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225 Cards in this Set

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Amplicon
The amplified product of a PCR reaction
cDNA
Complementary or copy DNA synthesised from a mRNA template using reverse transcriptase.
Cytogenetics
The study of the relationships between the structure and number of chromosomes and variation in genotype and phenotype.
Endonuclease
An enzyme that cleaves a nucleic acid at internal sites.
Exons
Protein coding sequences of the gene.
Exonuclease
An enzyme that cleaves a nucleic acid sequentially from a free end.
Haplotype
A particular combination of alleles or sequence variations that are closely linked (ie. are likely to be inherited together) on the same chromosome
Proteome
The complete set of proteins encoded by the genome
Pseudogene
A region of DNA that shows extensive similarity to a known gene, but which cannot itself function
Sensitivity of a clinical test
The proportion of individuals with a disease phenotype who test positive.
Southern blotting
A technique to transfer electrophoretically separated fragments of DNA, after denaturation, from the gel to an absorbent sheet of material (such as nitrocellulose) to which the DNA binds. The sheet is immersed in a solution containing a labelled probe that will hybridize to fragment(s) of interest. The method was first devised by E. M. Southern to transfer DNA fragments from an agarose gel to a nitrocellulose paper for hybridization, but similar transfer methods are now also used for transferring RNA or protein to papers of a variety of types followed by hybridization (RNA) or labelled antibody treatment (protein) to identify specific molecules.
Specificity of a clinical test
The proportion of individuals without a disease phenotype who test negative.
Tandem repeats
Multiple copies of the same sequence on a chromosome, often found in microsatellite markers
Transcriptome
The complete set of RNAs transcribed from the genome
Achondroplasia
small stature, single gene mutation
CADASIL
a single gene defect, predisposition to stroke: cerebral autosomal dominant arteriopathy
OLA:
genetic test for single gene mutation
MLPA
genetic test for gene duplication or deletion
Pharmacogenomics:
Analysing entire genomes, across groups of individuals, to identify the genetic factors influencing responses to a drug
Pharmacogenetics:
Studying an individual's genetic make up in order to predict responses to a drug and guide prescribing
Gleevec:
treatment for Chronic myeloid leukemia.
Cause of CML:
translocation between chr9 and chr22. Gleevec blocks action of overproduced signaling protein so WBCs are not overproduced. This is somatic treatment, not germline.
3 single gene autosomal dominant disorders:,

Marfans, Huntingdons, Myotonic Dystrophy (is a triplet repeat disorder)
autosomal recessive disorders:
Cystic fibrosis, sickle cell
mitochondrial disorders:
diabetes, deafness
X-linked Dominant disorders:
Rett’s and Fragile X. Fragile X is a triplet repeat disorder. Retts is a lethal brain disorder, only female phenotypes as lethal for males.
X-linked recessive disorders:
duchenne muscular dystrophy, colour blindness, haemophilia, haemochromatosis (iron buildup)
Penetrance:
The frequency with which a specific genotype is expressed by those individuals that possess it, usually given as a percentage.eg Huntington disease by 80 years 100% penetrance
Expressivity
variation in expression - the extent to which a heritable trait is manifested by an individual.
Marfan Syndrome:
aortic dilatation, lens dislocation, stretch marks
Anticipation:
the symptoms of a genetic disorder become apparent at an earlier age as it is passed from one generation to the next. In most cases there is an increase in the severity of symptoms too.
Myotonic dystrophy description:
progressive muscle wasting and weakness. prolonged muscle contractions (myotonia)
Compound heterozygous:
means that there are 2 different mutations there, both alleles of the gene are mutations, they are affected because both are mutations, but technically the genes are different.
X-linked (XL) inheritance (can be XLD or XLR):
Males affected, Females may be unaffected, mildly through to fully affected
X-inactivation, another name:
Lyonisation, the process of evening up X chr gene dosage
X-linked activation, describe:
The process of random inactivation of one of the X chromosomes in cells with more than one X chromosome. Compensates for the presence of the double X gene dose. ALL FUTURE CELL DESCENDANTS ARE AFFECTED. Most, but not all genes switched off on the inactivated X. Is normal and occurs when there is 2 or more X chromosomes in a cell. Occurs in early embryogenesis.
