Week 1 - Genetics Flashcards
Transcription occurs in the nucleus. What enzyme is responsible for making messenger RNA during this process?
RNA polymerase
Translation occurs on a ribosome in the cytoplasm. What is the name of the first amino acid in the newly formed polypeptide chain?
Methionine
What capabilities must be acquired for a cell to develop into a cancer?
- Proliferative signalling
- Avoidance of apoptosis
- Bypassing replicative senescence
- Insensitivity to anti-growth signalling
What are three functions of tumour suppressor genes?
- inhibit progression through cell cycle
- promote apoptosis
- repair DNA damage
How many faulty copies of a tumour suppressor gene do you need to cause cancer?
2 (i.e. on both chromosomes)
The mutation of which kind of gene leads to a loss of function mutation?
Tumour suppressor gene
What effect do proto-oncogenes have on the cell cycle?
They stimulate it.
How many faulty copies of a proto-oncogene do you need to cause cancer?
1
The mutation of what kind of gene produces a gain of function mutation?
Proto-oncogene
Stability (aka caretaker) genes are a type of tumour suppressor gene. What do they do?
Repair damaged DNA.
In what three ways are familial cancers different to sporadic cancers?
Familial cancers are less common and earlier onset than sporadic cancers and often involve multiple primary tumours as opposed to one.
What pattern of inheritance is involved in most of the more common cancer predisposition syndromes?
Autosomal dominant inheritance
What is the ‘two hits’ hypothesis?
Cancer is the result of accumulated mutations to a cell’s DNA.
In familial cancer, what is there to look out for in a persons family history?
More than one individual in the same family affected by the same cancer or cancers at related sites with early age of onset.
What genes are associated with a high risk of developing breast cancer?
BRCA1 BRCA2 TP53 PALB2 PTEN
Which gene is associated with breast cancer in men?
BRCA2
What is the function of BRCA1 and BRCA2 genes?
DNA repair by homologous recombination of double stranded breaks.
What measures may be taken to prevent breast cancer?
Examinations
Screening by mammography or MRI
Carriers of BRCA1/2 may be offered prophylactic bilateral mastectomy or oophorectomy
What mutations commonly cause ovarian cancer?
BRCA1
BRCA2
HNPCC gene: MLH1 or MSH2
What mutations can cause ovarian cancer in more rare cases?
RAD51c, PTEN, STK11, PTCH
How can ovarian cancer be prevented in people with a BRCA1/BRCA2 mutation?
Prophylactic oophorectomy
PARP (poly ADP ribose polymerase) inhibition
Hereditary non-polyposis colon cancer (HNPCC) is the most common form of familial colon cancer. Apart from the colon, what other organs can it cause tumours in?
Uterus, stomach, ovary
A mutation to genes in what system causes hereditary non-polyposis colon cancer (HNPCC)? How many polyps would this condition be associated with?
Genes of the DNA mismatch repair system (MMR system)
Less than 10
What genes are responsible for causing hereditary non-polyposis colon cancer (HNPCC)?
MLH1, MSH2, MSH6, PMS2
Familial adenomatous polyposis (FAP) is caused by a mutation in what gene? How many polyps would be associated with FAP?
APC gene
> 100
What is the inheritance pattern for MYH polyposis?
Autosomal recessive
Mutation of what gene causes Li Fraumeni syndrome? Name 5 cancers associated with this condition.
TP53
Breast cancer, brain tumours, sarcoma, leukaemia, adrenocortical carcinoma.
What are three features of autosomal dominant inheritance?
- vertical pattern of inheritance
- generally equal frequency and severity in males and females
- variable expressivity
Many autosomal dominant conditions show incomplete penetrance. Describe incomplete penetrance.
When some individuals with the gene mutation don’t develop the disease.
A mutated FGFR3 gene causes what autosomal dominant condition?
Achondroplasia
What are two features of autosomal recessive inheritance?
Horizontal rather than vertical transmission
males and females affected equally
If both parents are unaffected carriers of an autosomal recessive condition, what is the likelihood that there child will:
a) be an unaffected carrier - heterozygous
b) affected - homozygous
c) unaffected and not a carrier - normal
a) 50%
b) 25%
c) 25%
Give two examples of autosomal recessive conditions.
