Genetics in Medicine 2 Flashcards
What are the 3 types of mendelian inheritance?
1) Dominant
2) Recessive
3) X linked
What does ‘complex’ mean in a genetic disease sense?
Describes something with an inherited but not mendelian component
What does the term ‘polygenic’ mean?
the result of the action of multiple genes
What does the term multifactorial mean?
the result of multiple factors often involving genetic and environmental factors
What does lamba s refer to?
Statistic that refers to your risk of developing a condition if you have an affected sibling relative to the general population
What is familial clustering?
Refers to a condition that tends to run in families where sufferers get reoccurring headaches only on one side of the head and they can last for week
Is schizophrenia an inherited condition?
It does have an inherited component but its not mendelian, its multifactorial
What does the increased risk of developing schizophrenia if you have an affected fraternal twin compared to if you have an affected sibling suggest?
That there is an environmental component as like siblings, fraternal twins have different genotypes but share a significant environmental factor that siblings dont - a uterus
What are fraternal twins?
Non identical twins - ie. Di-zygotic twins
What does this increased risk of having schizophrenia if you have an affected identical twin compared to having an affected fraternal twin suggest?
That there is a significant genetic factor because although fraternal and identical twins share a similar environment ie a uterus etc. the difference is identical twins have the same genotype
What can a high lamba s show about a condition?
That it has a genetic component
Should a genetic disease have a higher concordance in mono zygotic or dizygotic twins?
Mono zygotic
Do cancer, hypertension, manic depression and acute infection and death have a higher concordance in MZ or DZ twins?
Cancer, hypertension, manic depression all have higher concordance in MZ twins suggesting a genetic component
Acute infection and death dont have a higher concordance in MZ twins suggesting no genetic component
What are the 2 main problems with twin studies?
1) Assumption that the degree of environmental sharing is the same for all MZ twins - can be large differences in birth weight in MZ demonstrating a different pre natal environment, variation in the time of splitting of the early embryo, diamniotic MZ twins survive better than monchorionic
2) DZ can share more than half their genes
Why are adoption studies performed, what kinds of conditions are they usually carried out for and why are they no longer carried out as often?
Child is put in different environment because of adoption
Can compare the fates of its adoptive versus biological family
Share genes but not environments with its biological parents
Share environments but not genes with its adoptive parents
Most often performed for psychiatric conditions
Adoptions are becoming rarer and there are ethical issues about contacting the biological family
Are genes dominant or recessive in multifactorial conditions?
Neither they are additive
How do traits with multifactorial inheritance tend to be distributed in the population?
Normally distributed - Gaussian, bell shaped curve
Do conditions with polygenic/multifactorial/complex inheritance tend to run in families, if so in what pattern?
Yes but not in a simple mendelian fashion
Name 6 congenital malformations with multifactorial inheritance?
1) Cleft lip/palate
2) Congenital hip dislocation
3) Congenital heart defects
4) NTDs
5) Pyloric stenosis
6) Talipes
Name 16 acquired diseases of childhood and adult life with multifactorial inheritance?
1) Cancer
2) Autism
3) Bipolar disorder
4) Chrohn’s disease
5) Diabetes
6) Parkinsons disease
7) Asthma
8) Epilepsy
9) Glaucoma
10) IHD
11) Stroke
12) Psoriasis
13) Hypertension
14) Schizophrenia
15) Multiple Sclerosis
16) Rheumatoid Arthritis
Although NTDs are a congenital defect showing multifactorial inheritance, what environmental factor can significantly reduce the risk?
Maternal folic acid supplementation
50-70% of NTDs can be prevented
Roughly how does a genome wide association study (GWAS) work?
Have a control and a case sample
Controls are as similar ‘environmentally’ as possible to cases, same sex ethnicity, socioeconomic back ground etc.
Look for common variants (SNPs) that are present much more significantly in the cases than the controls - if significantly more frequent in the cases then you have found an allele with an association
What kind of analysis is used to identify genes implicated in mendelian diseases?
Linkage analysis
Look for the pattern of inheritance in a family, look for an allele or patch of chromosome that exactly follows that inheritance pattern
Are genes with high magnitude of effect and low frequency in the population more likely to be implicated in mendelian or multifactorial disease and how are they likely to be identified?
Likely to be mendelian
Identified by linkage analysis
Are genes with a low magnitude of effect and high frequency in the population likely to be implicated in mendelian or multifactorial disease and how are the likely to be identified?
Multifactorial
Association studies
Why are genes with low magnitude of effect and low frequency in the population not analysed?
They have little clinical significance
What are SNPs?
