Genetics - Phenotypic Variability Flashcards
What is the problem with classifying diseases through their symptoms?
Diseases that have different causes are often grouped together as the same disease
What is an example of classifying diseases through symptoms?
Osteogenesis imperfecta (9 sub types): subtypes 1-4 are all caused by the same gene (Col1A1 and Col1A2) with the same AD inheritance pattern
What is MEN1?
Multiple Endocrine Neoplasia type 1. AD disease that increases risk of developing endocrine adenoma due to tumour suppressing MEN1 mutation.
What variation may we see with MEN1 patients?
Some people develop tumours at different stages in their life.
Why do we see a variation in MEN1 patients?
Second event has to occur to trigger adenoma development
What can variation be attributed to in MEN1?
Environmental triggers can be related to the secondary tumour triggering event.
What is hereditary haemochromatosis?
AR condition due to HFE ion regulator protein mutation.
What is the effect of the environment on hereditary haemochromatosis?
Lower iron dietary intake leads to overall lower iron accumulation.
How does HFE affect HH?
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.
What is the effect of sex on phenotypic variability?
Men and women will often be affected differently by the same mutation simply due to physiological differences.
What is the significance of the BRCA-1/2 gene in men?
Increased risk of prostate cancer
What is the significance of the BRCA-1/2 gene in women?
Increased risk of breast cancer.
How is there variation between sex for HH?
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.
What is congenital long-QT syndrome?
Ventricular arrhythmias and sudden death from this condition
How does congenital long-QT syndrome differ between males and females?
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.
How do other genes affect the phenotype?
Interaction with other genes can either improve a condition or make it worse.
How is eye colour affected by more than one gene?
Autosomal dominant
active OCA-2 gene = melanin = brown eyes (80%)
HERC-2 is also needed t be active fro brown eyes
How is CF affected by other genes?
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.
What is Von Hippel-Lindau syndrome?
autosomal dominantly inherited familial cancer syndrome predisposing to many different malignant or benign neoplasms.
How is VHL affected by other genes?
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.
What are genetic modifiers?
Genetic modifiers are genes which can either worsen or improve a condition if they are present.
How do mutations to the same gene affect phenotypic variation?
Some diseases can be due to only one mutation, some are the result of many mutations in the same gene
What is the difference between Becker and Dechenne muscle dystrophy?
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
What type of mutation occurs in muscular dystrophy?
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.
