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Flashcards in Autosomal dominant Deck (71):
1

Achondroplasia
inheritance

autosomal dominant

2

Achondroplasia
incidence

1/15,000-40,000

3

Achondroplasia
mutation rate?

80%

4

Achondroplasia
penetrance?

100%

5

Achnodroplasia
Clinical manifestations

Short
Rhizomelic limb shortening (proximal shortening)
short fingers
genu varum (bow legs)
large head / frontal bossing
midfacial retrusion
small foramen magnum / craniocervical instability

6

Achondroplasia
Mutated gene?

FGFR3
Fibroblast growth factor receptor 3

7

What does FGFR3 do?

Regulates bone growth by limiting the formation of bone from cartilage

8

FGF43 locus?

4p16.3 nucleotide 1138

9

Achondroplasia mutation?

nucleotide 1138 missense
1138G>A
amino acid substitution
Gly380Arg

10

Achondroplasia mutation consequence

Mutation increases the activity of the protein, interfering with skeletal development

11

What is special about the achondroplasia mutation 1138

The 1138 of FGFR3 has the highest known mutation rate in man

12

Men and de novo autosomal dominant conditions?

Men over the age of 40 are noted to have hgiher rate of children with de-novo autosomal dominant conditions - i.e. Achondroplasia

13

Paternal age effect

old dudes yield autosomal dominant mutated sperm

14

4 syndromes associated with paternal age effect

Achondroplasia
Apert syndrome
Crouzon syndrome
Pfeiffer syndrome

15

Retinoblastoma
what is it?

autosomal dominant condition
causes malignant tumor of retina

16

retinoblastoma incidence

1/15,000

17

retinoblastoma gene?

RB1 gene on chromsome 13

18

Retinoblastoma gene product role?

Retinoblastoma associated protein regulates the cell cycle

19

Retinoblastoma penetrance?

90%

20

Notable clinical finding in retinoblastoma?

no reflection of red retina - looks white

21

Neurofibromatosis Type 1 (NF1)
inheritance
frequency
mutation rate

autosomal dominant
1/3000
50% new mutation

22

NF-1
expressivity?

variable

23

NF-1 Diagnostic criteria
2 or more of the following

6 or more cafe au lait
2 or more neurofibromas
1 plexiform neurofibroma
freckling in axillary or inguinal area
optic glioma
2 or more Lisch nodules
distinctive osseous lesions
affected first degree relative

24

NF1 mutation?

NF1 gene

25

NF1 gene is what?

Neurofibromin - tumor suppressor gene

26

NF1 locus

17q11.2

27

NF1 type of mutation

loss of function

28

NF1 mutation?

over 1000 mutations have been described

29

What is unique about NF1 and autosomal dominant categorization

Must have a mutation in both genes to show phenotype - but inevitably you will get a second random one

30

Tuberous Sclerosis
inheritance?
incidence
expressivity
mutation rate?
penetrance?

autosomal dominant

1/6000

variable expressivity

1/3 inherited 2/3 de novo

fully penetrant

31

Tuberous sclerosis
skin findings?

hypopigmented patches
angiofibroma
shagreen patch
ungual fibroma

32

Tuberous sclerosis
kidneys

renal cysts
renal angiomyolipomas

33

Tuberous sclerosis
lungs

lymphangioeiomyomatosis
lung muscle cells multiply abnormally

34

Tuberous sclerosis
heart

cardiac rhabdomyoma (in infants)

35

Tuberous sclerosis
CNS

Subependymal nodules
Subependymal giant cell astrocytomas (SEGAs)
Other cortical dysplasias

Seizures

36

Tuberous sclerosis
Neuropsychiatric

cognitive impairment
autism
adhd

37

Tuberous sclerosis
clinical criteria - two major features or one major and 2 minor

Major features

angiofibroma
cardiac rhabdomyoma
cortical dysplasia
hypomelanotic macules
Lymphangioleiomyomatosis
multiple retinal nodular harmartomas
renal angiomyolipoma
shagreen patch
subependymal nodule
SEGA
ungual fibroma

38

Tuberous sclerosis

Minor features

confetti skin lesions
dental enamel pits
intraoral fibromas
multiple renal cysts
nonrenal hamartomas
retinal achomic patch

39

Tuberous sclerosis
Mutation?