Skewed X-inactivation:
random preference for “normal” X chromosome to be inactivated – significant phenotype
Tissue variability in x-linked disorders:
random preference for the X chromosome with the mutation to be active in crucial tissue group – eg muscle in Duchenne Muscular dystrophy
Fragile X syndrome – females:
asymptomatic to fully symptomatic ( due to X-inactivation pattern) (this is an inherited condition characterized by an X chromosome that is abnormally susceptible to damage, especially by folic acid deficiency. Affected individuals tend to have limited intellectual functions)
Mitochondrial Inheritance, who is affected:
All the children of an affected man will be unaffected
Proband:
the person consulting the doctor, aka the consultand
carrier
put dot in middle
How can CF be tested for?
Demonstrating abnormally elevated concentration of chloride ion in sweat (the sweat test), Molecular genetic testing, Immunoreactive Trypsin (IRT)- used as a screening test for CF in the newborn screening programme. Raised levels indicate infant with CF.
What is the inheritance pattern of CF?
autosomal recessive
Mutations in which gene cause CF?
CFTR cystic fibrosis transmembrane conductance regulator 7q31
What is the ARMS test:
One example is ‘allele-specific PCR’ e.g. the ARMS test (amplification refractory mutation system). In the ARMS test, the allele-specific primers are designed so that their 3’ end nucleotides base-pair with the changed nucleotide that distinguishes the normal and mutant alleles. With the correct PCR conditions, amplification will not take place when the 3’ end nucleotide is not perfectly base-paired, thereby distinguishing the two alleles.
What symptoms does Huntington’s disease cause?
Depression, aggression, clumsiness, Progressive neurogenerative disorder, Tremors, nervous movements, 35-55 onset, movement, memory and cognition, psychiatric
What is a Triplet Repeat Disorder?
Trinucleotide repeats more and more. CAG repeats, if more than 40 repeats (11-36 is normal) protein aggregates in the brain cells (inclusion bodies). CAG codes for glutamine
Can you name any other triplet repeat disorders?
Fragile X (leads to mental retardation), Myotonic dystrophy, Spinocerebellar ataxias
Why does anticipation occur?
Slippage during meiosis – errors in replication, loops between daughter strands and increase in number of repeats in the gamete. Germine instability of the triplet repeat.
What causes EMARDD?
This condition is caused by mutations in the gene MEGF10.
What sort of problems does EMARDD cause?
A type of muscular dystrophy, congenital myopathy cleft palate, feeding diffs, resp probs, joint contractures, scoliosis
How is EMARDD inherited?
autosomal recessive
Symptoms of JOUBERT SYNDROME
This condition causes developmental delay, seizures and specific MRI changes.
What causes Joubert Syndrome and how do you test for it?
There are many genes known to cause Joubert Syndrome (autosomal recessive condition) and so WES (whole exome sequencing) has been performed to test all these genes at once.
What are oligonucleotides?
Small synthetic primers which define the boundaries of DNA synthesis
What charge is on DNA and why?
DNA IS NEGATIVELY CHARGED BECAUSE OF THE PHOSPHATE GROUPS
What is OLA?
Oligonucleotide ligation assay: uses PCR but the basis of the test is ligation. You can look for an allele specific mutation differing by only a single nucleotide. the assay/reaction will not take place when the 3’ end nucleotide is not perfectly base-paired, thereby distinguishing the two alleles
Most common cause of inherited deafness?
connexion 26 (GJB2) D35G
What is MLPA and what is it used for?
Multiplex Ligation-dependent Probe Amplification (MLPA) analysis. A multiplex PCR method for detecting chromosomal DNA copy number changes in multiple targets. MLPA is a laboratory technique used for detecting deletions or duplications of one or more parts of a gene.
