M2M Genetic Diseases

Question 1

hereditary neuropathy with liability to pressure palsies (HNPP)

mode of inheritance

Answer 1

autosomal dominant

Question 2

hereditary neuropathy with liability to pressure palsies (HNPP)

mechanism

Answer 2

loss of function: deletion of PMP22 gene due to unequal crossing-over

Question 3

PMP22

function

Answer 3

integral glycoprotein in nerves

Question 4

hereditary neuropathy with liability to pressure palsies (HNPP)

clinical presentation

Answer 4

temporary (usually reversible) neuropathy upon applied pressure to nerves

limbs may “go to sleep” for hours, days or months

onset at 20-30 years old

Question 5

osteogenesis imperfecta type 1

mode of inheritance

Answer 5

autosomal dominant

Question 6

osteogenesis imperfecta type 1

mechanism

Answer 6

loss of function: nonsense frameshift in COL1A1, causes unstable mRNA

Question 7

COL1A1

Answer 7

implicit in collagen strength

Question 8

osteogenesis imperfecta type 1

clinical presentation

Answer 8

brittle bones, increased fractures, blue sclerae, normal stature, progressive hearing loss in adulthood

Question 9

charcot-marie-tooth type 1A

mode of inheritance

Answer 9

autosomal dominant

Question 10

charcot-marie-tooth type 1A

mechanism

Answer 10

gain of function: duplication of PMP22 gene on chr. 17p11.2

Question 11

charcot-marie-tooth type 1A

clinical presentation

Answer 11

demyelinating motor and sensory neuropathy, lower extremity weakness, muscle atrophy and mild sensory loss, hammertoes deformity

Question 12

osteogenesis imperfecta types II, III, IV

mode of inheritance

Answer 12

autosomal dominant

Question 13

osteogenesis imperfecta types II, III, IV

mechanism

Answer 13

novel property mutation: COL1A2 protein acquires new property due to new/different folding, forming collagen trimers

classified as a problem of monomer assembly into homodimer

Question 14

osteogenesis imperfecta types II, III, IV

clinical presentation

Answer 14

brittle bones, increased fracture, blue sclerae

type II is much more severe, usually lethal in perinatal period

Question 15

huntington’s disease

mode of inheritance

Answer 15

autosomal dominant

NOTE: can also be autosomal recessive or X-linked

Question 16

huntington’s disease

mechanism

Answer 16

polyglutamate disease: increased CAG repeats in huntington gene (>40 penetrant,

Question 17

huntington’s disease

clinical presentation

Answer 17

progressive neurodegenerative disorder with adult onset, chorea, death within 15 years of onset

Question 18

myotonic dystrophy 1

mode of inheritance

Answer 18

autosomal dominant

Question 19

myotonic dystrophy 1

mechanism

Answer 19

increased CTG repeats in 3’ UTR of DMPK gene

Question 20

myotonic dystrophy 1

clinical presentation

Answer 20

droopy eyes, intellectual difficulty, hypotonia

Question 21

achondroplasia

mode of inheritance

Answer 21

autosomal dominant, incomplete dominance

Question 22

achondroplasia

mechanism

Answer 22

gain of function: Gly380Arg mutation in FGFR3 gene

receptor normally inhibits bone growth; defective receptor is always on and constantly inhibiting bone growth, leading to shortened limbs

de novo mutations occur almost exclusively on paternal germline and increase with paternal age

homozygous state is lethal, only see heterozygotes (incomplete dominance)

Question 23

FGFR3

Answer 23

hotspot for mutations

Question 24

achondroplasia

clinical presentation

Answer 24

short stature, rhizomelic limb shortening (proximal limbs shorter than distal limbs), large head with frontal bossing (prominent forehead), megalencephaly, “trident” hand, spinal cord compression (small cranial foramina)

3-7% die suddenly during first year

Question 25

neurofibromatosis type 1

mode of inheritance

Answer 25

autosomal dominant

Question 26

neurofibromatosis type 1

mechanism

Answer 26

mutation on chromosome 17 in NF1 gene coding for neurofibroma protein

Question 27

neurofibromatosis type 1

clinical presentation

Answer 27

cafe au last spots (>6 of clinical significance), axillary and inguinal freckling, multiple neurofibromas, lisch nodules (spots/bumps on eye)

100% penetrance, variable expressivity

Question 28

marfan syndrome

mode of inheritance

Answer 28

autosomal dominant

Question 29

marfan syndrome

mechanism

Answer 29

mutation in FBN1 gene coding for fibrillin

Question 30

marfan syndrome

clinical presentation

Answer 30

connective tissue disorder

ocular, skeletal and cardiovascular manifestations, risk of aortic aneurysm, appear tall and skinny, long-limbed, hypermobile joints, pectus excavatum/carnatum

Question 31

ad polycystic kidney disease

mode of inheritance

Answer 31

autosomal dominant

Question 32

ad polycystic kidney disease

mechanism

Answer 32

mutation in ADPKD-1 (85%; chromosome 16) or ADPKD-2 (14.5%, chromosome 4)

locus heterogeneity - mutation in more than one locus can cause the same clinical condition

Question 33

ad polycystic kidney disease

clinical presentation

Answer 33

enlarged kidneys with multiple cysts, end stage renal disease, extra-renal cysts (i.e. in pancreas), intracranial aneurysms

Question 34

familial hypercholesterolemia

mode of inheritance

Answer 34

autosomal dominant

Question 35

familial hypercholesterolemia

mechanism

Answer 35

mutations in the gene encoding LDL receptor

cannot clear LDL from bloodstream

Question 36

familial hypercholesterolemia

clinical presentation

Answer 36

high cholesterol levels, deposition of cholesterol throughout the body, premature coronary artery disease