Cystic fibrosis
phenylketonuria
Which type of inheritance is associated with consanguinity (2 relatives having children)?
Autosomal recessive
Is disease expressed in heterozygotes in:
a) autosomal dominant conditions
b) autosomal recessive
a) yes disease is expressed
b) no disease is not expressed
Name 3 features of X-linked recessive inheritance.
Knight’s move pattern, no male to male transmission, usually only males affected
If you have a female heterozygote for an X-linked condition, what is the likelihood that her son will be affected? What is the likelihood that her daughter will be a carrier?
50%
50%
If you have a male heterozygote for an X-linked condition, what is the likelihood that his son will be affected? What is the likelihood that his daughter will be a carrier?
roughly 0%
roughly 100%
Name 3 features of X-linked dominant inheritance.
Vertical pattern of inheritance, males and females affected, no male to male transmission.
Describe genetic anticipation. Name 2 conditions that it is seen in.
When a condition becomes more severe and has an earlier age of onset as it goes down the successive generations. Huntington’s disease, myotonic dystrophy.
Name a condition that has X-linked dominant inheritance.
Vitamin D resistant rickets.
What is gonadal mocaicism?
When a mutation occurs in a precursor sperm or egg cell and is passed on to all derivatives of that cell. (this means the parent may not be affected by the disease because none of their somatic cells have the mutation but the child has the disease because all their somatic cells derive from the mutated gamete).
Mutations in mitochondrial DNA lead to conditions affecting certain organs/tissues. Name 3.
brain, eyes, muscle
Is mitochondrial DNA inherited from the mother or the father?
Mother
What is the risk of a child of a father with a mitochondrial disorder inheriting the condition?
Around 0% because it is all inherited from the mother.
What is the typical age of onset of Huntington’s disease? Describe some of the clinical features.
Age 30-50 Progressive chorea (involuntary movements), dementia, psychiatric symptoms (i.e. depression).
A mutation in what gene causes Huntington’s disease? What chromosome is this on?
Huntingtin
Chromosome 4
Huntington’s disease is caused by a trinucleotide repeat mutation. This mutation is caused by repeats of what 3 bases? This repeat unit codes for what amino acid?
CAG
Glutamine
Huntington’s disease is caused by an unstable length mutation caused by repeating units of CAG. How many repeats of will an individual have if they:
a) are unaffected
b) show incomplete penetrance (may or may not be affected)
c) have the disease
a) 35 or less
b) 36-39
c) 40 or more
X is an autosomal dominant condition with genetic anticipation. The symptoms are progressive muscle weakness in early adulthood with bilateral ptosis, drooping face and cataracts. What is X?
Myotonic dystrophy
Myotonic dystrophy is a trinucleotide repeat disorder. The repeat of which three bases causes the disease? What gene does the mutation occur on? How many repeats are necessary to cause the disease?
CTG
DMPK
50 or more repeats
What autosomal recessive condition causes recurrent lung infections and exocrine pancreatic insufficiency (85-95% of cases)?
Cystic fibrosis
How is cystic fibrosis diagnosed?
Screening of newborns by immunoreactive trypsin, confirmation by DNA testing or sweat testing for increased chloride.
A mutation in what gene is responsible for cystic fibrosis? What is the name of the most common mutation? What type of ion channel does this mutation make defective?
CFTR gene
F508del - deletion of phenylalanine at position 508.
Chloride ion channel.
What are the common clinical features of Neurofibromatosis type 1?
Cafe au lait macules and neurofibromas, short stature, macrocephaly, mild learning difficulties, lisch nodules (brown spots on iris)
What conditions does Neurofibromatosis type 1 increase your risk of? Name 4 things.
Significant tumours
Tibial fractures
Scoliosis
Hypertension
What is the name of the gene that when mutated causes Duchenne Muscular Dystrophy? What is the location of this gene?
DMD gene
Xp21 (short arm of X chromosome at position 21).
People with DMD will have raised levels of what protein in their blood from birth?
Creatine Kinase.
In Becker muscular dystrophy, mutations are normally ‘in frame deletion’. Explain how this leads to a milder form of disease as opposed to DMD which is normally an ‘out of frame’ deletion.