Why is MLPA used?
Each individual has two copies of a gene, one inherited from the mother and one from the father. Some genetic conditions are associated with a change in just one of the copies and MLPA is a test designed to detect this situation.
How does MLPA work?
MLPA uses custom-designed probes, which are short DNA fragments made to bind specifically to each exon that is to be tested (target sequence). Each probe comes in two pieces which are able to be joined together (ligated) to form a complete probe. Once the complete probe has been made, this can be copied many times using PCR. The two parts of the probe can only join together in the presence of the complete and correct DNA target sequence. For example if part of the DNA sequence is missing in the patients DNA sample the two parts of the probe will not join together. The amount of complete probe, and hence the amount of the eventual PCR product, enables scientists to determine if there is any alteration in the DNA sample being tested.
What do the results from MLPA mean?
The amount of DNA which has been copied at the end of the reaction allows clinical scientist to determine if there was a deletion or duplication of that section of DNA in the patient sample. For example, if there is a deletion in both copies of the gene being tested (homozygous deletion), the probes will not have been able to join together and there will be no PCR product. If there is a deletion in one of these genes (heterozygous deletion) it will result in half the amount of final PCR product.
Which conditions are tested for by MLPA?
MLPA is used to detect certain clinically important changes in a gene which may cause a genetic condition such as alterations in genes associated with inherited forms of breast cancer (BRCA1 and BRCA2) and Duchene muscular dystrophy (DMD).
Why can’t some mutations be analysed using PCR?
gene might be too big for PCR, fragile X mutation in FMR1 gene is repetitive tract of (CGG)n sequence. GC-rich regions are difficult to PCR!
What could you use instead of PCR if it’s unsuitable for the condition?
can use Southern blotting: an old technique that is still important for diagnostic work
What is western blotting for?
Protein
What is northern blotting for?
RNA
Describe aCGH (assay CGH)
Comparative genomic hybridization (CGH) is a technique that allows the detection of losses and gains in DNA copy number across the entire genome without prior knowledge of specific chromosomal abnormalities. Comparative genomic hybridization utilizes the hybridization of differentially labeled tumor and reference DNA to generate a map of DNA copy number changes in tumor genomes. Comparative genomic hybridization is an ideal tool for analyzing chromosomal imbalances in archived tumor material and for examining possible correlations between these findings and tumor phenotypes.
DNA SEQUENCING – why would you do this?
This is when you don’t know what the change is so you need to check out the whole sequence
How is DNA sequencing done?
ddNTP has a H instead of an OH – so the chain can’t carry on. A small amount of each dideoxynucleotide is also incorporated into the reaction mix (ddTTP etc.). The ddNTP is incorporated into the growing DNA strand, BUT ddNTP lacks the 3’hydroxyl group that is needed to form a phosphodiester bond with the next nucleotide phosphate. Each strand will terminate randomly when a ddTTP is incorporated at the growing 3’ end of the strand. Then the reader can establish the sequence.
What is Ascertainment bias?
because you collect data on the best examples
What are Twin Studies for and what are the two types?
MZ and DZ twins: Heritability A key way to determine if a particular condition has a genetic basis, is to explore the similarities and differences among identical twins (monozygotic, ie from the same fertilized egg) and non-identical/fraternal twins (dizygotic, i.e. from two different fertilised eggs). A measure of genetic contribution that is calculated by comparing the proportion of monozygotic (MZ) twins that share a particular condition, with that of dizygotic (DZ) twins that share the condition.
What is an Association study?
Lots of people who have something, plus lots of similar control people who don’t, age, sex social, ethnically matched. Compare genome, look for a statistically significant difference. Assoc study looks for alleles which increase susceptibility. Assoc studies can be totally wrong though.
Linkage disequilibrium:
where other genes hitchhike along with others into future generations. Some alleles tend to be inherited together.
What is a manhattan plot and what is it used to display?
