Genetics

Question 1

what are monogenic disorders caused by?

Answer 1

single gene

Question 2

six patterns of monogenic disorder inheritance?

Answer 2

AD
AR 
XLD
XLR
Y-linked
mitochondrial

Question 3

what causes polygenic diseases

Answer 3

multiple genes with environmental influences

Question 4

genetic abnormalities that lead to monogenic disease

Answer 4

• single nucleotide variants (SNVs)
• small insertions and deletions (indels)
• loss of function mutations

Question 5

examples of single nucleotide variants (SNVs)

Answer 5

missense
nonsense
splice site alteration

Question 6

what can indels cause?

Answer 6

in-frame or out-of frame mutations

Question 7

examples of loss of function mutations

Answer 7

nonsense
frameshift
canonical splice site mutations

Question 8

benefits of genetic testing

Answer 8

patient
first degree relative and/or progeny
research and future clinical studies

Question 9

negative impacts of genetic testing

Answer 9

fear over positive results
anxiety regarding family
discrimination (work/insurance)
false positives
secondary findings

Question 10

approaches to genetic testing

Answer 10

first generation

next generation sequencing

Question 11

two examples of monogenic endocrine tumour syndromes

Answer 11

MEN1

MEN2a/b

Question 12

presentation of MEN1

Answer 12

3P's
parathyroid
pancreatic
pituitary tumours
but there can be numerous others too

Question 13

genetics of MEN1

Answer 13

AD mutation in MEN1 gene located 11q13 (tumour suppressor)

Question 14

negative consequences of MEN1

Answer 14

premature morbidity

considerable psychological burden

Question 15

when is genetic testing indicated for MEN1?

Answer 15

presentation suspicion

first degree relative is known to have it

Question 16

when should testing begin for MEN1?

Answer 16

from age 5

Question 17

management of MEN1

Answer 17

expectant approach

Question 18

genetics of MEN2

Answer 18

AD mutation in the RET gene on 10q which is a proto-oncogene leading to activation of receptor tyrosine kinase

Question 19

classification of MEN2

Answer 19

• MEN2a

MEN2b

Question 20

presentation of MEN2a

Answer 20

medullary thyroid cancer with phaeochromocytoma and parathyroid tumours

Question 21

presentation of MEN2b

Answer 21

less frequent
MTC
phaeochromocytoma 
marfanoid habitus
mucosal neuromas
medullated corneal fibres
intestinal autonomic ganglion dysfunction

Question 22

presentation of MEN2

Answer 22

neck mass
diarrhoea and flushing (metastatic disease)
ectopic ACTH and Cushing’s
risk of overactive parathyroid glands

Question 23

diagnosis of MEN2

Answer 23

USS-FNA
basal serum calcitonin and CEA
phaeochromocytoma has elevated urinary or plasma metanephrines
imaging to detect local and advanced disease

Question 24

management of MEN2

Answer 24

surgery or tyrosine kinase inhibitors

Question 25

what does the timing of prophylactic thyroidectomy in MEN2 depend on?

Answer 25

type of mutation

Question 26

other monogenic endocrine tumour syndromes

Answer 26

- neurofibromatosis 1 - von hippel lindau - carney complex - McCune-Albright

Question 27

presentation of neurofibromatosis 1

Answer 27

``` axillary freckling cafe au lait patches neurofibromas optic gliomas scoliosis learning difficulties (some) phaeochromocytoma (rare) ```

Question 28

mutation in neurofibromatosis 1

Answer 28

NF1 gene | presents in childhood

Question 29

presentation of von hippel lindau (VHL)

Answer 29

multiple vascular tumour surveillance done annually and family screening accumulation of HIF proteins and stimulation of cellular proliferation

Question 30

mutation in VHL

Answer 30

VHL gene AD

Question 31

presentation of carney complex

Answer 31

spotty pigmentation of skin with endocrine and non-endocrine tumours

Question 32

mutation in carney complex

Answer 32

mutation in PRKAR1A leading to defect regulatory subunit and aberrant PKA signalling causing uncontrolled proliferation

Question 33

presentation of McCune Albright

Answer 33

``` cafe au lait pigmentation (Coast of Maine appearance) polyostotic fibrous dysplasia (bones) precocious puberty (females) thyroid nodules pituitary GH excess Cushings syndrome (adrenal) ```

Question 34

mutation in McCune Albright

Answer 34

post-zygotic GNAS mutation leading to constitutive adenylyl cyclase signalling and overproduction of several hormones mosaicism