Single nucleotide polymorphisms
Alleles with one base changed, present in more than 1% of the population
What is the difference between a mutation and a polymorphism?
Polymorphism is a mutation that is present in more than 1% of the population
What does linkage disequilibrium refer to and how does this affect association studies?
Refers to the fact that there will be some SNPs that have a high association with a disease causing SNP but arent actually disease causing themselves
This is because most disease causing mutations are descended from one or few ancestral chromosomes and over generations as that mutated allele is inherited, the alleles around it are inherited too
Means in association studies some of the SNPs with associations shown will not be disease causing themselves but are strongly associated with the disease causing allele
Why is it important when taking a family history for familial cancer to confirm the types of cancers with medical records, cancer registries or death certificates?
You need the correct anatomical region and histological diagnosis
You do not inherit a generalised risk, its tissue and histology specific
Why should you include age at diagnosis in a family history for risk of cancer?
Because familial cancers tend to have an earlier onset
How many generations should be asked about in a family history for cancer risk?
At least 3
Do you have tend to have multiple primary in familial or sporadic cancer?
Multiple primaries in familial cancer
Tends to be one in sporadic cancer
Name 2 cancers that are rarely genetic?
1) Lung
2) Cervical
When is diagnostic testing performed in the case of familial cancer and when is predictive testing performed?
Diagnostic testing - performed on DNA affected with cancer to try to identify the familial mutation
Predictive testing - if a mutation is identified in the family, predictive testing for the specific mutation may then be offered to the other relatives to determine whether or not they are at risk
What is retinoblastoma and what gene is it caused by, with what kind of inheritance?
Childhood occular cancer
Very rare
Caused by retinoblastoma (Rb1) gene, classic example following Knudson 2 hit hypothesis
Is inherited retinoblastoma (with one mutated gene in the germline) usually unilateral or bilateral?
Bilateral
but 15% of unilateral cases are germline
What other cancer are children with inherited retinoblastoma at risk of?
Osteosarcoma
What is Familial adenomatous polyposis and which cancer does it increase the risk of?
Hundreds of bowel polyps (adenomas) from teens onwards - blanket of polyps that are impossible to remove them all High risk (up to 100%) of bowel cancer if left untreated (one of polyps suddenly becomes malignant)
What is the treatment for familial adenomatous polyposis (FAP)?
Colonoscopies to monitor
Total colectomy in late teens/early 20s
What are the 3 other features of familial adenomatous polyposis (FAP) other than polyps?
1) CHRPE
2) Desmoid tumours
3) Osteomas
Which gene is implicated in familial adenomatous polyposis and what i the mode of inheritance?
APC tumour suppressor gene
Autosomal dominant inheritance
What is hereditary non polyposis colorectal cancer (HNPCC)?
Polyps are common but not polyposis (blanket of polyps)
60-80% risk of bowel adenomas or cancer from mid 20s onwards
What 4 other types of cancer have increased risk with hereditary non polyposis colorectal cancer (HNPCC)?
1) Endometrial
2) Ovarian
3) Stomach
4) Gynaecological
Hereditary non polyposis colorectal cancer is caused by 4 genes, what type of genes are they and what is there mode of inheritance?
1) MLH1
2) MSH2
3) MSH6
4) PMS1/2
Mismatch repair enzymes
Autosomal dominant inheritance
Whats the name of the criteria that must be met to confirm HNPCC? And what are they?
amsterdam criteria
1) One family member diagnosed with colorectal cancer under 50 years
2) Two affected generations
3) Three affected relatives, 1 a first degree of the other 2
4) FAP should be excluded
5) Tumours should be verified through pathological examination
What is the therapy for HNPCC? 3
1) Regular colonoscopies where polyps can be removed and can detect cancer early has been shown to improve survival
2) Regular aspirin
3) Prophylactic colectomy not recommended but women may consider hysterectomy
What is the role of BRCA1 and BRCA2 gene in terms of DNA:?
Involved in DNA repair
What is the risk of breast cancer with either the BRCA1 or BRCA 2 gene?
80%
What is the risk of developing ovarian cancer with the BRCA1 or BRCA 2 gene?
BRCA 1 - 40%
BRCA 2 - 10-20%
Other than female breast cancer and ovarian cancer what 3 other cancers do the BRCA genes increase the risk of?
1) Prostate
2) Melanoma
3) Male breast cancer
What are the 5 options for BRCA 1 and BRCA 2 carriers?
1) Breast screening - annual MRI/ mammography
2) Risk reducing mastectomies
3) Risk reducing BSO (reduce ovarian cancer risk)
4) Lifestyle changes
5) Pharmacological prevention studies
What is Li Fraumeni syndrome?