A scatter plot with many many data points, used in genome-wide association studies. It can be used to tally up which SNPs tally to people with the disease.
What is lambda S?
Lambda S is the risk to second sibling – a marker of how much extra familial risk there is.
How do you calculate lambda s?
Relative Risk Ratio (λ) =
Prevalence of disease in relatives of affected persons / Prevalence of disease in the general population
What causes Alzheimers Brain changes:
Beta amyloid plaques. APP normally cleaved in two places but in alzheimers there are little fragments which are insoluble. Microtubules fall apart because tau proteins aren’t present – cells don’t work as well – neurones not functioning
Is alzheimers familial?
Yes, shows familial clustering (relative risk to second sibling ls is 3 to 10)
What are the genes for alzheimers?
presenilin 1 (PSEN1) and presenilin 2 (PSEN2) both encode -proteases responsible for cleavage of amyloid beta A4 precursor protein (APP) and NOTCH receptor proteins: missense mutations in APP
Which is the worst type of mutation for getting alzheimers?
E4 haplotype confers increase in susceptibility. This is a gene for apoliprotein E. ApoE can help to dissolve the plaques which cause alzheimers.
What is the E2 haplotype?
This type of AP protein mutation confers a protective effect against alzheimers. This is a gene for apoliprotein E. ApoE can help to dissolve the plaques which cause alzheimers.
Describe AMD
Age-related Macular Degeneration multifactorial genetic trait Leading cause of irreversible central visual dysfunction caused by degeneration of the macula
What are the Medical problems associated with trisomy 21,

risk (mainly leukaemia) cancer, Alzheimer’s, Hypothyroid, Obesity/coeliac, arthritis, diabetes, hearing loss, seizures
What is the chromosome disorder associated with Edward’s syndrome?,

Trisomy 18
List 10 problems with trisomy 18:,

Head: microcephaly; low set ears; micrognathia; ears low set; cleft lip and palate, Hands & feet: Clenched hands, overlapping fingers; Rockerbottom feet, Short sternum, Severe mental retardation, Eye abnormalities eg. cataracts, micropthalmia
What is trisomy 13 known as?,

Patau syndrome
List some problems with patau syndrome
Holoprosencephaly – absent development of forebrain – can be cyclops, eye below nose, one eye only (mid face abnormalities) – usu detect on ultrasound, Mental retardation severe, Microcephaly/ sloping forehead, microphthalmia, coloboma (gap in eye structure), retinal dysplasia, palpebral fissures slanted (the gap between the eyelids, Cleft lip and/or palate, Abnormal genitalia
Advancing maternal age is associated with
an increased frequency of maternal meiotic errors resulting in nondisjunction
advancing paternal age is associated with
an increased frequency of de novo point mutations in single genes
How does RNA and DNA differ?
RNA differs only by the OH on C2 – which can launch a nucleophilic attack on phophodiester bond and splits the chain – RNA is more unstable than DNA. RNA easily falls to bits
What is the sense strand?
the “sense” strand is usually written (the one that ends up in the mRNA).
What is SATELLITE DNA:
big blocks at centromeres and in other regions. (called ‘heterochromatin’ because of its appearance). There are ‘deserts’ of repeating sequences.
what is ALPHOID DNA?
One type of Satellite DNA, 171 bp repeat unit, because it’s a bit different for different chr, it can be used to ID the chr (using a probe). Alphoid DNA is needed for the centromere assembly.
PSEUDOGENES
inactivated genes. can be close to functional genes and complicate diagnosis. Inaccuracies or crossing over leads to gene duplication (more than one copy of the same gene on the genome).
PROCESSED GENES
Where spliced RNA copies are reverse transcribed and reintegrated back into DNA. – results in copies of genes elsewhere in DNA, but without introns. Usually remote from the parent gene, most non-functional, but some remain functional e.g. PGK2.