In frame deletion does not disrupt the translation after the mutation. Out of frame deletion means that the entire translation after the mutation is disrupted, meaning that all amino acids downstream of the mutation are affected, causing more severe disease.
I am an X linked recessive with genetic anticipation due to repeats in the 5’ UTR region of FMR1 gene. What condition am I?
Fragile X syndrome
In fragile X syndrome how many repeats are required for full disease? Is the phenotype more severe in males or females?
> 200
Males
What is the chromosome abnormality in Down’s Syndrome? What causes this abnormality?
Trisomy 21 caused by non-disjunction
What is the chromosome abnormality in Edward’s syndrome? What are some of the clinical features? What is the normal life expectancy for an individual with this syndrome?
Trisomy 18 caused by non-disjunction.
Small chin, clenched hands with overlapping fingers. Malformations of heart, kidney and other organs.
Less than 1 year
What is the chromosome abnormality in Patau syndrome? What are some of the clinical features of this condition?
Trisomy 13 caused by non disjunction.
Cleft lip and palate, microphtalmia, abnormal ears, clenched fists, post-axial polydactyly (extra little finger).
What 2 methods can be used to analyse whole chromosomes?
Karyotyping
QF-PCR (for specific aneuploidys)
What methods can be used to detect sub-microscopic deletions/duplications if the position of the mutation is known?
FISH
MLPA
What methods can be used to detect sub-microscopic deletions/duplications if the position of the mutation is unknown?
aCGH
What methods can be used to detect point mutations?
DNA sequencing or ARMS
How does ivacaftor work in the treatment of cystic fibrosis? What gene mutation does it target?
Reopens the chloride ion channel that the mutation causes to be blocked.
G551D
What is PGD? What methods can be used for analysis?
Pre-Implantation Diagnosis is the genetic profiling of embryos before implantation.
FISH, PCR, QF-PCR,
Discuss some of the pros and cons of PGD.
Pros Permits implantation of unaffected embryos Prevents TOP Cons Not available for every woman Long wait Take home baby rate only 50% per cycle.
What are some of the main criteria for a screening programme?
- Important health problem
- Well understood natural history
- Benefit to early detection
- Risk marker or detectable early stage
- test is acceptable to society
- Test is low risk
- Test has high sensitivity and specificity
- Benefit outweighs cost
- Cost effective
- Agreed pathway after results
- Adequate staff and facilities for programme.
Define sensitivity. How is it calculated?
The proportion of actual positive results that are accurately identified as such.
sensitivity = TP/(TP+FN)
Define specificity. How is it calculated?
The proportion of true negatives that are correctly identified as such.
Specificity = TN/(TN+FP)
Down syndrome is a condition that can be screened for prenatally. How is it screened for? What diagnostic tests could be performed after a positive screening test?
CUB (combined ultrasound and biochemistry) - maternal blood biochemical markers (raised βhCG or lowered PAPP-A) and nuchal translucency test on ultrasound.
Amniocentesis or chorionic villus sampling.
How is blood collected from neonates for screening? Name 5 conditions screened for in neonates.
Heel prick test.
PKU, MCADD, cystic fibrosis, sickle cell disorder, congenital hypothyroidism.
Name two genetic conditions screened for postnatally.
Tay Sachs disease for jewish people.
Thalassaemia.
How does non-invasive prenatal diagnosis (NIPD) work? What is it used to detect?
Fetal DNA is taken from maternal serum and tested.
For male pregnancies (in X linked recessive conditions) or the fathers mutation.
Explain what precision medicine is. What are 2 benefits?
When treatment is targeted to a specific disease causing mutation.
Increases efficacy, reduces side effects.
What targeted therapy can patients with non-small cell lung cancer caused by an EGFR mutation receive?
EGFR inhibitors i.e. gefitinib
What targeted therapy can be used to treat people with HER2 breast cancer?
Trastuzumab (herceptin)
What potential future gene therapy could be used to treat DMD? How does it work?
Antisense oligonucleotide therapy
Skipping of exons 45 and 53 of DMD gene. Should convert phenotype from DMD to BMD.
