Molecular Basis of Genetic Disease

Question 1

What muddles the Genotype-Phenotype correlation in Mendelian disorders? (4)

Answer 1

hetergeneity
pleiotropy
variable expressivity
penetrance

Question 2

define phenotypica heterogeneity

Answer 2

different mutations in same gene give different disease

Question 3

define allelic hetergeneity

Answer 3

different mutations in same gene give same disease

Question 4

define locus hetereogeneity

Answer 4

mutations in different disease give same disease

Question 5

CFTR and phenotypic predictions

Answer 5

can predict pancreatic function

can’t predict severity of lung disease

Question 6

CFTR - Genotype/Phenotype and CBAVD and Pancreatic Sufficiency

Answer 6

CBAVD most mild, usually a 5T

any CFTR expression will give PS

Question 7

give 4 mechanisms of variable expressivity

Answer 7

epistasis (modifier genes)
environment
polygenic background
cis polymorphisms

Question 8

CFTR - variable expressivity and modifier genes

Answer 8

TGFbeta high expression, mannose binding lectin 2 low expression affects phenotype

Question 9

What type of mendelian disorders is incomplete penetrance found most commonly?

Answer 9

autosomal dominant

Question 10

Give 5 mechanisms for dominant inheritance

Answer 10

gain of fxn
haploinsufficiency
dominant-negative
loss of heterozygosity
sporadic events

Question 11

How is DMD/BMD inherited?

Answer 11

X linked

Question 12

what is the clinical spectrumm of dystrophinopathies?

Answer 12

dilated cardiomyopathy –> BMD –> DMD

Question 13

how do you detect dystrophinopathies?

Answer 13

PCR or array CGH or muscle biopsy

Question 14

what are the clinical features of BMD

Answer 14

calf hypertrophy, wheel chair use by 16 maybe, dilated cardiomyopathy, normal cognition, elevated CK

Question 15

what are the clinical features of DMD

Answer 15

calf hypertrophy, wheelchair by 13, cardiomyopathy, respiratory failure, progressive muscle weakness, cognitive disability, elevated CK, loss of motor skills

Question 16

genotype-phenotype in DMD/BMD

Answer 16

DMD - large deletions, small deletions/insertions, large duplications, out of frame. no protein produced

BMD - small deletions, in frame, missense. some protein produced

Question 17

inheritance in DMD/BMD

Answer 17

males have 0 fitness (lethal)

deletions in oogenesis, point mutations in spermatogenesis

1/3 de novo, 2/3 inherited from mom

Question 18

Germline mosaicism increases recurrence risk in what type of mendelian inherited disorders?

Answer 18

x linked

autosomal dominant

Question 19

what are the 4 criteria for germline mosaicism

Answer 19

parents phenotypically normal
parents test negative for the condition of the blood
disorder is highly penetrant XL/AD
two affected children

Question 20

BMD/DMD carrier effects

Answer 20

skewed X-inactivation
8% have dilated cardiomyopathy
50% have abnormal echocardiograms
all have elevated CK levels

Question 21

what are the 7 clinical diagnostic criteria in neurofibromatosis type 1?

Answer 21

cafe au lait spots (min. 6)
axillary/inguinal freckles
neurofibromas (2)
lisch nodules (2)
skeletal muscle abnormality
optic glioma
family history NF1

Question 22

what genetic phenomena occur in NF1?

Answer 22

age related penetrance (tumor supp)
variable expressivity (diff. severity in family)
allelic heterogeneity (large gene)
pleiotropy
somatic mosaicism (segmental, germline, both)

Question 23

recurrence risk in NF1?

Answer 23

somatic mosaicism - population level

germline - risk increases

Question 24

recurrence risk in DMD for germline mosaic mother

Answer 24

15% for GM x 50% that allele is passed on = 8% for affected boy/carrier girl