Conservative missense point mutation:
chemical change is mild – e.g. one acidic for another, may be harmless, just a polymorphism
Non-conservative missense point mutation
different a.a. type. changes protein structure
Interspersed repeats
Unequal crossing over, usually happens at the Alu repeats. products are no longer balanced – one has an extra intron, one has none. Results in Chr imbalance.
What type of mutation is Duchenne muscular dystrophy
Deletion disorder
Name a Duplication disorder
Charcot-marie-tooth disease – nerve conduction disorder
What goes wrong with Haemophilia?
abnormal recombination. Gross rearrangement. X-linked Recessive, Coag factor 8 missing (coded by F8C)
What type of inheritance does haemophilia have?
X linked recessive
What goes wrong to cause haemophilia?
F8C gene is chopped in half (and another bit of chr stuck into middle), the other bit of F8C is inverted, so that it doesn’t work any more. Invisible to PCR as exons still there!!
Which parts of DNA are more likely to mutate?
CpG (a C base, then phosphate between, then G base)
Why is CpG vulnerable to mutations?
This is because CG gets methylated on Cytosines – and methylcytosine is very similar to thymine – so if T is there instead of methylcytosine DNA repair mechanisms don’t pick it up. Can result in a nonsense point mutation – truncated protein. Stop codon introduced. Likely to be pathogenic
What is a Splice junction mutations
Point mutations (pathogenic) can also occur outside coding region – these affect splicing
how do you show a change in DNA, coding DNA and protein?
Genomic DNA (g.), cDNA
what is the Hardy-weingberg principle for?
working out carrier frequency
cause of achondroplasia
FGFR3 gene: G380R (glycine à arginine)
what is G-banding?
Conventional cytogenetics, this means just observing chromosomes under the microscope. G bands stain dark. described as heterochromatic, and correlate to genetically inactive chromosomal regions; g banding allows you to link certain genes to patterns of G bands.
What are Telomeres?
Ends of chromosomes
Position effect:
A gene in a new chromosomal environment functions inappropriately
Unmasking of recessive disorder:
translocation means the disorder is revealed.
What is the chr abnormality of Turner’s syndrome?
45,X)
What is 47, XXY?
Klinefelter’s syndrome
two maternal pronuclei:
gynogenetic embryos
two paternal pronuclei:
androgenetic embryos
digyny:
diploid egg, small placenta, small fetus, mainly head development, maternal genome favours the fetus
diplospermy:
diploid sperm, large overdeveloped cystic placenta, increased carcinoma risk to mother after abnormal placenta. paternal genome favours the placenta:
dispermy
2 sperms fertilise 1 egg
what causes a MOLAR PREGNANCY:
double paternal, no maternal
what is conceptus without an embryo
Haploid sperm and empty egg –: massive cystic placenta
what does acrocentric mean?
P arm is shorter than q arm of chromosome
what is Mosaicism?
the post-fertilization occurrence of two or more cell lines with different genetic or chromosomal constitutions within a single individual or tissue, it is a classic cause of the developmental disorder Pallister Killian syndrome.
Pallister-Killian mosaic syndrome
is a developmental disorder that affects many parts of the body. This condition is characterized by extremely weak muscle tone (hypotonia) in infancy and early childhood, intellectual disability, distinctive facial features, sparse hair, areas of unusual skin coloring (pigmentation), and other birth defects.
Reciprocal Translocation
a balanced rearrangement, ends break off and swap places
Robertsonian translocation
balanced rearrangement, With acrocentric chromosomes (1 short arm). Chromosome attaches on to another one.
Inversion
a balanced rearrangement. There is a break in two places and it swaps round
Pericentric inversion:
Breaks are one either side of the centromere
Paracentric inversion
Both breaks are on the same side of the centromere
Interstitial deletion
segment out of a chr lost, the ends rejoin
Terminal deletion
segment lost off of end of chr
Direct duplication:
A chunk is gained, same again (a chunk repeated)
Inverted duplication:
same again but other way around
Digeorge syndrome is caused by:
deletion of chr 22 – phenotype varies with size of deletion
What is TP53
“gatekeeper of the genome” – directly regulate cellular growth
What is a TSG?
