Unit 2: 14

Question 1

Fragile X syndrome

Answer 1

most common cause of inherited mental retardation and is an example of a disease resulting from dynamic mutations

Question 2

Hemoglobinopathies

Answer 2

example of a class of disease with many types of mutations and diseases of global importance

Question 3

Cystic Fibrosis

Answer 3

common autosomal recessive with very significant allelic heterogenity

Question 4

name the five types of molecular genetic diagnostic methods discussed in class

Answer 4

• carrier testing
• diagnosis
• prenatal diagnosis
• presymptomatic test
• prenatal exclusion

Question 5

What is the incidence and inheritance pattern of Fragile X?

Answer 5

• incidence 1/1250 male births
• incidence 1/2500 female births
• not the expected result of X linked dominant or recessive
• but it has been decided that it is an X linked dominant with reduced penetrance (80% in males and 30% in females)

Question 6

Phenotypic manifestations of Fragile X syndrome?

Answer 6

normal structues, broad forhead, elongated face, large prominant ears, strabismus, enlarged testicles, soft flesh skin, flat feet, hyperextensible joints, highly arched palate, mitral valve prolapse

Question 7

What are >99 % of Fragile X syndrome due to?

Answer 7

expansion of a CGG triplet repeat in the first exon and methylation of the FMR1 gene leading to deficiency of protein

Question 8

What are the three mutation classes of Fragile X syndrome?

Answer 8

• normal
• premutation
• full mutation

Question 9

What individual in the pedigree will tell you who is at the highest risk for Fragile X ?

Answer 9

probability of further expansion is related to size of expansion in female carrier

Question 10

What is Anticipation (or Sherman Paradox)?

Answer 10

refers to the anomalous pattern of inheritance of Fragile X syndrome, such that it seems to increase in frequency in every subsequent generation

Question 11

Discuss premutation classification in Fragile X

Answer 11

• females with premutation may have mild symptoms- premature ovarian failure
• “normal transmitting males” is a misnomer - as they may have mild symptoms and over a third of them will develop Fragile X assosciated tremor/ataxia (FXTAS) in later life -we can’t predict this either
• FXTAS is rare in females with premutation
• NTM may have FRAXA affected grandchildren with full mutation, but their daughters will have premutations

Question 12

What is thought to be the mechanism of premutation effects such as POF, and FXTAS?

Answer 12

• gain of function mutation

- RNA toxic -due to excess FMR1 mRNA

Question 13

Why does a premutation-carrying female have four bands (in gel electrophoresis) ?

Answer 13

methylation

Question 14

How are repeat length and instability related?

Answer 14

proportional - direct relationship

Question 15

Where do 5 alpha like genes cluster ?

Answer 15

Chromosome 16

Question 16

Where do 6 beta-like genes cluster?

Answer 16

Chromosome 11

Question 17

What is the normal structure of a molecule of hemoglobin?

Answer 17

there are two alpha and two beta chians each associated with a heme moiety.
as hemoglobin shifts from oxgenated to deoxygenated state, critical movement of the chains occurs

Question 18

Development of erythropoiesis in the human fetus and infant

Answer 18

beta gene activity replaces the gamma gene activity after birth

Question 19

Sickle Cell disease

Answer 19

• 1/600 african americas
• HbS is a GAG (G) -> GTG(G) in codon 6 of beta globin gene resulting in the substitution of glutamic acid with valine which also results in the destruction of an Mnl I site in (GAGG)

Question 20

Describe the Hb C mutation of sickle cell disease

Answer 20

milder
-Hb C is a GAG (G) -> AAG(G) results in the substitution of glutamic acid with lysine which also destroys the same Mnl I site

Question 21

Heterozygotes of sickle cell disease

Answer 21

• have sickle cell trait

- are usually asymptomatic and have a selsetive advantage conferred from providing some resistance to Malaria parasite

Question 22

Homozygotes of Hb S or Hb C

Answer 22

Have sickle cell disease

• which is often fatal in early childhood but with good medical care life span can be normal
• suffer from anemia, failure to thrive, splenomegaly, painful swelling of hands and feet, repeated infections

Question 23

Overview of beta thalassemia

Answer 23

• reduced beta globin chain production
• B + reduced
• B 0 null
• 100 + point mutations

Question 24

Beta thalamessia in-depth

Answer 24

• usually due to a single base pair substitution
• a large degree of allelic heterogenity
• not apparent until a few months after birth
• Homosygotes -B null - thalamessia major (severe) ave little or no beta globin production (transfusion dependent)
• carriers are clincally well and are said to have thalamessia minor
• Beta + thalamessia is when reduced Hb A is detected
• share many features with alpha thalassemias

Question 25

Alpha thalamessia overview

Answer 25

• underproduction of alpha globin cain
• common in southeast asia
• often the deletion of one or both of the two globin structural genes in tandem on 16

Question 26

Describe the manifestation of Alpha thalamessia

Answer 26

• in the absence of the alpha globin chains with which to associate, the beta globin cluster are free to form homotetrameric hemoglobin called Hb H
• the most common form of alpha thalamessia are the results of deletions which are found as a result of the close proximity of the two identical alpha globin genes in tandem on chromosome 16 which facilitates mismatch leading to duplication and deletion

Question 27

What is hydrops fetalis and where is it primarily found?

Answer 27

• homozygous deletion o the alpha thalamessia genes and

- primarily found in SE Asia

Question 28

What are the most common deletions (genetic mechanisms) behind alpha thalamessia?

Answer 28

many alpha thalamessia deletions result from unequal cross-overs between regions of homology in a 4kb repeat
- misalignment of homologous pairing and recombination btw the alpha 1 gene on the chromosome and the alpha 2 gene on homologous chromosome result in deletion of the alpha gene

Question 29

Hb Constant Spring

Answer 29

• mutation from UAA to CAA in normal termination codon at 142 so that a longer (31+ amino acids) unstable alpha chain mRNA is produced
• results in tetramers of the beta globin chains (Hb H) which do not release oxygen in the peripheral tissues
• alpha thal in –/alpha CS alpha