Condition with a 50% risk of cancer by age 40 and 100% in lifetime
Why should people with Li Fraumeni syndrome avoid radiotherapy?
Risk of inducing cancers
Name 5 cancers common in Li Fraumeni syndrome?
1) Breast
2) Sarcoma
3) Brain
4) Adrenocortical
5) Leukaemia
Li Fraumeni syndrome is caused by what mutations which are inherited in what pattern?
Autosomal dominant
P53 mutations
What is cytogenetics?
Study of chromosomes, anything more than just a single gene
How many chromosomes in the nucleus?
46 (23 pairs)
How many autosomes and how many sex chromosomes?
Autosomes - 1-22
Sex chromosomes - X,Y
What percentage of miscarriages are due to chromosome abnormalities?
50%
What percentage of live births have some sort of chromosomal abnormality?
0.7%
What analysis is used in conventional cytogenetics?
Metaphase chromosome analysis - G-banding
What is molecular cytogenetics?
Cytogenetic analysis (chromosome analysis) at the molecular resolution, at all stages of the cell cycle - DNA of importance is extracted or left in situ
What are the 6 analysis techniques used in molecular cytogenetics?
1) FISH
2) Microarray CGH
3) Next generation sequencing (NGS)
4) MLPA
5) QF-PCR
6) qPCR
At what point are chromosomes most visible in the cells?
Metaphase of mitosis
What is a telomere?
The caps on the ends of the p and q arms
What are the 2 types of cytogenetic abnormality?
1) Numerical
2) Structural
What are the 4 ways in which cytogenetic abnormalities produce an abnormal phenotype?
1) Dosage effect
2) Disruption of a gene
3) Effect due to parental origin - genomic inprinting
4) Position effect - A gene in a new chromosomal environment functions inappropriately
5) Unmasking of a recessive disorder
Does a sex chromosome or an autosome imbalance produce a more severe phenotype?
A sex chromosome inbalance produces a more severe phenotype
Many cytogenetic abnormalities are lethal in utero, what 3 things are common to survivable imbalances?
1) Organ malformation
2) Facial dysmorphism
3) Compromised mental/intellectual function
What is meant by diploidy?
2 of each chromosome - a normal karyotype
What are the 3 types of numerical chromosome abnormality?
1) Aneuploidy - gain (trisomy) or loss (monosomy) of one chromosome
2) Polyploidy - gain whole sets (triploidy or tertaploidy)
3) Mosaicism - diploidy and aneuploidy
What is meant by aneuploidy?
Gain or loss of one chromsome - trisomy or monosomy
What is meant by polyploidy?
Gain whole sets of chromsomes - triploidy - 3 sets or tetraploidy - 4 sets
What is meant by mosaicism in numerical cytogenetic abnormalities?
Have 2 cells lines - one with diploidy (normal cell make up) and one with aneuploidy
What are the 3 origins of numerical cytogenetic abnormalities?
1) Gametogenesis - meiosis
2) Fertilisation
3) Early cleavage - post zygotic non dysjunction
What factor increases the chance of a cytogenetic abnormalities that originate from gametogenesis and why?
Maternal age, with increasing maternal age there is greater chance of aneuploidy
In the female foetus - all the eggs that that woman will produce are held in meiosis 1 from 5 months and suspended there until puberty - meiosis 2 occurs as each is ovulated
You then have an age dependent, deterioration of meiotic structures due to environmental factors such as hormonal inbalance, irradiation, oral contraceptives, alcohol etc.
You can also get unfavourable chiasmata distribution in the foetus
What is the product from the end of meiosis 1 and how many chromosomes does it contain?
Secondary gametocyte - 46 - 23 pairs
What is the difference between metaphase 1 in meiosis and metaphase in mitosis?
In metaphase 1 the homologous chromosomes (each made up of 2 chromatids) line up next to eachother so crossing over can occur and whole chromsomes are pulled to each side rather than the 2 chromatids getting separated
In metaphase of mitosis the lining up is random, not neatly next to eachother and rather than whole chromosomes being pulled to each side, the chromatids are pulled apart
What is the product at the end of meiosis 2 and how many chromosomes does it contain?
Mature gametocytes
Contain 23 chromosomes
What is non dysjunction?
Failure of chromsome or chromatid seperation during meiosis 1 or 2
In which meiosis does most non dysjunction occur?
Meiosis 1
Chromosome non dysjunction in meiosis 1 results in what being formed?
2 Disomic gametes (have 2 copies of the chromosome)
and 2 nullisomic gametes (have no copies of the chromosome)
Chromatid non dysjunction in meiosis 2 results in what being formed?
