Genetics - Cases and Mechanisms Flashcards
what is precision medicine?
using some form of testing to identify a subgroup of patients who respond to a treatment
can involve genetic testing
what is precision medicine used in right now?
cancer
some diseases
what is the benefit of precision medicine?
can test whether treatment will be effective in people so people will get effective treatment instead of giving everyone the same and it not working for some
what are periungual fibromata? are they always pathological?
fibrous, bulbous overgrowths at cuticle of nail
one can be normal but many is pathological
what is periungual fibromata diagnostic of?
tuberous sclerosis
what is tuberous sclerosis?
autosomal dominant genodermatoses
causes infantile seizures and can produce ash leaf macules in skin (depigmented)
how can ash leaf macules be seen on pale skin?
woods lamp
what are the signs of tuberous sclerosis?
periungual fibromas facial angiofibromas cortical tumours - epilepsy hamartomas - angiomyolipomas bone cysts shagreen patches enamel pitting
what are angiofibromas?
erythematous papules
can be misdiagnosed as acne, but doesn’t form comodones
begin in first year of life and progress through life
what causes tuberous sclerosis?
autosomal dominant mutation in either 9q34 or 16p13.3 AFFECTING TSC1 and TSC2 genes (codes for tuberin and hamartin - tumour regulating genes)
is tuberous sclerosis always inherited?
not always
can be a spontaneous mutation
are new mutations common?
yes
can have around 120 new mutations that aren’t present in parents
depends on how old father is (older = more mutations)
% chance of being affected by autosomal dominant mutation if parent is affected?
50%
but disease not always shown
how does a mutation cause a problem?
affects central dogma
i.e can effect protein synthesis
what are the types of mutation?
missence - single nucleotide mutation
deletion (in frame) - deletion of a codon
Premature stop - premature stop codon
deletion (frameshift) - deletion of a number of nucleotides not divisible by 3
give an example of a treatment created through precision medicine?
rapamycin
what type of mutation does precision medicine work best for?
high penetrance disorders
how does precision medicine work?
identify genes for a disease which tells you the pathway
pathways can then be targeted for treatments
what is genetic heterogeneity?
the causative mutation in a genetic disease can be in one of two genes
skin of baby blistered at birth which then progresses to extensive skin loss occurring with any movement/handling of baby?
EB - Epidermolysis Bullosa
what is EB?
group of genetic fragility conditions
variable severity of blistering and skin loss
what is EB?
group of genetic skin fragility conditions
variable severity of blistering and skin loss
simplex type?
split in epidermis, surface of blister is upper epidermis
almost normal life, just blister very easily
simplex type EB?
split in epidermis, surface of blister is upper epidermis
almost normal life, just blister very easily
junctional type EB?
split is at dermo-epidermal junction
heals with scarring
dystrophic type EB?
split is in the dermis
cant heal, causes extensive scarring (mitten deformity)
types of keratin?
type 1 and type 2 which bind to form a dimer > tetramer giving structural integrity
what are the types of keratin and what do they do?
type 1 and type 2 which bind to form a dimer > 2 dimers form a tetramer giving structural integrity
through what 4 mechanisms can a mutation cause a disease?
good gene not producing enough (e.g protein) so deficiency causes disease
= haploinsufficiency
OR
mutation makes abnormal protein which stops the normal protein working
= dominant negative (more severe effect)
mutant protein gains new function affecting cell process
= gain of function
2 faulty copies of gene produce no protein
= complete loss of protein (autosomal recessive)
how can mutations arise in offspring when the parents don’t have the mutation?
new mutation occurs in one parents gametes
one parent is mosaic so has some copies of mutation but not all
asymptomatic coffee coloured flat marks?
café au lait macules
>5 indicates neurofibromatosis type 1
clinical signs of neurofibromatosis?
café au lait macules neurofibromas (soft and squishy tumours) axillary/inguinal freckles plexiform neuroma optic gliomas (eye tumours) Lisch nodules Bony lesions
is neurofibromatosis autosomal dominant?
quite often (50-60%) or can be a new mutation
what does neurofibromine do?
involved in cell growth
red, rough patches of skin at 2 weeks old which becomes more itchy and broken?
atopic eczema
which components of atopic eczema do genetic factors effect?
skin barrier effect (filaggrin) and immunology (interleukin 4 and 13)
what does a filaggrin mutation cause?
hyperlinear palms (wrinkly)
dry skin
more severe ichthygosis vulgaris effects if both copied affected
has a role in atopic diseases
what does a filaggrin mutation cause?
hyperlinear palms (wrinkly)
dry skin
more severe ichthygosis vulgaris effects if both copied affected
has a role in atopic diseases
what can a filaggrin mutation predispose to?
atopy hayfever asthma eczema food allergy (esp. peanuts) due to leakiness caused
are most human diseases monomeric?
no
most are comlex - many genes interacting with many environments
