Molecular Genetics Syndromes

Question 1

What is most common cause of infant mortality?

Answer 1

Sma

Question 2

What is the clinical phenotype of sma?

Answer 2

Muscle weakness and progressive loss of movement caused by deterioration of motor neurons. Often legs first

Question 3

What are the different types of sma?

Answer 3

Type 1: most severe. Type 2: less severe, type 3: mildest of kids, type 4: adult onset. Also prenatal and atypical types. I’m

Question 4

Phenotype of sma type 1

Answer 4

Profound hypotonia, never able to sit unaided. Most die by 2 years of severe respiratory problems

Question 5

Phenotype of sma type 2

Answer 5

Can sit , some stand but not walk. Care improvements mean many live to adulthood

Question 6

Mode of inheritance of sma

Answer 6

Autosomal recessive sma, uba1 gene is X linked, vapB gene causes adult onset sma and is autosomal dominant

Question 7

What is the range of copies of smn2? What effect does the different sizes cause?

Answer 7

0-5. More copies means less severe phenotype

Question 8

Protein encoded by smn1 and 2

Answer 8

Survival motor neuron protein - important for Motor neuron maintainance

Question 9

Mechanism of disease of sma

Answer 9

Smn1 mutation leads to a shortage of SMN protein causing motor neurons to die. Additional copies of smn2 can replace some of lost protein which is why increased smn2copies mean milder phenotype

Question 10

Genetic abnormalities seen in smn1 that cause sma

Answer 10

95-98% are homozygous for a deletion in exon 7 in both copies of smn1. 2-5 % are compound heteros with the deletion of exon7 and another interagenic activating mutation of smn1.

Question 11

Carrier freq of sma

Answer 11

1/40-60

Question 12

Where is fraxA located

Answer 12

Xq27.3

Question 13

Role of FMR1 protein

Answer 13

Shuttles mRNA round cell, development of synapses, exp in many tissues inc brain and gonads, regulate transcription of other proteins

Question 14

Example of toxic Gof phenotype

Answer 14

Fxtas and pof - fmr1

Question 15

% fragile site at xq27.3,seen by g Bandung

Answer 15

2-40%

Question 16

Fmr1 Repeat sequence and numbers of each seen in normal, pm and fm

Answer 16

CGG in 5’ UTR. 200 fm

Question 17

What other repeat sequence decrease risk of increase of fmr1 pm to fm?

Answer 17

2 or more AGG interspersed repeats decrease transmission risk

Question 18

% fm fmr1 that is mosaic with pm

Answer 18

20% either meth or size mosaic

Question 19

Number of permutation CGG repeats in fmr1 with Greatest risk to develop pof

Answer 19

80-100. Non linear rship between repeat number and risk of pof

Question 20

% pof due to fmr1 permutation this can conceive normally

Answer 20

5-10%

Question 21

Repeat sequence expanded in FraxE

Answer 21

Gcc

Question 22

Genetic basis of gene sequence changes in friedrichs ataxia

Answer 22

98% homozygous for GAA rpts expansion of FXN gene at 9q13. Loss of function. AR. Interspersed repeats = stabilise. 2% have repeat expansion on one allele and a point mutation or exon deletion on other- these have later onset

Question 23

Number of repeats in FRDA for normal, intermediate and affected

Answer 23

GAA repeats. Normal 70-100 ( 600-12000 most common).

Question 24

Phenotype of friedrichs ataxia

Answer 24

Progressive multi-systemic degenerative disease. Slurred speech, weak mouth, progressive ataxia , gait, muscle weakness. Usually paraplegic in 10 years.

Question 25

Incidence and carrier freq of friedrichs ataxia

Answer 25

1/50,000 and 1/60-100

Question 26

Mean age onset of friedrichs ataxia and mean age of death

Answer 26

10-15. Death by mean of 38 usually cardiac

Question 27

What is consequence of point mutations on both FXN alleles in friedrichs ataxia

Answer 27

Embryonic lethality

Question 28

How does transmission of GAA repeat in friedrichs ataxia differ between male and female

Answer 28

Female: ass with expansions and contractions. Male ass primarily with contractions

Question 29

What are triplet repeat disorders

Answer 29

Dynamic mutations. Phenotype when reach s certain threshold

Question 30

Example. Of loss of function triplet repeat disorder

Answer 30

Friedrichs ataxia

Question 31

Example gain of function triplet repeat disorder

Answer 31

Huntington disease, myotonic dystrophy

Question 32

Genetic basis of Huntington disease

Answer 32

Polyglutamine repeat disorder. AD. CAG repeats. 6-34 repeats is normal. 36-121 repeats is affected. Mostly male inheritance. Homo and hetero have same phenotype. Deletions in hd gene do not cause hd!

Question 33

Phenotype of Huntington disease

Answer 33

Progressive motor disability. Mental disturbance issues (decreased cognitive ability and depression). Average onset age 40

Question 34

Triplet repeat disorders showing anticipation

Answer 34

Fragile X, Huntington disease

Question 35

Genetic basis of Huntington disease

Answer 35

AD, rna mediated repeat disorder. DMPK 3’ UTR. CTG repeats. Length of repeat correlate with severity/onset

Question 36

Range of repeat sizes in huntingtons disease

Answer 36

N- 5-34, PM: 34-49, FM: > 50