

A

Gain (trisomy) or loss (monosomy)

41
Q

Polyploidy

A

Gain whole sets (triploidy or tetraploidy)

42
Q

Mosaicism

A

Diploidy & aneuploidy

43
Q

Origins of numerical abnormality

A

Gametogenesis - meiosis
Fertilisation
Early cleavage

44
Q

Errors occurring at gametogenesis risk factors

A

Maternal age increase increases aneuploidy risk

Paternal age increase shows no significant risk

45
Q

Meiotic errors

A

Non-disjunction
Failure of chromosome or chromatid separation
Meiosis I (80-90%) is chromosome non-disjunction
Meiosis II is chromatid non-disjunction

46
Q

Chromosome non-disjunction

A

Chromosomes dont separate
Two disomic gametes made
Two mullisomic gametes made

47
Q

Chromatid non-disjunction

A

One disomic gamete
One nullisomic gamete
Two normal gametes

48
Q

Edwards syndrome

A

Trisomy 18
1 in 6000 livebirths
10% survive >1year
Small head, low ears, cleft palate + lip, clenched hands, overlapping fingers, rockerbottom feet, severe mental retardation

90% have congenital heart disease

49
Q

Patau syndrome

A 
Trisomy 13
1/12k 
Small 
Severe mental retardation
Microcephaly/sloping forehead
Defects of brain holoprosencephaly
50
Q

Autosomal aneuploidy and maternal age

A

Female eggs are made and stored from 5months until puberty.

2 steps: unfavourable chiasmata distribution at development stage

Age-dependent deterioration of meiotic structures over 10-40 years. Worsened by hormone imbalance, irradiation, oral contraceptives, alcohol

51
Q

Sex chromosome aneuploidy

A

No age-related risk
Phenotype less severe
Sexual orientation not affected

52
Q

Turner’s Syndrome chromosomes and chance

A

45, X

1/2.5k

53
Q

Klinefelter’s syndrome chromosomes and chance

A

47, XXY

1/1k

54
Q

Features of Turner’s syndrome

A

Reproductive: loss of ovarian function, no puberty and infertile.

Lymphatic: webbed neck, swelling of hands or feet

Others: short stature, coarctation of aorta, normal IQ more inclined to be reduced though

55
Q

Klinefelter syndrome features

A

Most undiagnosed (64%)
Identified via infertility or hypogonadism
80% is 47, XXY; 20% is mosaic
Infertile - may lack 2nd sexual characteristics, testicular dysgenesis, 20x risk of breast cancer

Growth is normal in infancy but accelerates and has long legs and arms.

Normal IQ but IQ does decrease with increases chromosomes

56
Q

Two errors at fertilisation

A

Polyploidy - usually triploidy

Molar pregnancy - double paternal, no maternal.

57
Q

Triploidy facts

A 
69, XXY
69, XYY
69, XXX
2% all pregnancies
99.9% spontaneously abort
1/570k live births
58
Q

Origins of triploidy

A

A sperm could have 2N
An egg could have 2N
Two sperms could fertilise one egg

59
Q

Double paternal

A

Massive placenta with growth delay

60
Q

Double maternal

A

Tiny placenta, significant growth delay, head-saving macrocephaly - needs operation

61
Q

Whats conclusions can we draw from parental origins of triploidy

A

Maternal genome is responsible for foetus

The paternal genome is responsible for placenta

62
Q

What is a molar pregnancy

A

Haploid sperm enters an empty egg. The body naturally double the haploid sperm so you have 2N male zygote. This leads to double paternal genome = massive cystic placenta.

63
Q

Errors at early cleavage

Mosaicism = mitotic non-disjunction

A

2nd mitotic division from a one cell zygote can produce either monosomy, trisomy normal disomy.

64
Q

Consequences of mosaicism

A

Variable phenotype, lethality, non-identical twin, lateral asymmetry tissue-specificity, may generate uniparental disomy.

65
Q

Reciprocal translocation

A

Break and exchange
1/500
5-10% phenotype risk

66
Q

Robertsonian translocation

A 
Whole arm fusion
Acrocentrics
1/1000
No phenotype risk
Reproductive risk
67
Q

Inversions

A

2 breaks which rotate and rejoin
1/1000
5-10% phenotype risk

68
Q

Unbalanced rearrangements

A 
1/2000
Copy number variation so can have lots of cytogenetic copies
Commonest = deletions and duplications
Several genes
Mostly sporadic
69
Q

Types of deletion

A

Terminal (end of)

Interstitial (loss of segment in middle)

70
Q

Types of duplication

A

Direct - same direction just doubled in size

Inverted

71
Q

Features of deletions and duplications

A

Phenotype - abnormal gene dosage

Variable clinical expression due to variable size of imbalance and its multifactorial nature.

72
Q

Ring chromosome

A

Breakage then circularisation of the chromosome.

GiM (7 decks)

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