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1

Achondroplasia
Phenotypic features?

Rhizomelic short stature
Spinal cord compression
Brainstem compression (10%)

2

Achodroplasia risk of death?

Between 3-7% of patients die unexpectedly in first year because of brainstem compression (central apnea) or obstructive apnea

3

Achondroplasia
Inheritance?

Autosomal dominant
Mutation in FGFR3

4

Achondroplasia
Mutated gene?

FGFR3 (fibroblast growth factor receptor 3)
Two mutations (both converting Gly380Arg) account for 99%

5

Achondroplasia
Type of mutation?

Gly380Arg
Gain of function
Cause ligand independent activation of FGFR3 (a transmembrane tyrosine kinase receptor)

6

What happens in achondroplasia when FGFR3 is independently on?

Inappropriately inhibits bony growth

7

Achondroplasia due to de novo mutation in whose germline?

Father!
And increase with age

8

Mutations in FGFR gene frequently lead to?

Issues with boney growth and bone fusion

9

FGFR3 Gly380Arg -->

Gain of function leading to achondroplasia

10

Congenital deafness (From birth) is usually ?

Recessive

11

Progressive childhood deafness is usually?

Dominant

12

Of genetic congenital deafness, what fraction is syndromic and what fraction is nonsyndromic (meaning there is no other issue)

3/4 non
1/4 syn

13

Which mutation accounts for 1/2 of all nonsyndromic autosomal recessive deafness?

GJB2

14

GJB2 implicated in ?

1/2 all recessive nonsyndromic deafness

15

Syndromic deafness
retinitis pigmentosa suggests

Usher (AR) syndrome

16

Syndromic deafness
Thyroid goiter suggests?

Pendred (#2 AR) syndrome

17

Syndromic deafness
sudden death suggests

Jurvell and Lange-Nielson (AR) syndrome

18

Syndromic deafness
white forelock suggests?

Waardenburg (#1 AD) syndrome

19

Syndromic deafness
8th nerve schwannomas suggests?

NF type II

20

What percent of congenital deafness is genetic?

50

21

What percent of genetic congenital deafness is nonsyndromic?

70

22

Of nonsyndromic congenital genetic deafness, what percent is autosomal recessive?

75-85

23

Of autosomal recessive congential nonsyndromic deafness, which gene is reponsible for 1/2

DFNB1 (GJB2)

24

Severe congenital deafness is typically due to?

Recessive inheritance

25

nonsyndromic progressive deafness with childhood onset is typically due to?

Autosomal dominant

26

To calculate risk from pedigree, must be certain you are not dealing with genetic heterogeneity, e.g. the risk of two deaf people (homozygous recessive for their deaf gene) to have a deaf child is?

15 %
Because you don't know if their same gene is effected?

27

Most common category of congenital deafness?

Genetic, autosomal recessive, nonsyndromic due to GJB2

28

Fragile X syndrome
Effected gene?

FMR1 gene

29

Fragile X syndrome
What is the cause?

Full triple repeat expansion

30

What is FXTAS?

Premutation due to partial triplet repeat expansion in FMR1

31

What is POF

Premutation repeat expansion in FMR1

32

What is the function of the FMRP protein (encoded by FMR1 gene - Fragile X associated)

Expressed abundently in neurons - may chaperone mRNAs from nucleus to translational machinery - both protein and mRNA have function

33

FMR1 full mutation --> fragile X (>200) what happens with the gene?

Hypermethylated
Reduced/Absent FMRP protein

34

FMR1 premutation --> FXTAS/POF (59-200) what happens to the gene?

Note hypermethylated
Increased FMRP RNA - may be toxic to the cell

35

Haplotype FMR1 and risk?

AGG nearby reduces risk

36

Which sex expansion risk

female (maternally unstable)

37

Where is triplet repeat expansion in fragile x?

5" UTR

38

Fragile X
Mutation type?

Loss of function

39

Fragile X tremor ataxia
Mutation type?

Gain of function

40

Huntington disease
Mutation type

Novel function