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