1 disomic gamete (2 copies of the chromosome)
1 Nullisomic gamete (no copies of the chromosome)
2 normal gametes (each with one copy of the chromosome)
What are the 3 autosomal antibodies and why just these 3?
Trisomy 21 - downs
Trisomy 18 - Edwards syndrome
Trisomy 13 - Patau syndrome
These 3 chromosomes are relatively small chromosomes with few genes, we can tolerate gains of this amount of genetic info but other chromosomes are just too large
How many pregnancies are affected by down syndrome and how many spontaneously abort?
1/700 pregnancies affected
75% spontaneously abort
What 8 features of the head are common in down syndrome?
1) Eyes - upwards slanting, brushfield spots
2) Nose - small
3) Ears - abnormally shaped/low set
4) Tongue - protruding
General - flat face and short neck
What are the 4 features of the hands and feet common in down syndrome?
Single palmar crease
Short broad hands
5th finger clinodactyly (small 5th finger)
Wide sandal gap
How is fertility affected in down syndrome?
Males are usually infertile
In females fertility is usually unaffected
What is the average life expectancy of a person with down syndrome?
55-68 years
What medical problems are you at increased risk of in downs syndrome?
Leukaemia in children
Alzheimers
Hypothyroid
Obesity/coeliac, arthritis, diabetes, hearing loss, seizures
How many live births are affected by edwards syndrome and what percentage spontaneously abort?
1 in 6000 live births
95% spontaneously abort
What is the life expectancy of a baby born with edwards syndrome, what is the likely case if they live longer?
Most die before reaching 1 year
Those that survive are likely to have mosaicism
How is the head affected in edwards syndrome? 4
Microcephaly
Low set ears
micrognathia
cleft lip and palate
What is meant by the term micrognathia?
Small jaw
How are the hands and feet affected in edwards syndrome? 3
Clenched hands
Overlapping fingers
Rockerbottom feet
Other than clinical features of the head and hands and feet in edwards syndrome what are the 3 other clinical features?
1) Low birth weight
2) Short sternum
3) Severe mental retardation
What are the 4 organ malformations in trisomy 18?
1) Umbilical or inguinal hernia
2) Congenital heart disease (90%)
3) Congenital kidney abnormalities
4) Eye abnormalities eg. cataracts micropthalmia
Trisomy 13 affects how many live births and what percentage spontaneously abort?
1/12000 live births
95% spontaneously abort
What are the 3 main clinical effects in trisomy 13?
1) severe mental retardation
2) microcephaly/ sloping forehead
3) Defects of the brain - holoprosencephaly
What are the 6 features of the trisomy 13 phenotype?
1) Eyes - Micropthalmia, coloboma, retinal dyplasia, palpebral fissures slanted
2) Cleft lip and or palate
3) Ears abnormal and low
4) Polydactyly and fingers flexed
5) Heart defect
6) Abnormal genitalia
What are the 2 sex chromosome aneuploidy syndromes and how many people do they affect?
Turner syndrome 45 X- 1/2500
Klinefelter syndrome 47 XXY - 1/1000
Is there a syndrome associated with the karyotypes 47 XYY or 47 XXX?
No, they are sometimes referred to as super males or super females
What are the 3 reproductive, 2 lymphatic and 3 other features of turner’s syndrome?
Reproductive 1) loss of ovarian function 2) no puberty 3) infertility Lymphatic 1) Webbed neck 2) Swelling of hands and or feet Other 1) Skeletal abnormalities - short stature 2) Coarctation of the aorta 3) IQ can be normal or reduced compared to siblings
How is klinefelter syndrome normally diagnosed?
Identified through infertility and/or hypogonadism
What percentage of sufferers of klinefelter syndrome are mosaic or variant?
20%
Is IQ affected in Klinefelter syndrome?
No
How is fertility and sexual characteristics affected in klinefelter syndrome?
Have infertility
May lack secondary sexual characteristics
Testicular dysgenesis (doesnt develop normally)
30-50% Gynacomastia (development of breast tissue) with 20x risk of breast cancer
How is growth affected in Klinefelter syndrome?
Normal in infants then accelerates in adults
Adults end up with long legs and arms
Errors at fertilisation can result in what 2 types of numerical cytogenetic abnormality?
1) Polyploidy - usually triploidy
2) Molar pregnancy (double paternal no maternal)
Triploidy affects how many pregnancies, what percentage spontaneously abort and how many live births are affected?
2% of all pregnancies
99.9% spontaneously abort
1/57000 live births
There are 3 origins of triploidy, digyny, diplospermy and dispermy, what does each mean?
