Non-Mendelian Inheritance

Question 1

De novo mutations are most common from what origin?

Answer 1

Almost all cases of a new mutation arise from a gamete of one parent

Question 2

If a couple had a pregnancy with a rare genetic mutation observed in the fetus, what would you say to them with regards to future pregnancies?

Answer 2

Once a rare genetic event has occurred, there is an increased risk for recurrence. This increased risk may be high or low but it is no longer the same as the overall population risk.

Question 3

Mosaicism

• Gonadal
• Somatic

Answer 3

• Gonadal mosaicism is the presence of 2 or more populations of cells with different genotypes in sperm or ova but not the rest of the body
• Somatic mosaicism is the presence of 2 or more populations of cells with different genotypes in somatic tissue and possibly gonadal tissue also

Question 4

What is uniparental disomy

Answer 4

When both members of a pair of homologous chromosomes, or a segment of the pair, are inherited from the same parent with no chromosome of that pair from the other parent. Can be maternal or paternal.

Question 5

What are the 2 sub-categories of UPD?

Answer 5

Isodisomy (2 copies of the exact same chromsome are inherited)

Heterodisomy (2 different copies of the chromosome are inherited)

Question 6

Why does UPD occur?

Answer 6

In gametogenesis, it is possible for an ova or sperm to undergo non-disjunction and end up with 2 copies of the same chromosome in their gamete(s) instead of 1. When this gamete combines with a normal gamete from the mate, a trisomy occurs for that chromosome. Sometimes, the developing zygote undergoes trisomy rescue, in which one of these 3 chromosomes is degraded. If the lost chromosome happens to be from the normal mate, then both inherited copies of the chromosome in question would be from only one parent (the one who had the non-disjunction).

Question 7

Why is UPD dangerous

Answer 7

1) It can expose recessive alleles
2) It can result in phenotypic problems if the chromosome involved has imprinted genes that need to be present from the parent whose chromosome was lost in trisomy rescue in order for the offspring to be normal

Question 8

Explain 4 reasons why the phenotype below might be observed.

Answer 8

Question 9

What is genetic imprinting

Answer 9

Either maternal or paternal copy of a gene is “stamped” or silenced during meiosis resulting in expression of only one copy of gene. In order for an offpsring to be normal, it must inherit one active copy and one silenced copy of imprinted genes.Approx. 1% of all genes in human genome are imprinted.

Question 10

What is Prader - Willi Syndrome?

What can result in PWS?

What is it characterized by?

Answer 10

• There are 2 loci on chromsome 15 that are involved; one that is called the Prader Willi gene and the other is the angelman syndrome gene. In ova, the locus of the PW gene is imprinted and the locus of the AS gene is not. The opposite is true in sperm. In order for an offpspring to not develop PW, their mother’s chromosome must be imprinted for PW and normal for AS genes and their father’s chromosome must be imprinted for AS gene and normal for PW gene.
• Causes:
  
  • Maternal UPD
  • Deletion of the father’s AS - PW loci on chromosome 15
  • Defects with imprinting
• Hypotonia, excessive eating (unable to stop eating), behavioral problems, short stature, intellectual disability

Question 11

What is Klinefelter syndrome (KS)?

Answer 11

• 47,XXY or XXY
• Set of symptoms that result from two or more X chromosomes in males​

Question 12

What is Angelman Syndrome?

What can result in AS?

What is it characterized by?

Answer 12

• There are 2 loci on chromsome 15 that are involved; one that is called the Prader Willi gene and the other is the angelman syndrome gene. In ova, the locus of the PW gene is imprinted and the locus of the AS gene is not. The opposite is true in sperm. In order for an offpspring to not develop AS, their mother’s chromosome must be imprinted for PW and normal for AS genes and their father’s chromosome must be imprinted for AS gene and normal for PW gene.
• Causes:
  
  • Paternal UPD
  • Deletion of the mother’s AS - PW loci on chromosome 15
  • Defects with imprinting
  • De novo mutation
• Severe intellectual disability, inability to speak, ataxic (uncoordinated) gait, seizures, microcephaly, inappropriately happy

Question 13

Mitochondrial Inheritance

• # genes in mtDNA and what they encode?
• Connection to nucleus?

Answer 13

• 37 genes, mostly encode for rRNA or tRNA, remainder encode for subunits of OxPhos
• Most proteins and RNAs in mitochondria are made from transcripts from nucleus

Question 14

What parts of the body are most affectd by mitochondrial disorders?

Answer 14

Brain and muscle

Question 15

Pleiotropy is always present in mutations in mtDNA. Why?

Answer 15

Mitochondria undergo fission to replicate. During this process, their DNA is segregated randomly into daughter organelles, so there is a high degree of random inheritance of mtDNA during mitochondrial replication. As such, a single mutation in mtDNA can result in a wide array of phenotypic expression depending on how much of the mutated DNA is present in their mitochondria. This is described as homoplasmy (all mitochondria have identical genomes) vs. heteroplasmy (there is a mix of DNA populations within one cell’s mitochondria). As such, there is a gradient of phenotypic expression.