What does it do? What happens if it’s not working?, TUMOUR SUPPRESSOR GENES. Protects cells from becoming cancerous, Loss of function increases the risk of cancer
Examples of TSGs
APC, BRCA1/2, TP53, Rb
What is an ONCOGENE?
Regulates cell growth and differentiation
What is the inheritance of most cancer syndromes?
autosomal dominant inheritance
What is the inheritance of Retinoblastoma?
autosomal recessive
What gene is associated with retinoblastoma?
Rb1 gene
What is LCA?
Leber congenital amaurosis
What is the inheritance of LCA?
autosomal recessive
What is Leber congenital amaurosis?
LCA is an eye disorder that primarily affects the retina, severe visual impairment beginning in infancy.
What causes bowel polyps and has AD inheritance?
Familial Adenomatous Polyposis (FAP):
What gene is associated with FAP?
APC tumour suppressor gene
What is the inheritance of HNPCC?
Autosomal dominant
What happens with Hereditary Non-Polyposis Colorectal Cancer (HNPCC)?
Polyps are common, but not polyposis. Mismatch repair genes are faulty.
What’s the inheritance of BRCA1/2? What do they do?
BRCA1/2 are involved in DNA repair: Autosomal dominant inheritance
Li Fraumeni Syndrome, inheritance and gene?
Autosomal dominant P53 mutations.. Get loads of cancers.
Where is the Gene for CF
on Chr 7
WHERE IS THE Gene for sickle cell
on Chr 11
Light bands – what do they contain a lot of?
GC rich. These contain more genes.
Dark bands – what do they contain a lot of?
AT rich. These replicate later.
46,XX,dup(2)(p13p22)
describes a female with 46 chromosomes and a duplication of the short arm of chromosome 2 from bands 13 -22.
45,XX,der(13;14)(p11;q11)
Robertsonian translocation
46,XY,t(2;4)(p12;q12)
Reciprocal translocation
46,XX,del(5)(p25)
Deletion tip of chromosome 5
46,XX,dup(2)(p13p22)
Duplication of part of short arm Chr 2
46,XY,inv(11)(p15q14)
Pericentric inversion chromosome 11
46,XY,fra(X)(q27.3)
Fragile X syndrome
FISH what is it used for
help identify where a particular gene falls within an individual's chromosomes. Make probes and label these probes by attaching one of a number of colors of fluorescent dye. When a probe binds to a chromosome, its fluorescent tag provides a way for researchers to see its location.
FISH: Locus specific probes
these bind to a particular region of a chromosome. This type of probe is useful when scientists have isolated a small portion of a gene and want to determine on which chromosome the gene is located, or how many copies of a gene exist within a particular genome.
FISH: Alphoid or centromeric repeat probes
determine whether an individual has the correct number of chromosomes.
Example of FISH centromeric probe use
check if bone marrow transplant has worked (has the new tissue taken on the sex of the recipient?)
Paints – on FISH what is this good for spotting?
great for translocations
What can CNV (copy number variation) confer?
Susceptibility to disease eg HIV or autoimmune
What does MLPA (Multiplex Ligation-dependent Probe Amplification) measure?
Copy no. changes in up to 50 different genomic locations simultaneously. Then do Fragment analysis with gene scanner. Analysis shows relative area under peaks of output graph. You can produce a list of DOSAGE RATES RATIOS where 1 = normal, anything significantly less or more is unbalanced.
What is a genome-wide screen, where you compare total DNA content for genomic imbalances
MICROARRAY CGH (ARRAY CGH) comparative genomic hybridisation
What do you need for array CGH?
BLOOD in EDTA + 1-2ml LITHIUM HEPARIN BLOOD for cell culture in case follow up studies are needed. Also NEED CONTROL DNA (same sex) – provided by the lab.
