Genetics - Phenotypic Variability

Question 1

What is the problem with classifying diseases through their symptoms?

Answer 1

Diseases that have different causes are often grouped together as the same disease

Question 2

What is an example of classifying diseases through symptoms?

Answer 2

Osteogenesis imperfecta (9 sub types): 
subtypes 1-4 are all caused by the same gene (Col1A1 and Col1A2) with the same AD inheritance pattern

Question 3

What is MEN1?

Answer 3

Multiple Endocrine Neoplasia type 1. AD disease that increases risk of developing endocrine adenoma due to tumour suppressing MEN1 mutation.

Question 4

What variation may we see with MEN1 patients?

Answer 4

Some people develop tumours at different stages in their life.

Question 5

Why do we see a variation in MEN1 patients?

Answer 5

Second event has to occur to trigger adenoma development

Question 6

What can variation be attributed to in MEN1?

Answer 6

Environmental triggers can be related to the secondary tumour triggering event.

Question 7

What is hereditary haemochromatosis?

Answer 7

AR condition due to HFE ion regulator protein mutation.

Question 8

What is the effect of the environment on hereditary haemochromatosis?

Answer 8

Lower iron dietary intake leads to overall lower iron accumulation.

Question 9

How does HFE affect HH?

Answer 9

Iron enters erythrocytes and exits in the blood via ferroportin. Hepcidin decreases iron in blood. HFE reduces hepicidin and leads to iron accumulation and thus organ damage.

Question 10

What is the effect of sex on phenotypic variability?

Answer 10

Men and women will often be affected differently by the same mutation simply due to physiological differences.

Question 11

What is the significance of the BRCA-1/2 gene in men?

Answer 11

Increased risk of prostate cancer

Question 12

What is the significance of the BRCA-1/2 gene in women?

Answer 12

Increased risk of breast cancer.

Question 13

How is there variation between sex for HH?

Answer 13

different time course for men and women. In men, they will develop symptoms between 40-60, females will develop symptoms after menopause, due to their lack of menstruation which allowed for a loss of blood and hence prevention of iron build up. Homozygous men and women are affected differently in terms of prevalence - 14% of men are affected, 4% of women are affected - and men on average experience more severe symptoms.

Question 14

What is congenital long-QT syndrome?

Answer 14

Ventricular arrhythmias and sudden death from this condition

Question 15

How does congenital long-QT syndrome differ between males and females?

Answer 15

Females typically have longer QT interval so ascertainment bias may account for more females being affected. More women encounter the condition possibly due to positive selection of the mutated allele due to reproductive advantage during gametogenesis, fertilisation, implantation/post-implantation.

Question 16

How do other genes affect the phenotype?

Answer 16

Interaction with other genes can either improve a condition or make it worse.

Question 17

How is eye colour affected by more than one gene?

Answer 17

Autosomal dominant
active OCA-2 gene = melanin = brown eyes (80%)
HERC-2 is also needed t be active fro brown eyes

Question 18

How is CF affected by other genes?

Answer 18

CF modifiers: patients who are homozygous for the most prevalent CF mutation may have either severe or mild lung disease due to variations of other genes. Also, variants of genes can modify the risk of developing CF lung infections by up to 4 times.

Question 19

What is Von Hippel-Lindau syndrome?

Answer 19

autosomal dominantly inherited familial cancer syndrome predisposing to many different malignant or benign neoplasms.

Question 20

How is VHL affected by other genes?

Answer 20

Variation of a cyclin (Cyclin D1 - acts as a genetic modifier) alters the phenotype - different alleles can increase the number of neoplasia, and also the time at which they form.

Question 21

What are genetic modifiers?

Answer 21

Genetic modifiers are genes which can either worsen or improve a condition if they are present.

Question 22

How do mutations to the same gene affect phenotypic variation?

Answer 22

Some diseases can be due to only one mutation, some are the result of many mutations in the same gene

Question 23

What is the difference between Becker and Dechenne muscle dystrophy?

Answer 23

Becker is mild, with onset at around 12 years, and death at around 40/50.
Duchenne (DMD) - much more severe with onset at around 4/5 years, and death at around 17/18

Question 24

What type of mutation occurs in muscular dystrophy?

Answer 24

Deletion. However, for DMD, there is a frame shift deletion - so no active dystrophin is produced, leading to severe symptoms. With BMD, deletion doesn’t cause a frame shift - active dystrophin is produced although it is shorter than it is supposed to be - leading to milder symptoms.

Question 25

How do unstable mutations cause phenotypic variability?

Answer 25

Can cause phenotypic variability, resulting in varying severity of a disease.

Question 26

What are trinucleotide repeat disorders?

Answer 26

These are a group of disorders all arising due to a mutation in which a region of three repeated nucleotides increase during DNA replication

Question 27

How many repeats is the threshold for TNR disorders?

Answer 27

27

Question 28

What is a example of a TNR disorder?

Answer 28

Huntington’s Disease

Question 29

What happens in Huntington’s disease?

Answer 29

Huntington’s is neurodegenerative and can cause mental decline as well as physical decline, CAG (glutamine) increases

Question 30

In Huntington’s disease, what happens with 27-35 repeats?

Answer 30

intermediate phenotype with mild effects

Question 31

In Huntington’s disease, what happens with 36-39 repeats?

Answer 31

characteristic phenotype, but not all carriers affected

Question 32

In Huntington’s disease, what happens with 40+ repeats?

Answer 32

Huntington’s disease in all carriers

Question 33

What is DNA slippage?

Answer 33

when repeats exceed the threshold, they become more unstable and this will perpetuate - more and more unstable repeats will be formed during subsequent rounds of DNA replication.