TSC1,
TSC2

40

What do TSC1 and TSC2 do?

Encode hamartin and tuberin proteins

41

What do the hamartin and tuerin proteins encoded by TSC1 and TSC2 do?

regulate cell growth and proliferation

42

Where are the TSC1 and TSC2 genes effected in tuberous sclerosis located?

9 and 16

43

What types of mutations in TSC1 and TSC2 cause tuberous sclerosis?

loss of function

44

Osteogenesis Imperfecta type 1
Inheritance?
incidence?
expressivity?

autosomal dominant
1/30,000-50,000
variable

45

Osteogenesis imperfecta
Clinical?

multiple fractures
mild short stature
adult onset hearing loss
blue sclera

46

Osteogenesis imperfect mutation?

COL1A1
Collagen type 1 alpha 1

47

OI mutation = COL1A1
locus?

7q21.3

48

OI-typeI
mutated COL1A1
Consequence?

Reduced production of pro-alpha 1 chains
Reduces the type 1 collagen production by 1/2

49

Marfan syndrome
inheritance
incidence
mutation rate
expressivity

AD

1/5000

25% NEW

Variable

50

Marfan syndrome
clinical

Systemic disorder of connective tissue
ocular
skeletal
cardiovascular

51

Marfan diagnosis
no family history

aortic root enlargement
plus one...
ectopia lentis
FBN1 mutation
systemic score>7

52

Marfan diagnosis
family history

any...
ectopia lentis
systemic score >7
aortic root enlargement

53

Most notable clinical manifestations of Marfan's

Aortic root enlargement
Scoliosis
Ectopia lentis
Thumb and wrist sign
Pectus excavatum

54

Marfan mutation in?

FBN1
Firbillin-extracellular matrix protein

55

FBN1
Locus?

15q21.1

56

Marfan mutation type?

Dominant negative

57

Marfan mutation consequence

severe reduction in the number of microfibrils

58

Trinucleotide repeat disorders

Expansion of segment of DNA consisting of three or more nucleotides

Slipped mispairing

Anticipation

Parental Transmission Bias

59

Trinucleotide repeat
mode of inheritance?

AD,
AR
X linked

60

Slipped mispairing

Mispairing of bases in regions of repetitive DNA replication couple with inadequate DNA repair

As the repeat grows longer, the probability of subsequent mispairing increases

In germ cells

61

Huntington Disease
inheritance
incidence

Autosomal dominant
1/10,000

62

Huntington disease
Parental bias

Early onset - paternal
later onset - maternal

63

Huntington disease
Clinical

Progressive neuronal degeneration causing motor, cognitive, and psychiatric disturbances

64

Huntington
age of onse

35-44

65

Huntington death?

15 yr post onset

66

Huntington
Mutation

HTT
Huntingtin
Cromosome 4p16.3
The expansion of glutmaine may cause an altered structure or biochemical protein property
CAG

67

CAG Repeat threshold?

>39 full penetrance
>60 juvenile onset

68

Myotonic dystrophy type 1
repeat?
incidence
parental bias?

CTG
1/20,000
Maternal

69

Myotonic dystrophy 1
Clinical

Adult onset muscular dystrophy
Progressive muscle wasting and weakness
myotonia
cataracts
cardiac conduction defects

70

Myotonic dystrophy mutation?

DMPK
Myotonic dystrophy protein kinase
19q13.3
plays important role in muscle heart and brain

71

Myotonic dystrophy
CTG threshold?

5-34 normal
34-49 premutation
>50 full mutation with 100% penetrance