How are results of Microarray CGH shown?
red and green spots on an array comparing the sample DNA with reference DNA. This is then converted to a ‘tramline’ chart which shows losses or gains. Can be used to ID regions of potential COPY NUMBER CHANGE
What sort of thing would you use array CGH for?
You would use array CGH for patients with a number of features / complaints, e.g. for learning disability (mod to severe) and developmental disability, or dysmorphic infants
What test does this describe? Good as an early diagnosis first line test, Gets you a quick and accurate answer. Accurate info on location and size of imbalances
array CGH
What doesn’t array CGH detect?
low level mosaicism is not detected (less than 10%), dosage changes, Also shows non-pathogenic changes, Good quality DNA needed
Describe NEXT GENERATION SEQUENCING
Comparing the relative amount of DNA sequence against a known reference. Analyse dosage changes.
What might QF-PCR – QUANTITATIVE FLUORESCENT PCR be used for?
Prenatal aneuploidy detection. It will Amplify areas where repeats are and Shows dosage changes
How does QF-PCR work?
Small sections of DNA are copied; typically 3-5 sections from chromosomes 13, 18, 21 and each sex chromosome. Primers used to copy each section of DNA are labelled with a different coloured fluorescent tags and are different sizes. This allows scientists to determine which parts of the chromosomes are represented by each result and the amount of DNA can be measured.
What do the results from QF-PCR mean?
The amount of fluorescence and size of the DNA which has been copied is measured, and ratios are presented on a graph. The number and height of each peak shows the number of copies of alleles at that region on the chromosome in the patients DNA sample i.e. how many copies of the chromosomes are present. If two copies of the chromosomes are present there will either be two peaks of equal size or one peak. If there are three copies of the chromosome (trisomy) there will be either three peaks or two peaks in a 2:1 ratio. If just one single large peak is seen it is not possible to tell if that single peak is indicating the presence of one chromosome, or two or three identical chromosomes.
qPCR – REAL TIME PCR – what is this used for?
Quantitative comparison vs reference gene & normal control patient (amplify & quantify). Confirming small CNVs, When FISH unsuitable
What is Wolf-Hirschung syndrome?
Chr 4 has 11p on it and a bit of 4 missing ID by FISH
When can you do Amniocentesis
16w
When can you do Chorionic villus biopsy
12w
What is CVS testing?
small bit of placenta
What is NIPT and when can you do it?
Non invasive pre natal testing: 12w
What does NIPT use?
Maternal blood sample, Extract circulating free fetal DNA
What does NIPT test for?
Assess aneuploidy of 13, 18, 21
Indicators for prenatal diagnosis
maternal age, serum screen risk (high afp alpha fetoprotein – indicates NTD? LOW oestriol (fetal problem), HIGH hcg can INDICATE TRI21), abnormal ultrasound scan (USS), Family history /previous chromosome abnormality
PRE-IMPLANTATION GENETIC ANALYSIS what is this
Establishes the genetic makeup of the preembryo
What use is cytogenetics in oncology?
A number of genetic changes at the same time – indicate cancer, e.g. MYCN gene amplification in neuroblastoma, also Translocation in leukaemia eg t(9;22) in CML makes bcr/abl gene which creates an abnormal protein (Philadelphia chromosome).
What is another use of cytogenetics in oncology?
Solid tumour genetics: Fresh tumour – FISH or G-banding (culture – 1-20 days). Archived tissue (paraffin embedded) – FISH or genotyping
AUTOSOMAL DOMINANT what is inheritance pattern?
males & females are affected M:F ratio ~ 1:1
AUTOSOMAL RECESSIVE – what is the inheritance pattern?
males & females are affected equally, often just seen in single generation, consanguinity increases
X-LINKED RECESSIVE INHERITANCE what is inheritance pattern?
males only affected, females are carriers. no male-to-male transmission
X-LINKED DOMINANT INHERITANCE- what is the inheritance pattern?
males and females affected, males more severely affected than females, no male-to-male transmission
What is Pharmacokinetics?
