GiM lectures 12,13,14 Flashcards
Where would you get bio information form
Internet
- regional genetic services website
- charities and support groups
- pubmed
- molecular clinical databases
inter/national bodies BSGM, UKGTN, NICE, GARD,
- NCBI national centre of biotechnology information
How to use OMIM - online mendelian inheritance in man
- search NCBI OMIM
- search OMIM for syndrome
- sees genes involved
- gives comprehensive clinical synopsis, and modes of inheritance
- to get coding DNA sequence
enter ERCC8 and select DNA then Ensembl
What does GeneReviews do?
gives expert unto date clinical and molecular information - diagnosis, management, prevalence, genetic counselling
What tests would you perform on a neonate?
Creating kinase, eye review, brain MRI, aCGH, gene test guided by phenotype
What is Parthenogenesis
46XX
reproduction from an ovum without fertilization
- common in animals, fish, reptiles
what is androgenesis
46XX
development of an embryo containing only paternal chromosomes due to failure of the egg to participate in fertilization
What is a Hydatidiform mole
Androgenic
homozygous 46XX
proliferation of abnormal trophoblast tissue
can develop into malignant trophoblastic tumour
No (remaining) embryo
What occurs from parthenogenesis
Benign ovarian teratomas
- oocytes have competed 1st or both meiotic division,
- diploid
- wide spectrum of tissues, mainly epithelial, no skeletal muscle or placenta
- can have teeth, bone, hair
What causes pathenogenic embryos to die?
failure to develop extra embryonic structures
- trophoblast
- yolk sac
What causes androgenic embryos
die at 6 somite stage
well developed extra embryonic membrane but poor embryo development
Why do uniparental conceptions fail?
parental genes have different roles developemental fate
- concept of genomic imprinting from both parents is necessary
- genes imprinted with maternal and paternal origin
What is genomic imprinting
mechanisms that ensures functional non-equivalence of maternal and paternal genomes
= epigenetic (not encoded in DNA nucleotide sequence)
depends on modification to the genome laid down during gametogenesis
affects expression of 100-200 genes (evolutionary conserved)
Angelman Syndrome
- Facial dysmorphism
- metal effects?
- other clinical?
- what is it?
Facial dysmorphism
- prognathism, wide mouth, drooling, smiling appearance
Mental - microcephaly, absent speech
Siezure disorder, ataxic jerky movements
“puppet children”
Deletion on chromosome 15 (del15q11-q13)
Always de novo - low recurrence risk
lack Maternal inactivation of 15
75% DELETION on maternal chromosome
1% double paternal 15 (uniparental)
2-5% point mutation on maternal chromosome UBE3A
Prader-Willi Syndrome
- clinical features
- cytogenetic abnormality
Infantile hypotonia - gross motor delay, feeding problems mental handicap male hypogenitalism, chyrptochidism small hands/feet hyperphagia - obesity stereotypic behaviour
deletion on chromosome 15 (del15q11-q13)
always de novo - low recurrence risk
lack paternal inactivation of 15
70% deletion in paternal chromosome
25% double maternal contribution (uniparental conception)
How does genetic imprinting occur?
DNA methylation
- post synthetic DNA modification
- epigenetic *doesnt usually alter DNA sequence
imprinted genes show mono allelic expression
- epigenetic differences between maternal and paternal copy allele
- memory of distinct gaetogenic histories
- chromatin structure differences between expressed and non expressed allele
How does imprinting affect fetal growth?
IGF2
Large baby
Paternal ++ = high metal fitness, evolutionary advantage
Maternal ++ = high mortality, poor long term reproductive potential
Small baby
Paternal – = increased maternal morality, decreased paternal reproductive fitness
Maternal ++ = better maternal survival rates and reproductive fitness
Beckwith Wiedemann syndrome
- what is it?
- Clinical features
- occurrence
- epigenetic abnormality
Fetal overgrowth
- high birthweight
Organomegaly - exomphalos
Hypoglycaemia, asymmetry, tumour risk,
sporadic occurrence
11p15 - abnormality
Hypermethylation - high IGF2
Russell-silver syndrome
- what is it
Growth retardation
- fetal and postnatal
Triangular face - brain mainly preserved
Asymmetry
Sporadic occurrence de novo
11p15
Hypomethylation - low IGF2
explain imprint switching
imprinting must be remembered during somatic development
forgotten before gametogenesis
erasure of grandparental imprint - establish new parental imprint
Define Genomics Pharmacokinetics Pharmacodynamics Stratified medicine personalised medicine germline somatic
Genomics – relating to the genome i.e. total DNA/RNA
Pharmacokinetics – What the body does to the drug
Pharmacodynamics – What the drug does to the body
Stratified medicine – Selecting therapies for groups of patients with shared biological characteristics
Personalised medicine – Therapies tailored to the individual
Germline – i.e. Hereditary
Somatic – Acquired, in non-germline cells, not hereditary
How do genetic variations - effect drugs
Absorption
Activation
Altered target
Catabolism (breakdown)
Excretion
NB Drugs may have complex metabolic pathways and single genes are unlikely to explain all variability
how can genetics help with prescribing
Identify genetic variations that lead to altered outcomes
Change dose of drug where appropriate
Use a different drug that works better and/or has reduced toxicity
Guide new targeted drug development
Stratified/personalised medicine
Reduce financial costs of inappropriate treatment
What does Thiopurine methyltransferase do?
