GiM lectures 12,13,14 Flashcards Preview

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Flashcards in GiM lectures 12,13,14 Deck (51):

Where would you get bio information form

- 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

reproduction from an ovum without fertilization
- common in animals, fish, reptiles


what is androgenesis

development of an embryo containing only paternal chromosomes due to failure of the egg to participate in fertilization


What is a Hydatidiform mole

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?


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
Sporadic occurrence de novo

Hypomethylation - low IGF2


explain imprint switching

imprinting must be remembered during somatic development

forgotten before gametogenesis

erasure of grandparental imprint - establish new parental imprint


Stratified medicine
personalised medicine

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



Altered target

Catabolism (breakdown)


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


- 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


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

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

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