Genetics and Clinical Cases

Question 1

What is the basis of precision medicine?

Answer 1

Use some form of testing to identify a subgroup of patients who respond to treatment

Question 2

What are two elements essential to precision medicine?

Answer 2

Genetic testing and understanding molecular pathways

Question 3

What types of conditions is precision medicine most effective in?

Answer 3

Rare diseases and high penetrance mutations

Question 4

How may tuberous sclerosis present?

Answer 4

Infantile seizures

Question 5

What is the earliest cutaneous sign of tuberous sclerosis?

Answer 5

Ash leaf macule (depigmented macule found in 90% of cases)

Question 6

What kind of inheritance does tuberous sclerosis?

Answer 6

Autosomal dominant (but new mutations are common)

Question 7

What are some tumours associated with tuberous sclerosis?

Answer 7

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)

Question 8

What are some other signs of tuberous sclerosis (besides tumours)?

Answer 8

Shagreen patches, enamel pitting

Question 9

What are the genetics involved in tuberous sclerosis?

Answer 9

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

Question 10

What are some treatments for tuberous sclerosis?

Answer 10

mTOR inhibitors, topical rapamycin

Question 11

What genetic deficiency causes seizures through the same pathway as tuberous sclerosis?

Answer 11

Genetic STRADA deficiency = causes intractable seizures

Question 12

How does tuberous sclerosis show genetic heterogeneity?

Answer 12

Mutation may be TSC1 or TSC2

Question 13

Is the penetrance and disease expression of tuberous sclerosis always constant?

Answer 13

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

Question 14

What does epidermolysis bullosa refer to?

Answer 14

Group of genetic skin fragility conditions, can be acquired, new mutations or autosomal recessive/dominant

Question 15

Does blistering at birth determine the severity of epidermolysis bullosa in later life?

Answer 15

No

Question 16

What are the three main types of epidermolysis bullosa?

Answer 16

Simplex, junctional, dystrophic

Question 17

How many genes are involved in epidermolysis bullosa and what are they involved in?

Answer 17

> 10 genes involved, involved in skin structure and adhesion (keratin 5/4, laminins, integrins, collagen 17)

Question 18

What is epidermolysis bullosa aquista?

Answer 18

Rare autoimmune disease, more common in adults

Question 19

What occurs in haploinsufficiency?

Answer 19

Only one copy of gene working so reduced protein production

Question 20

What occurs in double negative genetics?

Answer 20

Expression of abnormal protein interferes with normal protein

Question 21

How do mutations gain function?

Answer 21

Mutant protein gains a new function affecting cell processes

Question 22

Why would there be a complete loss of protein?

Answer 22

Autosomal recessive (2 faulty copies of gene) so no protein produced

Question 23

What is a de-novo mutation?

Answer 23

Child has a mutation that neither parent has

Question 24

What are some features of café-au lait macules?

Answer 24

Occur from birth onwards, 1 or 2 found in 10-20% of normal people, > 5 suggest genetic disease

Question 25

What are some signs of neurofibromatosis type 1?

Answer 25

Neurofibromas (soft neural tumours), plexiform neuroma (diffuse), axillary/inguinal freckling, optic glioma, 2 or more Lisch nodules, distinctive bony lesion

Question 26

How is neurofibromatosis type 1 treated?

Answer 26

MEK inhibitors

Question 27

Mutation of what gene causes neurofibromatosis type 1?

Answer 27

Mutation of neurofibromin 1 (NF1) on chromosome 17

Question 28

What does NF1 code for?

Answer 28

Codes for neurofibromin (GTPase-activating protein) which negatively regulates RAS/MAPK pathway activity by accelerating the hydrolysis of Ras-bound GTP

Question 29

What factors can influence atopic eczema?

Answer 29

Skin barrier function, genetic factors (filaggrin), environment, immunology (IL-4/5)

Question 30

Why is filaggrin (FLG) important in atopic eczema?

Answer 30

Skin barrier gene, loss of function mutations are common (1 in 10), mutations cause ichthyosis vulgaris

Question 31

By how much does a filaggrin mutation increase the risk of atopic eczema?

Answer 31

4x (also increases asthma/hayfever by 3x and peanut allergy by 5x)