Question 16

What is anticipation?

Answer 16

Increasing severity and/or earlier age of onset of an inherited disorder in successive generations within a family. Seen with Trinucleotide repeat disorders.

Question 17

What are 2 common diseases associated with unstable repeat disorders?

Answer 17

Huntington’s disease

Fragile X Syndrome

Question 18

Unstable Repeat Disorders

• Discuss the number of repeats that can be present in a person.
• Explain 2 means by which these disorders can lead to anticipation.
• What bodily system is always affected by these disorders?
• How does the gender of the parent affect these disorders?

Answer 18

• The number of repeats varies in normal individuals and in those who develop the disease. For each disease, there is an approximate threshold for the # of repeats before disease presents, when a person acquires more than the threshold value they phenotypically express the disease.
• Anticipation
  
  • A parent who is just below the threshold could pass on their abnormal (but not pathologic) # of repeats to their offpspring, who could then develop more repeats during subsequent cell divisions leading to earlier expression of disease in the child.
  • A parent could pass on a # of repeats that is above the threshold and their child would express the disease very early in life
• Neurologic deficits are always present
• Depending on the disorder, the offspring may be more or less likely to develop pathology depending on parent who passes on the repeats.
  
  • Ex: If father with Huntington’s passes on repeats, children are more likely to display anticipation than if mother passes on repeats.
  • Ex: In fragile X, expansion of TNR more likely to occur in ova of mother than sperm of father –> child more likely to experience anticipation if fragile X inherited from mother

Question 19

What is a polygenic trait?

Answer 19

A trait that results from the contributions of multiple genes, each making a small contribution to the phenotype

Question 20

What is a multifactorial trait?

Answer 20

A trait that results from the interactions of multiple gtenes and environmental factors

Question 21

What is a clinical clue indicating multifactorial trait?

Answer 21

Usually one organ system that is affected

Question 22

Family Study

• What is a family study?
• What are some downfalls of a family study?

Answer 22

• Studies the incidence of the disorder in relatives compared with the incidence in the general population
• Family members share a common environment and ascertainment bias (families with more affected individuals more likely to be studied)

Question 23

Twin Studies

• What is a twin study?
• What is disease concordance? Disease discordance?
• What does disease concordance < 100% in MZ twins indicate?
• What does greater concordance in MZ vs. DZ twins indicate?

Answer 23

• Studies the incidence of the disorder in monozygotic vs. dizygotic twins in order to distinguish between environmental and genetic influence
• Concordance = both twins are affected, discordance = only 1 twin affected
• Strong evidence that non-genetic factors play role in that disease
• Strong evidence of a genetic component to disease

Question 24

What is an adoption study?

Answer 24

Studies the incidence in children that are adopted into or away from families with the disorder in order to isolaet post-natal environmental factors

Question 25

What are population/migration studies?

Answer 25

Studies the changes in incidence of the disorder in a group of people who migrate to a different geographic area

Question 26

What is a genome wide association study?

Answer 26

Looks for an increased or decreased frequency of SNPs in affected individuals compared to control population. The results typically identify variants in multiple independent genes that contribute to risk of disease development.

Question 27

What is a multifactorial threshold trait?

Answer 27

A trait that is either present or absent (not a varying amount, binary) and one in which all individuals have a certain degree of susceptibility (genetic liability) to develop the trait. If an individual's genetic liability exceeds a critical threshold value, then the disease will be expressed.

Question 28

How much DNA do you share with: * First degree relative (parents, siblings, children) * Second degree relative (nieces, nephews, aunts, uncles, grandparents) * Third degree relatives (Cousins, great-trandparents)

Answer 28

* 50% * 25% * 12.5%

Question 29

What is commonly observed for multifactorial threshold traits if a family member is affected with the condition?

Answer 29

Depending on the degree of relation to the individual, the liability curve shifts to the right. This makes the individual's genetic liability higher because the threshold isn't changing but the probability of them surpassing the threshold increased.

Question 30

A woman is pregnant. She has previoulsy given birth to a child with a cleft lip and palate. How does the risk of the same event occurring to her new child change if her prior child had bilateral cleft lip and palate vs. unilteral cleft lip?

Answer 30

Risk of recurrence is affected by severity in previous child. If her prior child had a more severe case of cleft lip + palate, it is more likely that her new child will have some form of the condition. The more mild the presentation in her prior child, the less likely it will recurr in her new child.

Question 31

What factors influence the risk of recurrence of multifactorial disorders? (6)

Answer 31

* Population incidence (higher in pop = higher recurrence risk) * Number of affected individuals in family * Degree of relationship of affected individual * Severity of malformation * Sex differences (if affected family member is of the sex with lower incidence then relatives of that individual are at higher risk) * Consantuinity