TPMT inactivates some drugs
Azathioprine (immunosuppressant)
6-mercaptopurine (chemo)
6-thioguanine (chemo)
converts drugs into inactive forms
can cause severe toxicity if both copies of the gene have the variant
How does N-Acetyltransferase affect medication?
Liver enzyme that inactivate some drugs by acetylation
fast and slow acetylator variants
- isoniazid used for TB - increase risk of side effects inc neuritis, and liver toxicity
- sulfasaliazine (chohn’s)
- hydralazine (hypertension)
what affects succinylcholine
what is succinylcholine
related to poison curare
muscle relaxant used in anaesthesia
rare BCHE gene variant homozygotes reduce activity
cause effects of anaesthesia to last for hours no minutes and death if artificial ventilation not continued
How doe amino glycoside induce hearing loss?
MT-RNR! gene encodes mitochondrial 12s rRNA
G>A mutation at 1555 causes non syndromic hearing loss
mutation causes rRNA to resemble e coli 16s rRNA
amnioglycosides bind to patient rRNA in error and cause early hearing loss
maternally inherited
30% tendency of amino glycoside ototoxicity
how can warfarin be affected?
decreased it K availability
too low - still at embolus risk
too high - haemorrhage risk
CYP2C9 (a cytochrome P450) and VKORC1 Vit K oxidoreductase complex 1
cause massive genetic variability within warfarin activity
how could genetics improve cancer treatment
Cancers contain genetic variations that are not present in germline DNA
These variations are potential targets
Many new drugs are in development and entering clinical use
Increase overall response rates & survival
Reduce treatment failure and toxicities
Trastuzumab
- who benefits?
20% breast cancer patients over express HER2 human epidermal growth factor receptor
benefit significantly as trastuzumab is a monoclonal antibody to HER2 receptor
BRACA1 and BRACA 2 what % of familial cancers? what % breast cancers? how much increasase risk how much increase ovarian
16% familial
5-10% breast cancers
increased risk 85% by 70years old (increase from 12% by 90)
Increased ovarian 55% BRCA1, 25% BRCA2 (increase from 2%)
How much does prophylactic surgery reduce risk
removal of ovaries - 85%
preventative mastectomy - 90%
what pre symptomatic screening programmes are available
huntington’s
retinitis pigmentosa
breast cancer
colon cancer
- predictive but not preventative
What does preimplantation diagnosis allow?
implantation of non affected embryo
non disclosure testing can be performed
HLA typing to match cord blood stems for siblings
How does leptin affect weight
What does leptin deficiency cause
how can leptin deficiency be treated
fat cells increase leptin
leptin causes decrease in food intake, increase in thermogenesis, increase in physical activity,
decrease fat cell mass
lack of leptin can cause obesity
leptin replacement therapy is very effective
What is gene therapy
use of genetic material as medicne
What is Lebers congenital amaurosis
rare innherited eye disorder blindness at birth/infancy 10-18% of congenital blindness 18 genes implicated recessive inheritance RPE65 - one of the affected genes
Why would gene therapy in the eye work?
eye is immune privileged
accessible for sub retinal injection
What is the importance of pharmacogenetic
5-7% of hospital admissions due to adverse drug responses
What is cytochrome P450 oxidases
family of enzymes found in liver
responsible for metabolic emlimination of most drugs
important for converting some drugs into active form e.g codeine
What is CYP2D6?
What % of the caucasian population are non metabolisers/ultrametabolisers
highly polymorphic cytochrome 450 member
metabolises 25% drugs
6-10% caucasians non metabolisers (no cyp2d6)
7% caucasians ultra rapid metabolisers (multiple cyp2d6)
What is the relationship of CYP2D6 and Tamoxifen metabolism
CYP2D6 = rate limiting step of tamoxifen conversion to active metabolic
poor metabolises due to polymorphism have lower survival rate due to decreased activation of drug
What is personalised medicine
information of genotype/gene expression profile used to tailor personal medicine
What is 23andme
company that offers genetic testing - for 240 diseases and traits for £100
e.g. BRCA, CF, parkinson,
patients can have access to this without concelling or explanation.
What is huntington disease?
- what disorders does it cause
- what is the mean age of onset
- what is the median survival post onset
Progressive neurodegenerative disorder
-motor,cognitive, psychiatric distrubances
Movement disorder - chorea, dystonia, bradykineasia, choking, dysarthria
Mood - depression, euphoria, apathy, anxiety, aggression, psychotic symptoms
Cognition - loss of executive functioning, rigidity of thought, memory loss, dementia
Mean age of onset - 35-44 years
Median survival - 15-18 years post onset
What are the genetics of HD
autosomal dominant
complete penetrance
HTT gene - 4q16.3
HD mutation - expansion of CAG repeats >40
What is “normal” for the huntington gene
Normal
everyone has 2 copies of HTT gene CAG repeat
3114 amino acids = protein
normal range = 6-35CAG repeats
What is the abnormal huntington protein
increased glutamine aminoacids –> polygluatmine expansion
change in tertiary structure and function
What is anticipation
onset of disorder occurs at earlier age as passed down generations, increase in severity of symptoms
- linked to triple repeat disorder
Why do triple repeat disorders cause anticipation
- name 3 triple repeat diseases
- of these 3 diseases which parental inheritance has highest anticipation risk
- unstable therefore increase when passed down generations
1) HD - paternal
2) myotonic dystophy - maternal
3) fragile X - maternal
What are the treatments for HD
symptomatic only
no prevention or cure
testing will not save lives
What does predictive testing enable
plan for future care, decisions about offspring, inform family
