MM 16-18

Question 1

Which occurs more? Loss of protein function mutation or gain of protein function mutation?

Answer 1

Loss of protein

Question 2

Mutation nomenclature: R408W

Answer 2

Arginine (R) at codon 408 becomes Tryptophan (W).

R408X would mean that Arginine was replaced with a stop codon.

del means deletion

Question 3

Monogenic disease

Answer 3

Single gene defect

Question 4

Locus heterogeneity

Answer 4

A disease that can have a phenotype upon mutations on several different genes. Normally the disease is the result of complex pathways or structures.

Question 5

Allelic heterogeneity mutation and examples

Answer 5

A disease that arises from a mutation on one specific gene. The disease phenotype does not arise from mutations on other genes. Mutations can still come from different places on the gene and have different severities, but only the same gene is always involved in the disease.

PKU
Cystic Fibrosis

Question 6

Compound heterozygosity

Answer 6

Compound heterozygosity is the condition of having two heterogeneous recessive alleles at a particular locus that can cause genetic disease in a heterozygous state.

For example, both alleles might be mutated but at different locations.

Question 7

Complex inheritance

Answer 7

A disease that may not show Mandelian inheritance patterns to to its polygenic complexity and environmental factors. Eg, cardiovascular disease.

Question 8

Polymorphic

Answer 8

Genetic predisposition for a disease due to mutations in many gene loci that each have a small contribution. Can be oligogenic or polygenic inheritance.

Question 9

Epigenetics

Answer 9

Epigenetics studies genetic effects not encoded in the DNA sequence. Such effects on cellular and physiological phenotypic traits may result from external or environmental factors that switch genes on and off and affect how cells express genes. They may or may not be heritable.

Eg. Methylation or Acetylation, tagging of DNA or histone to change the expression of a gene.

Question 10

Genomic imprinting

Answer 10

Genomic imprinting is the epigenetic phenomenon by which certain genes are expressed in a parent-of-origin-specific manner. If the allele inherited from the father is imprinted, it is thereby silenced, and only the allele from the mother is expressed. If the allele from the mother is imprinted, then only the allele from the father is expressed. There are about 60 known genes that undergo imprinting.

Disease can come when a mutation occurs on the active gene while the other is silenced.

Question 11

X-chromosome inactivation

Answer 11

Women do not produce twice as many X encoded proteins as men. This is because one of the X-chromosomes (random) on women is inactivated early in embryonic life. Heterochromatin on the inactivated chromosome is condensed so that it cannot be transcribed, called a Barr-body.

Question 12

Intermediate effect

Answer 12

Biochemically affected but clinically not.

Question 13

X-linked recessive

Answer 13

Most X-linked diseases. A disease that is variably expressed in females and fully expressed in males.

Diseases are characterized as XLR or XLD based on how many females are clinically affected.

Question 14

X-linked dominant

Answer 14

A disease that is expressed clinically in most people who carry the mutant gene. (Very Few disorders exist).

Question 15

Inheritance patterns of X-linked recessive

Answer 15

Complete absence of male to male transmission. Mainly males effected in the pedigree.

If a mother is a carrier, she will pass the disease on the half of her sons and half of her daughters will be carriers.

If a father has the disease, half of daughters will be carries and sons will be neither carriers or have the disease.

Question 16

Examples of X linked recessive diseases

Answer 16

Haemophilia

Duchenne muscular dystrophy

Question 17

Inheritance patterns of X-linked dominant

Answer 17

Complete absence of male to male transmission.

Fathers with disease will pass it on to all of his daughters and none of his sons. Mothers with the disease will pass it on to half of her children.

Question 18

Inheritance pattern of mtDNA

Answer 18

Disease passed on by mother only. All kids have a 50% of getting the disease.

Question 19

Homoplasmy (think mtDNA)

Answer 19

Homoplasmy is when a cell has identical copies of mitochondrial DNA. When in normal and healthy tissues, all cells are homoplasmic. Homoplasmic mitochondrial DNA copies may be normal or mutated; however, most mutations are heteroplastic.

Note: mothers do not pass only one come of mtDNA to kids. The oocyte has many mitochondria, so it it much more likely for mutations to occur in only one or two of them.

Question 20

Heteroplasmy (think mtDNA)

Answer 20

Heteroplasmy is when the mitochondria in a cell differ from each other. This would be the case if mtDNA mutated in a cell.

Question 21

Six stages for genetic counseling

Answer 21

1. Collect information - med/family history
2. Counseling - inform of possible outcomes
3. Assessment - lab testing (+/- cascade tests)
4. Counseling - treatment/management
5. Referral - support group
6. Followup

Question 22

For what type of diseases is genetic counseling appropriate for?

What is it not appropriate for?

Answer 22

• Chromosomal abnormalities
• Single gene mutations (but only 700/2500 single gene disorders have yet to be explained at a genetic level).

Not appropriate for common/complex disorders that may have locus heterogeneity or environmental factors.

Question 23

Why do prenatal genetic diagnosis?

Answer 23

Age of mother
History of miscarriage
Family history of specific single gene disease.
Allows immediate treatment to prevent development issues.

Question 24

Hardy Weinburg formula for population frequency:

Answer 24

p^2 + 2pq + q^2 = 1

p^2 = population of non carriers (AA)
2pq = population of carriers (Aa)
q^2 = population of diseased (aa)

Question 25

Fragile X Syndrome

Answer 25

Symptoms often include mild to moderate intellectual disability. Physical features include a long and narrow face, large ears, flexible fingers, and large testicles.

Fragile X syndrome is typically due to the expansion of the CGG triplet repeat on the X Chromosome. This results in a failure to express the fragile X protein, which is required for normal neural development. Depending on the length of the CGG repeat, an allele may be classified as normal (unaffected by the syndrome), a premutation (at risk of fragile X associated disorders), or full mutation (usually affected by the syndrome). Permutations can get passed on and expanded to full mutations.

Question 26

Huntington’s Disease

Answer 26

The Huntington’s disease triple repeat mutation that is genetically dominant and almost fully penetrant.

Question 27

Multifactorial Inheritance

Answer 27

A complex polygenic disease but the presence or absence of phenotype depends on environmental factors.

Question 28

Genomic Screening tests in Ireland (newborn bloodspot)

Answer 28

Most treatable AR diseases that need to be detected early.

PKU
Maple Syrup Urine Disease
Homocyctineuria
Cyctic Fibrosis
Congenital hypothyroidism

Question 29

Amniocentesis

Answer 29

An invasive prenatal test.

Withdrawal of amniotic fluid during early second trimester.

Can be used for karyotyping, DNA analysis, protein and enzyme assessment.

Question 30

Chorionic Villus sampling

Answer 30

An invasive prenatal test.

8-10 weeks.