Case Studies

Question 1

Achondroplasia

Phenotypic features?

Answer 1

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

Question 2

Achodroplasia risk of death?

Answer 2

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

Question 3

Achondroplasia

Inheritance?

Answer 3

Autosomal dominant

Mutation in FGFR3

Question 4

Achondroplasia

Mutated gene?

Answer 4

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

Question 5

Achondroplasia

Type of mutation?

Answer 5

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

Question 6

What happens in achondroplasia when FGFR3 is independently on?

Answer 6

Inappropriately inhibits bony growth

Question 7

Achondroplasia due to de novo mutation in whose germline?

Answer 7

Father!

And increase with age

Question 8

Mutations in FGFR gene frequently lead to?

Answer 8

Issues with boney growth and bone fusion

Question 9

FGFR3 Gly380Arg –>

Answer 9

Gain of function leading to achondroplasia

Question 10

Congenital deafness (From birth) is usually ?

Answer 10

Recessive

Question 11

Progressive childhood deafness is usually?

Answer 11

Dominant

Question 12

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

Answer 12

3/4 non

1/4 syn

Question 13

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

Answer 13

GJB2

Question 14

GJB2 implicated in ?

Answer 14

1/2 all recessive nonsyndromic deafness

Question 15

Syndromic deafness

retinitis pigmentosa suggests

Answer 15

Usher (AR) syndrome

Question 16

Syndromic deafness

Thyroid goiter suggests?

Answer 16

Pendred (#2 AR) syndrome

Question 17

Syndromic deafness

sudden death suggests

Answer 17

Jurvell and Lange-Nielson (AR) syndrome

Question 18

Syndromic deafness

white forelock suggests?

Answer 18

Waardenburg (#1 AD) syndrome

Question 19

Syndromic deafness

8th nerve schwannomas suggests?

Answer 19

NF type II

Question 20

What percent of congenital deafness is genetic?

Answer 20

50

Question 21

What percent of genetic congenital deafness is nonsyndromic?

Answer 21

70

Question 22

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

Answer 22

75-85

Question 23

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

Answer 23

DFNB1 (GJB2)

Question 24

Severe congenital deafness is typically due to?

Answer 24

Recessive inheritance

Question 25

nonsyndromic progressive deafness with childhood onset is typically due to?

Answer 25

Autosomal dominant

Question 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?

Answer 26

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

Question 27

Most common category of congenital deafness?

Answer 27

Genetic, autosomal recessive, nonsyndromic due to GJB2

Question 28

Fragile X syndrome | Effected gene?

Answer 28

FMR1 gene

Question 29

Fragile X syndrome | What is the cause?

Answer 29

Full triple repeat expansion

Question 30

What is FXTAS?

Answer 30

Premutation due to partial triplet repeat expansion in FMR1

Question 31

What is POF

Answer 31

Premutation repeat expansion in FMR1

Question 32

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

Answer 32

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

Question 33

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

Answer 33

Hypermethylated | Reduced/Absent FMRP protein

Question 34

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

Answer 34

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

Question 35

Haplotype FMR1 and risk?

Answer 35

AGG nearby reduces risk

Question 36

Which sex expansion risk

Answer 36

female (maternally unstable)

Question 37

Where is triplet repeat expansion in fragile x?

Answer 37

5" UTR

Question 38

Fragile X | Mutation type?

Answer 38

Loss of function

Question 39

Fragile X tremor ataxia | Mutation type?

Answer 39

Gain of function

Question 40

Huntington disease | Mutation type

Answer 40

Novel function