GiM lectures 12,13,14 Flashcards
(51 cards)
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)
