Genetics and Clinical Cases Flashcards
What is the basis of precision medicine?
Use some form of testing to identify a subgroup of patients who respond to treatment
What are two elements essential to precision medicine?
Genetic testing and understanding molecular pathways
What types of conditions is precision medicine most effective in?
Rare diseases and high penetrance mutations
How may tuberous sclerosis present?
Infantile seizures
What is the earliest cutaneous sign of tuberous sclerosis?
Ash leaf macule (depigmented macule found in 90% of cases)
What kind of inheritance does tuberous sclerosis?
Autosomal dominant (but new mutations are common)
What are some tumours associated with tuberous sclerosis?
Periungal fibromas (around nails)
Facial angiofibromas (also called adenoma sebaceum, start to develop in first few years of life)
Cortical tubers and/or calcification of the falx cerebri (epilepsy, varying degrees of mental impairment)
Bone cysts
Hamartomas (angiomyolipomas, heart, lungs, kidneys)
What are some other signs of tuberous sclerosis (besides tumours)?
Shagreen patches, enamel pitting
What are the genetics involved in tuberous sclerosis?
Mutations in TSC1 (chromosome 9q34), which codes for tuberin, or TSC2 (chromosome 16p13.3), which codes for hamartin; both are tumour regulating genes in the same pathway
What are some treatments for tuberous sclerosis?
mTOR inhibitors, topical rapamycin
What genetic deficiency causes seizures through the same pathway as tuberous sclerosis?
Genetic STRADA deficiency = causes intractable seizures
How does tuberous sclerosis show genetic heterogeneity?
Mutation may be TSC1 or TSC2
Is the penetrance and disease expression of tuberous sclerosis always constant?
No = penetrance is variable (but high) so some people don’t show features of disease, disease expression is variable and different people are affected differently
What does epidermolysis bullosa refer to?
Group of genetic skin fragility conditions, can be acquired, new mutations or autosomal recessive/dominant
Does blistering at birth determine the severity of epidermolysis bullosa in later life?
No
What are the three main types of epidermolysis bullosa?
Simplex, junctional, dystrophic
How many genes are involved in epidermolysis bullosa and what are they involved in?
> 10 genes involved, involved in skin structure and adhesion (keratin 5/4, laminins, integrins, collagen 17)
What is epidermolysis bullosa aquista?
Rare autoimmune disease, more common in adults
What occurs in haploinsufficiency?
Only one copy of gene working so reduced protein production
What occurs in double negative genetics?
Expression of abnormal protein interferes with normal protein
How do mutations gain function?
Mutant protein gains a new function affecting cell processes
Why would there be a complete loss of protein?
Autosomal recessive (2 faulty copies of gene) so no protein produced
What is a de-novo mutation?
Child has a mutation that neither parent has
What are some features of café-au lait macules?
Occur from birth onwards, 1 or 2 found in 10-20% of normal people, > 5 suggest genetic disease
What are some signs of neurofibromatosis type 1?
Neurofibromas (soft neural tumours), plexiform neuroma (diffuse), axillary/inguinal freckling, optic glioma, 2 or more Lisch nodules, distinctive bony lesion
How is neurofibromatosis type 1 treated?
MEK inhibitors
Mutation of what gene causes neurofibromatosis type 1?
Mutation of neurofibromin 1 (NF1) on chromosome 17
What does NF1 code for?
Codes for neurofibromin (GTPase-activating protein) which negatively regulates RAS/MAPK pathway activity by accelerating the hydrolysis of Ras-bound GTP
What factors can influence atopic eczema?
Skin barrier function, genetic factors (filaggrin), environment, immunology (IL-4/5)
Why is filaggrin (FLG) important in atopic eczema?
Skin barrier gene, loss of function mutations are common (1 in 10), mutations cause ichthyosis vulgaris
By how much does a filaggrin mutation increase the risk of atopic eczema?
4x (also increases asthma/hayfever by 3x and peanut allergy by 5x)
