Lec: 60 Medical Genetics III - Atypical patterns of inheritance and multifactorial disease

Question 1

What is “epigenetics” ?

Answer 1

The study of gene expression changes that are not rooted in DNA changes.

Question 2

What proteins make up histones?

Answer 2

Two copies each of H2A/H2B, H3 and H4

Question 3

What are some possible epigenetic mutations of histones?

Answer 3

Acetylation, methylation, and phosphorylation.

Question 4

What is the basis of unstable mutations?

Answer 4

They’re a function of “unstable repeats” di/tri/tetra/ or pentanucleotides. The repeats over and over create instability which leads to slipped mispairing mutations.

Question 5

What is a “normal transmitting male”?

Answer 5

A person carrying a gene that has potential to mutate (more so than normal because of the repeats), that can get progressively more unstable and likely to mutate when he passes the gene on to his progeny.

Question 6

What is a premutation?

Answer 6

An unstable repeat that doesn’t yet manifest as disease but has the potential to cause a slipped mispairing and disease.

Question 7

What are some diseases of unstable repeat expansion?

Answer 7

Fragile X syndrome, Huntington disease, Friedrich’s ataxia, and Myotonic dystrophy.

Question 8

What is dosage compensation?

Answer 8

Equalizing the contribution of X-linked genes in males and females.

Question 9

What is X inactivation?

Answer 9

Random inactivation of one of the X chromosomes in females.

Question 10

What is the implication of X inactivation with regard to X linked disease?

Answer 10

Because X inactivation is random some genes will activate maternally and some paternally. This leads to a natural mosaicism. Which means x-linked disease are much more variable and detecting carriers of disease biochemically is much more difficult.

Question 11

The presence of more than one type of mitochondrial DNA due to mutations is known as?

Answer 11

Heteroplasmy

Question 12

What is the pattern of inheritance of mitochondrial DNA?

Answer 12

Maternal.

Question 13

Parent of origin gene imprinting is known as?

Answer 13

Genomic imprinting

Question 14

When are genes imprinted?

Answer 14

During gametogenesis

Question 15

Deletion of the imprinted gene 15q11-q13 leads to one of two syndromes, what are they and what differentiates them from a genetic perspective?

Answer 15

The two syndromes are Prader-Willi and Angelman. Prader-Willi is the result of the deletion of the paternally imprinted copy of the gene. Angelman syndrome is the deletion of the maternally imprinted copy of the gene.

Question 16

What are some of the clinical signs of Prader-Willi Syndrome?

Answer 16

Hypotonia, initial failure to thrive, distinctive facial features, mild to moderate mental retardation, hypogonadism, and an eating disorder (obesity).

Question 17

What are the clinical presentation symptoms of Angelman syndrome?

Answer 17

Hypotonia, seizures, jerky uncoordinated movements, severe mental retardation, unprovoked laughing/smiling, lack of speech. (Mental retardation is more pronounced in this syndrome than Prader-Willi.

Question 18

The idea that you need a certain quantity of mutant genes to be present before a disease will manifest phenotypically is known as?

Answer 18

The threshold model of multifactorial inheritance.

Question 19

What relationships qualify as “first degree” and how is this applied to multifactorial and polygenic disorders?

Answer 19

Parents children and siblings. The closer to first degree the relationship the more likely the person is to develop that condition.

Question 20

What relationships qualify as “Second degree” and how is this applied to multifactorial and polygenic disorders?

Answer 20

Aunts and uncles, nephews and nieces. The closer to first degree the relationship the more likely the person is to develop that condition.

Question 21

What relationships qualify as “third degree” and how is this applied to multifactorial and polygenic disorders?

Answer 21

Cousins. The closer to first degree the relationship the more likely the person is to develop that condition.

Question 22

A difference between concordance values for a genetic condition between monozygotic and dizygotic twins indicates what?

Answer 22

That there is a genetic role for development of the disease (as opposed to more of an epigenetic cause).

Question 23

Less than a 100% concordance values for a genetic condition between monozygotic twins indicates what?

Answer 23

A role for epigenetic factors in the development of disease.

Question 24

How does an Xchromosome become inactivated?

Answer 24

Inactivation center (XIC) produces XIST (X inactivation transcript) that spreads through entire chromosome, causing compaction of the chromatin to the histones (thus inactivating it without damaging it) to the point you can see it (Barr Body)

Question 25

Anticipation

Answer 25

Increasing severity of the disease in later generations due to unstable mutations

Question 26

Why is mitochondrial DNA so prone to mutation when compared to normal DNA in the nucleus?

Answer 26

Mitochondrial DNA does not have the extensive DNA repair capabilities seen in nucleic DNA. It also has a lot of oxygen radicals floating around.

Question 27

What do mitochondrial DNA mutations usually affect the most?

Answer 27

Tissues that require a lot of energy like muscle, heart, etc.

Question 28

LHON

Answer 28

Leber Hereditary Optic Neuropathy - Optic nerve degeneration caused by a missense mutation in any of the three genes coding for respiratory enzymes. This is a mitochondrial DNA disorder.