Autosomal dominant Flashcards
Achondroplasia
inheritance
autosomal dominant
Achondroplasia
incidence
1/15,000-40,000
Achondroplasia
mutation rate?
80%
Achondroplasia
penetrance?
100%
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
Achondroplasia
Mutated gene?
FGFR3
Fibroblast growth factor receptor 3
What does FGFR3 do?
Regulates bone growth by limiting the formation of bone from cartilage
FGF43 locus?
4p16.3 nucleotide 1138
Achondroplasia mutation?
nucleotide 1138 missense
1138G>A
amino acid substitution
Gly380Arg
Achondroplasia mutation consequence
Mutation increases the activity of the protein, interfering with skeletal development
What is special about the achondroplasia mutation 1138
The 1138 of FGFR3 has the highest known mutation rate in man
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
Paternal age effect
old dudes yield autosomal dominant mutated sperm
4 syndromes associated with paternal age effect
Achondroplasia
Apert syndrome
Crouzon syndrome
Pfeiffer syndrome
Retinoblastoma
what is it?
autosomal dominant condition
causes malignant tumor of retina
retinoblastoma incidence
1/15,000
retinoblastoma gene?
RB1 gene on chromsome 13
Retinoblastoma gene product role?
Retinoblastoma associated protein regulates the cell cycle
Retinoblastoma penetrance?
90%
Notable clinical finding in retinoblastoma?
no reflection of red retina - looks white
Neurofibromatosis Type 1 (NF1)
inheritance
frequency
mutation rate
autosomal dominant
1/3000
50% new mutation
NF-1
expressivity?
variable
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
NF1 mutation?
NF1 gene
NF1 gene is what?
Neurofibromin - tumor suppressor gene
NF1 locus
17q11.2
NF1 type of mutation
loss of function
NF1 mutation?
over 1000 mutations have been described
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
Tuberous Sclerosis inheritance? incidence expressivity mutation rate? penetrance?
autosomal dominant
1/6000
variable expressivity
1/3 inherited 2/3 de novo
fully penetrant
Tuberous sclerosis
skin findings?
hypopigmented patches
angiofibroma
shagreen patch
ungual fibroma
Tuberous sclerosis
kidneys
renal cysts
renal angiomyolipomas
Tuberous sclerosis
lungs
lymphangioeiomyomatosis
lung muscle cells multiply abnormally
Tuberous sclerosis
heart
cardiac rhabdomyoma (in infants)
Tuberous sclerosis
CNS
Subependymal nodules
Subependymal giant cell astrocytomas (SEGAs)
Other cortical dysplasias
Seizures
Tuberous sclerosis
Neuropsychiatric
cognitive impairment
autism
adhd
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
Tuberous sclerosis
Minor features
confetti skin lesions dental enamel pits intraoral fibromas multiple renal cysts nonrenal hamartomas retinal achomic patch
Tuberous sclerosis
Mutation?
TSC1,
TSC2
What do TSC1 and TSC2 do?
Encode hamartin and tuberin proteins
What do the hamartin and tuerin proteins encoded by TSC1 and TSC2 do?
regulate cell growth and proliferation
Where are the TSC1 and TSC2 genes effected in tuberous sclerosis located?
9 and 16
What types of mutations in TSC1 and TSC2 cause tuberous sclerosis?
loss of function
Osteogenesis Imperfecta type 1
Inheritance?
incidence?
expressivity?
autosomal dominant
1/30,000-50,000
variable
Osteogenesis imperfecta
Clinical?
multiple fractures
mild short stature
adult onset hearing loss
blue sclera
Osteogenesis imperfect mutation?
COL1A1
Collagen type 1 alpha 1
OI mutation = COL1A1
locus?
7q21.3
OI-typeI
mutated COL1A1
Consequence?
Reduced production of pro-alpha 1 chains
Reduces the type 1 collagen production by 1/2
Marfan syndrome inheritance incidence mutation rate expressivity
AD
1/5000
25% NEW
Variable
Marfan syndrome
clinical
Systemic disorder of connective tissue
ocular
skeletal
cardiovascular
Marfan diagnosis
no family history
aortic root enlargement plus one... ectopia lentis FBN1 mutation systemic score>7
Marfan diagnosis
family history
any…
ectopia lentis
systemic score >7
aortic root enlargement
Most notable clinical manifestations of Marfan’s
Aortic root enlargement Scoliosis Ectopia lentis Thumb and wrist sign Pectus excavatum
Marfan mutation in?
FBN1
Firbillin-extracellular matrix protein
FBN1
Locus?
15q21.1
Marfan mutation type?
Dominant negative
Marfan mutation consequence
severe reduction in the number of microfibrils
Trinucleotide repeat disorders
Expansion of segment of DNA consisting of three or more nucleotides
Slipped mispairing
Anticipation
Parental Transmission Bias
Trinucleotide repeat
mode of inheritance?
AD,
AR
X linked
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
Huntington Disease
inheritance
incidence
Autosomal dominant
1/10,000
Huntington disease
Parental bias
Early onset - paternal
later onset - maternal
Huntington disease
Clinical
Progressive neuronal degeneration causing motor, cognitive, and psychiatric disturbances
Huntington
age of onse
35-44
Huntington death?
15 yr post onset
Huntington
Mutation
HTT Huntingtin Cromosome 4p16.3 The expansion of glutmaine may cause an altered structure or biochemical protein property CAG
CAG Repeat threshold?
> 39 full penetrance
>60 juvenile onset
Myotonic dystrophy type 1
repeat?
incidence
parental bias?
CTG
1/20,000
Maternal
Myotonic dystrophy 1
Clinical
Adult onset muscular dystrophy Progressive muscle wasting and weakness myotonia cataracts cardiac conduction defects
Myotonic dystrophy mutation?
DMPK
Myotonic dystrophy protein kinase
19q13.3
plays important role in muscle heart and brain
Myotonic dystrophy
CTG threshold?
5-34 normal
34-49 premutation
>50 full mutation with 100% penetrance