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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
Knudson's two hits hypothesis
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.
26
Is cancer AR or AD?
AD
27
AR inheritance patterns examples
MYH associated polyposis, Fanconi anaemia, ataxia telangiectasia
28
Sporadic vs familial cancer
Familial = older age onset + Multiple primary cancers + Other family affected + Same type/genetically-related cancers Some cancers are rarely genetic: cervix + lung
29
Retinoblastoma
``` Childhood ocular cancer - yellow eye instead of redeye 1 in 15-30k 30-50 children Knudson 2-hit hypothesis Rb1 gene (retblast) ```
30
Familial adenomatous polyposis (FAP)
100s of bowel polyps from teen onwards 1% of bowel cancers Up to 100% of bowel cancer APC tumour suppressor gene
31
Herditary non-polyposis colorectal cancer (NHPCC)
``` 2-3% of bowel cancers Polyps common but not polyposis Other cancer risks Mismatch repair genes MLH1 (50%), MSH2 (40%), MSH6 (10%) AD ```
32
BRCA1 and BRCA2 genes
``` Involved in DNA repair 10% of breast cancers Jewish populations AD Risk of breast cancer 80% Ovarian (BRCA1) - 40% Ovarian (BRCA2) - 10-20% ```
33
Li Fraumeni Syndrome
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
Cytogenetics definition
Study of chromosomes
35
Conventional cytogenetics
Metaphase chromosome analysis - G-banding
36
Molecular cytogenetics
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
Chromosome bands
Above centromere = p banding Below centromere = q banding Numbered in bands from centromere outwards
38
How do cytogenetic abrnormalities produce an abnormal phenotype?
Dosage effect Disruption of gene (breakpoint) Effect due to the parental origin (genomic imprinting) Position effect (new chromosomal environment) Unmasking recessive disorder
39
Phenotypic severity in cytogenetic abnormalities
Many lethal in utero Survivable imbalances inc: organ malformation, facial dysmorphism, compromised mental function Sex chromosome imbalance possible and more severe than autosomal
40
Aneuploidy meaning
Gain (trisomy) or loss (monosomy)
41
Polyploidy
Gain whole sets (triploidy or tetraploidy)
42
Mosaicism
Diploidy & aneuploidy
43
Origins of numerical abnormality
Gametogenesis - meiosis Fertilisation Early cleavage
44
Errors occurring at gametogenesis risk factors
Maternal age increase increases aneuploidy risk Paternal age increase shows no significant risk
45
Meiotic errors
Non-disjunction Failure of chromosome or chromatid separation Meiosis I (80-90%) is chromosome non-disjunction Meiosis II is chromatid non-disjunction
46
Chromosome non-disjunction
Chromosomes dont separate Two disomic gametes made Two mullisomic gametes made
47
Chromatid non-disjunction
One disomic gamete One nullisomic gamete Two normal gametes
48
Edwards syndrome
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
Patau syndrome
``` Trisomy 13 1/12k Small Severe mental retardation Microcephaly/sloping forehead Defects of brain holoprosencephaly ```
50
Autosomal aneuploidy and maternal age
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
Sex chromosome aneuploidy
No age-related risk Phenotype less severe Sexual orientation not affected
52
Turner's Syndrome chromosomes and chance
45, X | 1/2.5k
53
Klinefelter's syndrome chromosomes and chance
47, XXY | 1/1k
54
Features of Turner's syndrome
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
Klinefelter syndrome features
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
Two errors at fertilisation
Polyploidy - usually triploidy | Molar pregnancy - double paternal, no maternal.
57
Triploidy facts
``` 69, XXY 69, XYY 69, XXX 2% all pregnancies 99.9% spontaneously abort 1/570k live births ```
58
Origins of triploidy
A sperm could have 2N An egg could have 2N Two sperms could fertilise one egg
59
Double paternal
Massive placenta with growth delay
60
Double maternal
Tiny placenta, significant growth delay, head-saving macrocephaly - needs operation
61
Whats conclusions can we draw from parental origins of triploidy
Maternal genome is responsible for foetus The paternal genome is responsible for placenta
62
What is a molar pregnancy
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
Errors at early cleavage Mosaicism = mitotic non-disjunction
2nd mitotic division from a one cell zygote can produce either monosomy, trisomy normal disomy.
64
Consequences of mosaicism
Variable phenotype, lethality, non-identical twin, lateral asymmetry tissue-specificity, may generate uniparental disomy.
65
Reciprocal translocation
Break and exchange 1/500 5-10% phenotype risk
66
Robertsonian translocation
``` Whole arm fusion Acrocentrics 1/1000 No phenotype risk Reproductive risk ```
67
Inversions
2 breaks which rotate and rejoin 1/1000 5-10% phenotype risk
68
Unbalanced rearrangements
``` 1/2000 Copy number variation so can have lots of cytogenetic copies Commonest = deletions and duplications Several genes Mostly sporadic ```
69
Types of deletion
Terminal (end of) | Interstitial (loss of segment in middle)
70
Types of duplication
Direct - same direction just doubled in size | Inverted
71
Features of deletions and duplications
Phenotype - abnormal gene dosage | Variable clinical expression due to variable size of imbalance and its multifactorial nature.
72
Ring chromosome
Breakage then circularisation of the chromosome.

GiM (7 decks)

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