What the body does to the drug HOW ABSORBED METABOLISED AND EXCRETED
What is Pharmacodynamics
What the drug does to the body
What is Stratified medicine
Selecting therapies for groups of patients with shared biological characteristics: tumours are treated in a certain manner, depending on tumour characteristics
What is Personalised medicine
Therapies tailored to the individual eg they have an enzyme which enables them to metabolise drug quicker
What is an ADR?
Adverse drug reaction. Genetics affect what dose is good or enough
What is an example of how an ADR might happen?
Thiopurine methyltransferase – TPMT This inactivates some drugs. TPMT polymorphisms reduce protein activity, so if the person is homozygous they can suffer severe toxicity. Problem with immunosuppressants and chemo – they aren’t metabolised as you’d expect.
What liver enzymes inactivate drugs by acetylation?
N-acetyl transferase. “Fast” and “slow” acetylators – due to SNP variations in genes e.g. NAT2. Different distributions in different ethnic populations e.g. isoniazid used for TB – Slow acetylators at increased risk of side effects including neuritis and liver toxicity. Other drugs – sulfasalazine (Crohn's dis), hydralazine (hypertension) these are inactivated by the enzyme
What gene affects the reaction to Succincylcholine (Muscle relaxant used in anaesthesia)
Rare BCHE gene variant homozygotes have reduced butyrylcholinesterase activity. risk of death if artificial ventilation is not continued.
Aminoglycoside induced hearing loss – what gene is responsible and what happens?
Mitochondrial MT-RNR1. Mutation changes the structure of the rRNA so that Aminoglycosides more likely to bind to patients rRNA → increased risk of hearing loss at younger age
Warfarin – what might affect its handling in the body?
Polymorphism which affects CYP2C9 will affect warfarin handling – Genotyping could reduce hospital admissions.
What do 20% of breast cancers have over-expression of?
HER2 (human epidermal growth factor receptor 2)
What would help breast cancer pts with over expression of HER2?
Trastuzumab (Herceptin) – a monoclonal antibody to the HER2 receptor
thumb missing
radius hypoplastic
Short, incurved little finger
clindodactyly
Infant with thumb right across palm (congenital clasped thumb) with hypocephalus, is indicative of
cytomegalovirus infection
Ectrodactyly
finger(s) missing - “lobster claw”.
Syndactyly
webs between two fingers / toes is common.
Polysyndactyly
extra fingers / toes.
What are dysmorphic features of Ears?
attached earlobes? Pits in earlobes? Skin tags? Question mark ear: diagnostic of auriculo-condylar syndrome. Ear creases – on earlobes?
Some indications of diGeorge?
Thin nose without flare at bottom, Very narrow mouth, Learning dis may not be picked up – not severe, Velopharyngeal insufficiency 32% - nasal voice – palate
Beckwith-Wiedemann syndrome is often associated with
changes in regions of DNA on chromosome 11 called imprinting centers (ICs)
About twenty percent of cases of Beckwith-Wiedemann syndrome are caused by
a genetic change known as paternal uniparental disomy (UPD). Paternal UPD causes people to have two active copies of paternally inherited genes rather than one active copy from the father and one inactive copy from the mother. People with paternal UPD are also missing genes that are active only on the maternally inherited copy of the chromosome
What do all Down Syndrome people get and why?
All get alzheimers as APP protein on 21 – and they have 3 copies
What are the problems with Peutz-Jeghers Syndrome?
Gastrointestinal polyps, Malignancies:
What is the inheritance of Treacher-Collins Syndrome?
Autosomal dominant
Prader–Willi syndrome – what is it and what’s the cause
PWS is a rare genetic disorder in which seven genes (or some subset thereof) on chromosome 15 (q 11–13) are deleted or unexpressed (chromosome 15q partial deletion) on the paternal chromosome.
Angelman Syndrome how does this happen
chr 15 some genes are non functional – ‘happy puppet’
Williams Syndrome what is the genetic cause
7q11 deletion