Genetics

Question 1

BMPR2

Answer 1

Primary arterial hypertension
Abnormal endothelial and vascular smooth muscle growth and proliferation
Young healthy appearing women
Poor prognosis

Question 2

Alpha 1-antitrypsin deficiency

Answer 2

Chromosome 14
Normally inhibits elastase
Deficiency results in early onset panacinar emphysema in LOWER lung
Some patients also present with liver cirrhosis due to alpha1 build up in liver that occurs with phenotypes that experience pathologic polymerization of AAT in ER of hepatocytes

Question 3

Kartageners syndrome

Answer 3

Mutation of dynein protein - ciliary dyskinesia
Chronic sinusitis, Bronchiectasis, male infertility, situs inversus
Classic case: child with recurrent sinus/ear infections, chronic cough, Bronchiectasis on CT, obstruction on PFTs, situs inversus

Question 4

MYD88 Mutation

Answer 4

severe necrotizing lobar pneumonia due to strep pneumo

Question 5

Phe508

Answer 5

aka delta-F-508 gene mutation
AR - Cystic fibrosis
Results in non-frameshift deletion
Chromosome 7 - CFTR gene

Question 6

Factor 5 Leiden Mutation

Answer 6

Most common inherited hypercoaguability in caucasians
production of mutant factor 5 (Arg506Gln point mutation near cleavage site) AD. resistant to degredation by activated protein C (APC). Result is accelerated prothrombin activation
Complications: DVT, cerebral vein thromboses, recurrent pregnancy loss

Question 7

protein C or S deficiency

Answer 7

Nonsense mutation AD - Decreased ability to inactive factor V and VIII
Complications: VTE, warfarin-induced skin necrosis, neonatal purpura fulminans

Question 8

Antithrombin III deficiency

Answer 8

AD. Two types
1. reduced synthesis
2. Functionally defective
Complications: VTE - VERY HIGH RISK

Question 9

Prothrombin mutation

Answer 9

AD. mutation in 3’ UTR - results in increased prothrombin production and thus high prothrombin plasma levels and VTE

Question 10

EGFR

Answer 10

Proto-oncogene - receptor tyrosine point mutation that causes spontaneous dimerization in abscence of a ligand
mutation seen commonly in lung cancer (adenocarcinoma)
Target of personalized treatment
(90-100% of epithelial head and neck tumors also have EGFR)

Question 11

ERBB2 (HER2/NEU)

Answer 11

Breast cancer tyrosine kinase receptor point mutation

Question 12

ALK

Answer 12

non-receptor tyrosine kinase
Seen in NSCLC as well (young non-smokers - adenocarincoma)
Results in EMLA4-ALK fusion protein that allows auto dimerization. Diagnose with FISH

Question 13

Ras

Answer 13

most commonly mutated proto-oncogene in human tumors
Point mutation of downstream signaling molecule in cell growth. Prevents Ras from kicking off GTP and is thus constituitively active
Seen in most pancreatic cancers
Also in 1/2 of colon, endometrial, and thyroid cancer. 1/3 of lung cancer

Question 14

B-Raf

Answer 14

directly downstream of Ras. Mutated in melanoma, NSCLC, colorectal cancer

Question 15

Retinoblastoma Protein (Rb)

Answer 15

Tumor suppressor that modulates G1 restriction point.
Normally binds to EF2 and prevents transcription unless phosphorylated by Cdk2
Mutations range from cytogenetic deletions, point mutations, and promoter hypermethylation and result in loss of function

NOTE: gain of function mutations in cyclin or Cdk, or decreased CDKI activity have similar effect

Question 16

Retinoblastoma

Answer 16

13q
most common ocular malignancy in childhood
1:3 have germline mutation in Rb protein
Presentation: Leukocoria, strabismus, uveitis, glaucoma
“Leukocoria and loss of red reflex

Question 17

Adenomatous polyposis coli (APC) gene

Answer 17

Normally inhibits beta catenin (transcription factor) and thus inhibits transcription. Release B-catenin in response to WNT signaling.
Mutation results in beta catenin accumulation and thus growth promotion
Seen in 70% of sporadic colon cancers
*WNT signaling: controls cell fate, adhesion, and polarity

Question 18

Familial Adenomatous polyposis

Answer 18

5q
AD APC gene mutation leading to inappropriate WNT signaling
100s-1000s of polyps develop in colon by early 20s. Develop cancer by age 35-50

Question 19

p53

Answer 19

Tumor suppressor: guardian - monitors cellular stress
most frequently mutated gene in human caner
Regulates cell cycle progression, DNA repair, cellular senescence, and apoptosis
o Anoxia, DNA damage, oncogene signaling →ATM/ATR kinases phosphorylates p53→active
o Cell cycle arrest at G1/S checkpoint→either repair or apoptosis
MDM2 targets p53 for degredation

Question 20

Li Fraumeni syndrome

Answer 20

AD germline mutation
One p53 allele mutated –> cancer syndrome
25x increase in cancer risk by age 50

Question 21

Lynch syndrome

Answer 21

MSH2, MLH1 mutation

Question 22

Von Hippel-Lindau Syndrome

Answer 22

o AD mutation in VHL protein, which normally regulates ubiquitination
o Result: defective or absent VHL → accumulation of undegraded products
o Clinical presentation: Retinal and CNS hemangioblastomas
o Pheochromocytomas
o Cysts in kidneys and pancreas

Question 23

Down syndrome

Answer 23

Early onset alzheimers (additional APP + SOD1)
Chromosome 21 – trisomy is primary cause. However, robertsonian translocation “rob (14,21) (q14, q21)” is cause in small number of cases. Results in triploid
Parent pass on normal 21 and the 21,14 combo. Then other parent passes normal 21 and patient is effectively triploid
Presentation: epicanthal folds, dysplastic ears, horizontal palmar crease, redundant neck skin, short trunk
Comorbidities: duodenal atresia, trachesophageal fistula, leukemia

Question 24

Turner syndrome

Answer 24

45 XO - Short stature, webbed neck

lymphedema in hands and feet, skeletal abnormalities, congenital heart defects, infertility

Question 25

Patau Syndrome

Answer 25

47, +13 (think - Puberty, 13)
intellectual disability, microcephaly, microphtalmia, polydactyly, cleft lip and palate
renal defects and cardiac abnormalities
Die before age 1

Question 26

Fragile X syndrome

Answer 26

X-linked DOMINANT
CGG trinucleotide repeat in FMR1 gene leading to hypermethylation and decreased expression
Macroorchidism in males (enlgared testes after puberty), large ears, prominent jaw and forehead

Question 27

Klinefelter syndrome

Answer 27

47, XXY
male with impaired sexual development, small testes unable to produce sufficient testosterone–>delay/incomplete puberty, gynecomastia, micropenis, undistended testes, infertility, tall

Question 28

Neurofibromatosis 2

Answer 28

bilateral acoustic neuromas, juvenile cataracts, meningiomas and ependymomas – effects 2 eyes, 2 ears, 2 parts of brain, chromosome 22

Question 29

Von hippel lindau

Answer 29

3p (3 letters)
VHL regulates HIF1 - mutated protein cant bind
angiomas, hemangioblastomas of CNS retina and spine, phepchromocytoma, bilateral renal cell carcinoma

Question 30

Neurofibromatosis 1

Answer 30

17, AD
Neurofibromin (negative regualtor of RAS) is mutated
Von Recklinghausen (17 yo are reckless)
cafe au lait spots (freckling of skin), neurofibromas, Lisch nodules, increased risk for astrocytomas