Multifactorial disease, familial cancer, chromosomal inheritance Flashcards
Mendelian definition
Obey’s Mendel’s laws of segregation (dominant, recessive, X-L)
Complex definition
Vaguely used to describe something inherited with non-Mendelian component
Polygenic definition
The result of multiple genes
Multifactorial definition
Multiple factors - genetic + environmental
Multifactorial diseases seen in:
Familial clustering Twin studies (DZvsMZ)
Problems with using MZ twins
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
DZ twins can share more than half their genes - why?
1 in 10 undergo blood transfusion during pregnancy
Can be chimeras - mixture of cells from two genetically distinct individuals
Prevention of NTDs
Neural tube defects
50-70% are prevented by maternal folic acid supplementation one month after conception to 3months after conception
Population Association study
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
Functional study
Low frequency in population and low morbidity
Linkage analysis
Low frequency in population but high magnitude in effect
Genetics of alzheimers
variants in polymorphic locus has large effect on age of onset. ApoE implicated in heart disease. Three haplotypes of ApoE: ApoE*E2, E3, E4
ApoE*E4
Increases susceptibility to Alzheimer’s
Apo*E2
Protective effect to Alzheimer’s
Age-related macular degeneration (AMD)
Leading cause of irreversible central visual disfunction caused by degeneration of the macula.
Characterised by early deposition of drusen
AMD multifactorial factors
Genetics (CFH), ARMS2
Major effect = smoking
Intermediate effect = smoking (70 fold increase)
Main examples of polygenic disease
Schizophrenia, T2DM, Alzheimers, AMD
Two types of genes involved in familial cancer
Caretaker genes - DNA repair, carcinogen metabolism
Gatekeeper genes - cell cycle control, apoptosis
Two groups of environmental factors affecting cancer formation
Macro - chemicals, viruses, radiation, physical agents
Mirco - oxyradicals, hormones, growth factors
Multi-stage carcinogenesis
Series of genetic changes occur within cells leading to increasingly cancerous activity
Normal epi -> hyperproliferative epi -> early adenoma -> intermediate adenoma -> late adenoma -> carcinoma -> metastasis
Penetrance definition
% with a gene change who develop the condition
Landscaper genes
Control surrounding stromal environment
Tumour supressor genes
Protects cell from cancer
Loss of function increase cancer e.g. APC, BRCA1/2, TP53, Rb
Oncogenes
Regulate cell growth and differentiation
Gain of function/activating mutations increase the risk of cancer
e.g. Growth and signal transduction factors, RET gene
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.
Is cancer AR or AD?
AD
AR inheritance patterns examples
MYH associated polyposis, Fanconi anaemia, ataxia telangiectasia
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
Retinoblastoma
Childhood ocular cancer - yellow eye instead of redeye 1 in 15-30k 30-50 children Knudson 2-hit hypothesis Rb1 gene (retblast)
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
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
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%
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
Cytogenetics definition
Study of chromosomes
Conventional cytogenetics
Metaphase chromosome analysis - G-banding
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
Chromosome bands
Above centromere = p banding
Below centromere = q banding
Numbered in bands from centromere outwards
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
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
Aneuploidy meaning
Gain (trisomy) or loss (monosomy)
Polyploidy
Gain whole sets (triploidy or tetraploidy)
Mosaicism
Diploidy & aneuploidy
Origins of numerical abnormality
Gametogenesis - meiosis
Fertilisation
Early cleavage
Errors occurring at gametogenesis risk factors
Maternal age increase increases aneuploidy risk
Paternal age increase shows no significant risk
Meiotic errors
Non-disjunction
Failure of chromosome or chromatid separation
Meiosis I (80-90%) is chromosome non-disjunction
Meiosis II is chromatid non-disjunction
Chromosome non-disjunction
Chromosomes dont separate
Two disomic gametes made
Two mullisomic gametes made
Chromatid non-disjunction
One disomic gamete
One nullisomic gamete
Two normal gametes
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
Patau syndrome
Trisomy 13 1/12k Small Severe mental retardation Microcephaly/sloping forehead Defects of brain holoprosencephaly
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
Sex chromosome aneuploidy
No age-related risk
Phenotype less severe
Sexual orientation not affected
Turner’s Syndrome chromosomes and chance
45, X
1/2.5k
Klinefelter’s syndrome chromosomes and chance
47, XXY
1/1k
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
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
Two errors at fertilisation
Polyploidy - usually triploidy
Molar pregnancy - double paternal, no maternal.
Triploidy facts
69, XXY 69, XYY 69, XXX 2% all pregnancies 99.9% spontaneously abort 1/570k live births
Origins of triploidy
A sperm could have 2N
An egg could have 2N
Two sperms could fertilise one egg
Double paternal
Massive placenta with growth delay
Double maternal
Tiny placenta, significant growth delay, head-saving macrocephaly - needs operation
Whats conclusions can we draw from parental origins of triploidy
Maternal genome is responsible for foetus
The paternal genome is responsible for placenta
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.
Errors at early cleavage
Mosaicism = mitotic non-disjunction
2nd mitotic division from a one cell zygote can produce either monosomy, trisomy normal disomy.
Consequences of mosaicism
Variable phenotype, lethality, non-identical twin, lateral asymmetry tissue-specificity, may generate uniparental disomy.
Reciprocal translocation
Break and exchange
1/500
5-10% phenotype risk
Robertsonian translocation
Whole arm fusion Acrocentrics 1/1000 No phenotype risk Reproductive risk
Inversions
2 breaks which rotate and rejoin
1/1000
5-10% phenotype risk
Unbalanced rearrangements
1/2000 Copy number variation so can have lots of cytogenetic copies Commonest = deletions and duplications Several genes Mostly sporadic
Types of deletion
Terminal (end of)
Interstitial (loss of segment in middle)
Types of duplication
Direct - same direction just doubled in size
Inverted
Features of deletions and duplications
Phenotype - abnormal gene dosage
Variable clinical expression due to variable size of imbalance and its multifactorial nature.
Ring chromosome
Breakage then circularisation of the chromosome.
