Case Studies Flashcards
Achondroplasia
Phenotypic features?
Rhizomelic short stature Spinal cord compression Brainstem compression (10%)
Achodroplasia risk of death?
Between 3-7% of patients die unexpectedly in first year because of brainstem compression (central apnea) or obstructive apnea
Achondroplasia
Inheritance?
Autosomal dominant
Mutation in FGFR3
Achondroplasia
Mutated gene?
FGFR3 (fibroblast growth factor receptor 3) Two mutations (both converting Gly380Arg) account for 99%
Achondroplasia
Type of mutation?
Gly380Arg
Gain of function
Cause ligand independent activation of FGFR3 (a transmembrane tyrosine kinase receptor)
What happens in achondroplasia when FGFR3 is independently on?
Inappropriately inhibits bony growth
Achondroplasia due to de novo mutation in whose germline?
Father!
And increase with age
Mutations in FGFR gene frequently lead to?
Issues with boney growth and bone fusion
FGFR3 Gly380Arg –>
Gain of function leading to achondroplasia
Congenital deafness (From birth) is usually ?
Recessive
Progressive childhood deafness is usually?
Dominant
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
Which mutation accounts for 1/2 of all nonsyndromic autosomal recessive deafness?
GJB2
GJB2 implicated in ?
1/2 all recessive nonsyndromic deafness
Syndromic deafness
retinitis pigmentosa suggests
Usher (AR) syndrome
Syndromic deafness
Thyroid goiter suggests?
Pendred (#2 AR) syndrome
Syndromic deafness
sudden death suggests
Jurvell and Lange-Nielson (AR) syndrome
Syndromic deafness
white forelock suggests?
Waardenburg (#1 AD) syndrome
Syndromic deafness
8th nerve schwannomas suggests?
NF type II
What percent of congenital deafness is genetic?
50
What percent of genetic congenital deafness is nonsyndromic?
70
Of nonsyndromic congenital genetic deafness, what percent is autosomal recessive?
75-85
Of autosomal recessive congential nonsyndromic deafness, which gene is reponsible for 1/2
DFNB1 (GJB2)
Severe congenital deafness is typically due to?
Recessive inheritance
nonsyndromic progressive deafness with childhood onset is typically due to?
Autosomal dominant
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?
Most common category of congenital deafness?
Genetic, autosomal recessive, nonsyndromic due to GJB2
Fragile X syndrome
Effected gene?
FMR1 gene
Fragile X syndrome
What is the cause?
Full triple repeat expansion
What is FXTAS?
Premutation due to partial triplet repeat expansion in FMR1
What is POF
Premutation repeat expansion in FMR1
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
FMR1 full mutation –> fragile X (>200) what happens with the gene?
Hypermethylated
Reduced/Absent FMRP protein
FMR1 premutation –> FXTAS/POF (59-200) what happens to the gene?
Note hypermethylated
Increased FMRP RNA - may be toxic to the cell
Haplotype FMR1 and risk?
AGG nearby reduces risk
Which sex expansion risk
female (maternally unstable)
Where is triplet repeat expansion in fragile x?
5” UTR
Fragile X
Mutation type?
Loss of function
Fragile X tremor ataxia
Mutation type?
Gain of function
Huntington disease
Mutation type
Novel function