DIGYNY - a haploid sperm fertilises a diploid egg
DIPLOSPERMY - a diploid sperm fertilises a haploid egg
DISPERMY - 2 haploid sperms fertilise a haploid egg
What is the major difference in a double maternal and double maternal pregnancy?
Double maternal - very small placenta, signicant growth delay foetus has a large head compared to body as all nutrients that can be obtained from the small placenta are directed to the head (head saving macrocephaly)
Double paternal - Over developed cystic placenta, some growth delay - there is an increased risk of developing carcinoma of the placenta in future pregancies after this
What conclusion can be drawn from the differences in double paternal and double maternal pregnancies?
Maternal genome for foetus
Paternal genome for placenta
What is a molar pregnancy?
Haploid sperm fertilises an empty egg you then have a haploid zygote and in most cases doubling up occurs so you end up with a diploid zygote with double paternal genome
This is called conceptus without an embryo
Massive cystic placenta develops - appears as a normal pregnancy and if not detected before by heavy bleeding may only become apparent at US
Errors at cleavage result in what?
Mosaicism
If an error of non dysjunction occurs in early cleavage what cells do you end up with?
1 Monosomy - this cell normally doesnt survive
1 Trisomy
2 disomy (normal cells)
End up with 2 cell lines developing, a trisomy and disomy
What is trisomic zygotic rescue?
Occurs after an error in early cleavage in the trisomic cell line. When the cells divide one of the chromosomes is chucked out so you end up with a disomic cell line again
What are the 5 outcomes of mosaicism?
1) variable phenotype
2) Non identical twin
3) Tissue specificity - lateral asymmetry
4) May generate uniparental disomy (UPD)
5) Recurrence risk if in gonadal tissue
Gain or loss of a single chromosome occurs at what stage in development?
Meiosis - gametogenesis
Gain or loss of a whole set of chromosomes can occur when?
Fertilisation
Early cleavage - mosaicism
What are the 3 kinds of balanced chromosome rearrangements?
1) Translocation
2) Inversion
3) Insertion
What is a reciprocal translocation?
Where 2 chromosomes break and then the broken off portions swap with eachother eg. a bit of 7 gets attached to 9 and a bit of 9 gets attached to 7
How common is reciprocal translocation, what is the phenotypic risk and what is the reproductive risk?
There is a reproductive risk
5-10% phenotypic risk
1/500
What are the 2 types of translocation?
1) Reciprocal
2) Robertsonian
What is a robertsonian translocation?
Only occurs in accrocentric chromosomes (13,14,15,21,22) as they have a short p arm containing no coding genetic info, 2 of these chromosomes break at the centromere, the short p arm is lost and the long q arms join together
Is there a phenotypic or reproductive risk with a robertsonian translocation and how common is it?
1/1000
No phenotypic risk, reproductive risk
What are the 2 types of inversions?
Pericentric and paracentric
What is a pericentric and a paracentric inversion?
In both the chromsome breaks at 2 points the broken portion turns 180 degrees and re inserts into the chromosome
Pericentric - 1 break either side of the centromere
Paracentric - both breaks on the same side
How common is an inversion and is there a phenotypic or reproductive risk?
1/1000
5-10% phenotypic risk
Reproductive risk exists
What are the 2 most common types of unbalanced chromosome rearrangements?
Duplications and deletions
What is meant by the copy number variation (CNV)?
Overall net cytogenetic loss or gain - from Kbs to Mbs, resulting from imbalanced cytogenetic rearragnements
Unbalanced rearrangements occur in how many people?
1/2000
What are the 2 types of deletions?
1) |nterstitial deletions - chromosome breaks at 2 points and a segment is lost
2) Terminal deletion - chromosome breaks at one point and that whole segment is lost
What happen in a duplication and what is the difference between a direct and inverted duplication?
Chromosome breaks at 2 points and the material in that location is replicated
In a direct duplication get the same segment again in same order ie. ABAB
In an inverted duplication you get the same segment again but in the opposite order
ie. ABBA
What is the phenotypic risk with deletions and duplications and which is more deleterious?
Get a phenotype as get an abnormal gene dosage
Variable clinical expression depending on the genes affected and the change to gene dosage
Loss of genetic info tends to be more deleterious than excess
At what points on a chromosome do deletions and duplications tend to occur?
At blocks of repeating sequences - can end up with wrong pairing when chromosomes line up at meiosis and non equivalent portions etc. can be exhcnaged
What is ring chromosome?
Where the 2 ends of a chromosome break off and then the ends that are left join together to form a circle
Breakage then circularisation
Are you more likely to have a phenotype with a balanced or unbalanced rearrangement?
Unbalanced - always have a phenotype with this
