Factors that affect expression of disease-causing genes

Question 1

What is a de novo mutation?

Answer 1

A new mutation in a gene transmitted by one parent that results in a disease-causing allele

De novo mutations can lead to genetic diseases without prior family history, affecting recurrence risks for offspring.

Question 2

What is the recurrence risk for siblings of a child with a de novo mutation?

Answer 2

Very low

However, the recurrence risk for the affected child’s offspring may be significantly increased.

Question 3

What is germline mosaicism?

Answer 3

A condition where a mutation affects all or part of a parent’s germline but not their somatic cells

It can lead to multiple offspring with a genetic disease without prior family history.

Question 4

Which diseases have been associated with germline mosaicism?

Answer 4

• Achondroplasia
• Neurofibromatosis type 1
• Duchenne muscular dystrophy
• Hemophilia A

Germline mosaicism accounts for a notable percentage of cases in these diseases.

Question 5

What is reduced penetrance?

Answer 5

The phenomenon where individuals with a disease-causing genotype do not express the disease phenotype

An example is retinoblastoma, where about 10% of obligate carriers do not develop the disease.

Question 6

What is age-dependent penetrance?

Answer 6

A delay in the age of onset of a genetic disease

Huntington disease is a classic example, often manifesting in adulthood.

Question 7

What is the inheritance pattern of Huntington disease?

Answer 7

Autosomal dominant

Affected individuals have a 50% chance of passing the allele to their offspring.

Question 8

What is the typical age of onset for Huntington disease?

Answer 8

Between 30 and 50 years

Symptoms can appear earlier or later, but this is the most common age range.

Question 9

What percentage of retinoblastoma cases are caused by inherited mutations?

Answer 9

Approximately 40%

The remaining cases are caused by somatic mutations occurring early in development.

Question 10

What is the survival rate for retinoblastoma patients in high-income countries?

Answer 10

Approximately 95%

Globally, the survival rate is less than 30%.

Question 11

What is the primary cause of death in Huntington disease patients?

Answer 11

Aspiration pneumonia

Other causes include cardiorespiratory failure and subdural hematoma due to head trauma.

Question 12

Fill in the blank: The retinoblastoma gene, RB1, encodes a protein product known as _______.

Answer 12

pRb

Question 13

True or False: Germline mosaicism is common in the general population.

Answer 13

False

Germline mosaicism is relatively rare but can significantly affect recurrence risks.

Question 14

What is the role of the pRb protein in cell cycle control?

Answer 14

To inactivate members of the E2F family of nuclear transcription factors

This action prevents progression from G1 to S phase of mitosis.

Question 15

What is the relationship between the age of onset and the frequency of a genetic disease in a population?

Answer 15

Delaying the age of onset reduces natural selection against the disease-causing allele, increasing its frequency

This is particularly evident in diseases like Huntington disease.

Question 16

How does reduced penetrance affect the analysis of genetic diseases?

Answer 16

It complicates the interpretation of inheritance patterns in families

Individuals may carry a disease-causing allele without developing the associated phenotype.

Question 17

What techniques are used to detect changes in DNA in relation to retinoblastoma?

Answer 17

• Polymerase chain reaction (PCR)
• Magnetic resonance imaging (MRI)
• Positron-emission tomography (PET)

These techniques help in understanding the mechanisms of the disease.

Question 18

What is the typical progression timeline from initial diagnosis to death for Huntington’s disease (HD)?

Answer 18

15 to 20 years

Patients with HD experience difficulties in swallowing, leading to aspiration pneumonia as the most common cause of death.

Question 19

What are the common causes of death in patients with Huntington’s disease?

Answer 19

• Aspiration pneumonia
• Cardiorespiratory failure
• Subdural hematoma (due to head trauma)

The suicide rate among HD patients is also significantly higher than in the general population.

Question 20

What types of medications are used to treat symptoms of Huntington’s disease?

Answer 20

• Benzodiazepines
• Antipsychotic drugs
• Antidepressants

These drugs help control some symptoms but do not alter the disease outcome.

Question 21

What is the range of CAG tandem repeats in the general population?

Answer 21

10 to 26

Individuals with 27 to 35 repeats are unaffected but may transmit larger numbers of repeats.

Question 22

What happens when an individual has 36 or more CAG repeats?

Answer 22

It can produce Huntington’s disease, although incomplete penetrance is seen for 36 to 40 repeats

A larger number of repeats is correlated with an earlier age of onset.

Question 23

What percentage of variation in age of onset of Huntington’s disease can be predicted by repeat number?

Answer 23

60% to 70%

There is little relationship between repeat number and the clinical course of the disease.

Question 24

What is the protein product of the HD gene called?

Answer 24

Huntingtin

It is involved in vesicle transport and the production of brain-derived neurotrophic factor.

Question 25

What is the consequence of the CAG repeat expansion in the huntingtin protein?

Answer 25

It produces a lengthened series of glutamine residues ## Footnote This is correlated with toxic protein aggregates and early neuronal death.

Question 26

What is the difference in clinical course between homozygotes and heterozygotes in Huntington's disease?

Answer 26

Affected homozygotes display a clinical course very similar to that of heterozygotes ## Footnote This is unlike most dominant disorders, where homozygotes are more severely affected.

Question 27

What is penetrance in the context of genetic diseases?

Answer 27

An all-or-none phenomenon where one either has the disease phenotype or does not ## Footnote Variable expression refers to the degree of severity of the disease phenotype.

Question 28

What factors can affect the expression of a genetic disease?

Answer 28

* Environmental influences * Modifier genes * Different types of mutations (allelic heterogeneity) ## Footnote These factors can lead to variable expression of genetic diseases.

Question 29

What is neurofibromatosis type 1 (NF1) also known as?

Answer 29

Von Recklinghausen disease ## Footnote It is one of the more common autosomal dominant disorders.

Question 30

What are the diagnostic criteria for neurofibromatosis type 1?

Answer 30

Two or more of the following must be present: * Six or more café-au-lait spots * Freckling in the armpits or groin * Two or more neurofibromas or one plexiform neurofibroma * Two or more Lisch nodules * Optic glioma * Distinctive bone lesions * A first-degree relative with NF1 ## Footnote NF1 has virtually 100% penetrance.

Question 31

What is the mutation rate for the NF1 gene?

Answer 31

Approximately 1 in 10,000 per generation ## Footnote This high rate is partly due to the large size of the NF1 gene.

Question 32

What is locus heterogeneity?

Answer 32

A single disease phenotype can be caused by mutations at different loci in different families ## Footnote An example is adult polycystic kidney disease (APKD).

Question 33

What is pleiotropy in genetics?

Answer 33

Genes that have more than one discernible effect on the body ## Footnote An example is Marfan syndrome, which affects multiple systems.

Question 34

What is an example of a disease exhibiting locus heterogeneity?

Answer 34

Adult polycystic kidney disease (APKD) ## Footnote It can be caused by mutations in either PKD1 or PKD2 genes.