Genetic Anticipation

Question 1

What is genetic anticipation?

Answer 1

Increased frequency of affected relatives, increased severity of phenotype, or earlier age of onset in successive generations

Question 2

What are the two types of trinucleotide repeat disorders?

Answer 2

There are either in the non-coding regions or the coding regions.

Question 3

What gene causes fragile X and where is it?

Answer 3

FMR1 gene on Xq27.3; Fragile X is the most common form of cognitive impairment; X-linked inheritance

Question 4

What are the physical features of Fragile X?

Answer 4

Macrocephaly, Large ears, gaze avoidance

Question 5

Relate fragile X to gene anticipation.

Answer 5

That the risk of expressing cognitive impairment could also be dependent on position of an individual in a pedigree. — i.e.: the daughter of an unaffected male carrier was more likely to have affected offspring, than the mother of the unaffected male carrier

Question 6

Relate the number of repeats to severity of fragile x

Answer 6

The greater the number of repeats the greater the chance that an individual will be affected

Question 7

What is a premutation?

Answer 7

An expansion of a repeat but not significant enough to cause the phenotype of the disorder.

Question 8

What is Myotonic Dystrophy?

Answer 8

CTG expansion in the 3’UTR of the DMPK gene. The DMPK gene codes for a myotonin protein kinase
Prevalence 1:100,000

Question 9

How does the number of the repeats affect the severity of Myotonic Dystrophy?

Answer 9

Symptoms worsen with more repeats and earlier onset.
Cataracts, myotonia, balding.
Cardiac arrythmias, pulmonary weakness. (See coursepack)

Question 10

What is Friedrich’s Ataxia?

Answer 10

Autosomal Recessive Disease that causes progressive neurological deterioration commencing during puberty.

• GAA triplet repeat expansion in INTRON of Frataxin gene
• Results in gene silencing, or lack of transcription of the frataxin mRNA. Frataxin localizes to mitochondrial membrane

Question 11

What are the symptoms of Friedrich’s Ataxia?

Answer 11

Ataxia, Dysarthria, diabetes, arrythmia

Question 12

Relate anticipation to Friedrich’s Ataxia

Answer 12

Larger expansions occur as gene is passed through generations with earlier onset and sever sypmtoms. Overall phenotype corresponds with the length of the shorter of the two frataxin alleles.

Question 13

Describe trinucleotide repeats in the coding regions of autosomal genes.

Answer 13

Polyglutamine diseases [CAG = codon for glutamine (Q)] affecting particular subsets of neurons.
-Polyglutamine causes protein aggregation in the nucleus.

Question 14

Describe Huntingtons Disease

Answer 14

Expansion primarily occurs after paternal inheritance. Progressive disorder of motor, cognitive and psychiatric disturbances.

Question 15

What and where is the repeat in huntington’s disease

Answer 15

Expansion of CAG trinucleotide sequence in the HD gene (Huntingtin) causes production of abnormal “huntingtin” protein, (expanded polyglutamine tract) which eventuates over time in neuronal dysfunction

Question 16

Which diseases are trinucleotide repeats in non-coding regions?

Answer 16

Fragile X syndrome, Myotonic Dystrophy, Friederich Ataxia, Spinocerebellar ataxia type 8 and 12

Question 17

Which diseases are in coding regions?

Answer 17

Huntington’s disease, Spinobulbar muscular atrophy, Haw-River syndrome, All spinocerebellar ataxias except for 8 and 12.

Question 18

What is the etiology of fragile x syndrome?

Answer 18

Trinucleotide expansion of a CGG repeat triplet sequence in the promoter (5’ end) of the FMR1 gene.

Question 19

What happens when more than 200 repeats are detected in fragile X?

Answer 19

There will be methylation of the promoter and an inability to express the FMR1 mRNA and protein.

Question 20

Describe normal individuals in terms of Fragile X syndrome?

Answer 20

Normal individuals have a CGG triplet number is stable and under 40. As length increases, the probability of additional repeats also increases during meiosis and gamete production.

Question 21

Why or how are carrier females carrying full mutation affected or not affected?

Answer 21

There may be X-inactivation of the mutant X chromosome. OR the ‘active’ X-chromosome is carrying the CGG expansion in their brain cells and needs more time to develop.

Question 22

What are the normal and premutation repeat sizes for myotonic dystrophy?

Answer 22

Normal: 5-37
Premutation: 38-49
Important to note that the DMPK protein levels are unaffected, the problem appears to be with expanded RNA and processing.

Question 23

Compare the number of GAA repeats in a normal individual to an affected individual in Friedrich Ataxia.

Answer 23

Normal: 7-22 repeats of GAA.
Affected: More than 200 repeats of GAA.