5.8 - Phenotypic Variability Flashcards
1
Q
What is the issue with classifying genetic diseases?
A
- they are rare and cause is initially unknown
- classified by their symptoms leading to conditions that don’t have the same cause/aren’t the same being labelled with the same name
- confusion being lessened through reclassification of disease using subtypes
- e.g. osteogenesis imperfecta (OI) has nine subtypes, which although they all result in fragile bones prone to fracture they have different disease outcomes, inheritance patterns and underlying causes
- e.g. OI one method of classification - there are those caused by mutations in collagen genes and those caused by mutation in other genes
- even for types I-IV which are caused by mutations in the same gene, there is variability in phenotype
2
Q
What is muscular dystrophy?
A
- group of diseases which cause progressive weakness and muscle breakdown
- most common type is Duchenne muscular dystrophy (DMD) - approx 50% of cases
- Becker muscular dystrophy is also common
- variety of other types with different causes e.g. congenital MD and Emery-Dreifuss MD (EDMD) are rare forms with similar symptoms but different aetiologies
- symptoms and presentation varies as does the affected gene
- all the genes affected are involved in attaching dystrophin through the cell membrane to the collagen in the ECM either directly or in the post-translation modification of the proteins involved
3
Q
How can the environment affect genetic disease?
A
- even though underlying causes are genetic, there is an important role for the environment in the progress and outcome of the disease
- environment - factors external to the patient
- natural history and prognosis will be affected by the environment
4
Q
How does the environment affect multiple endocrine neoplasia type I (MEN1)?
A
- disease which increases carriers’ chance of developing adenomas in endocrine tissue
- caused by tumour suppressor gene MEN1 mutation
- condition is autosomal dominant, but not all with mutation will develop same adenoma type or at same time, due to a second event which has to occur to promote tumour formation
- some develop tumours young, others late
- exact cause unknown but clearly an effect of environmental impact on course of disease
5
Q
How does the environment affect hereditary haemochromatosis?
A
- autosomal recessive disease
- caused by mutation in human haemostatic iron regulator protein (HFE)
- HFE affects the way dietary iron is absorbed, leads to excess iron absorption
- can lead to iron build-up in various organs –> organ damage
- only 10% with disorder have clinically relevant iron accumulation
- dietary load of iron can vary considerably and lower levels of intake are associated with improved prognosis
6
Q
How does the environment affect sickle cell disease?
A
- despite all sufferers having the identical mutation, their experience of the disease varies widely
- a number of factors affect symptoms and experience e.g. airborne pollution, where high levels of many pollutants are linked with more frequent crises and hospital admissions
7
Q
How can an individual’s sex affect genetic disease?
A
- physiological differences between males and females can affect phenotype displayed by individuals with same mutations
- simplest level - can be due to presence/absence of organs and tissues
- e.g. men with mutations in BRCA-1 and BRCA-2 have increased risk of prostate cancer, but this is not the case with females as they lack a prostate and instead have an increased risk of ovarian cancer
- not always obvious e.g. men with above mutations are at risk of breast cancer although much less than women with same mutations
- females with hypercholesterolaemia have an equally elevated risk of heart disease as men
8
Q
How does sex affect hereditary haemochromatosis?
A
- causes iron build-up in tissues –> tissue damage
- disease has different time course in males and females
- men - symptoms start developing between 40 and 60
- women - symptoms don’t develop until several years after menopause
- as females lose a significant amount of blood during menstruation, preventing build-up of iron in other tissues
- homozygous for mutation - symptoms in 14% men and 4% women
- men tend to have more severe phenotypes
9
Q
How does sex affect congenital long-QT syndrome?
A
- group of rare cardiac disorders characterised by prolonged QT interval –> syncope, ventricular arrhythmias and sudden death
- most common subtypes LQT1 & LQT2, caused by mutations in KCNQ1 & KCNH2 respectively
- autosomal dominant
- females more likely to be diagnosed, possibly due to ascertainment bias since diagnostic criteria is based on QTc and females on average have a longer QTc
- studies show females more likely to inherit the mutation than males, and mothers are more prone to pass on the mutation than fathers
- thought to be due to positive selection of the mutated allele due to a reproductive advantage
- males who inherit LQT1/2 are more likely to present at a younger age and with a fatal cardiac event, but symptoms develop in fewer than half of those affected
- females who inherit LQT1/2 all develop symptoms which first occur when they are older and more likely to be non-fatal
- after puberty this changes with females more likely to experience fatal cardiac events while rate of all cardiac events in males drops
10
Q
How do other genes affect eye colour?
A
- autosomal dominant trait
- number of other genes that interact with OCA-2 to alter eye colour
- type of OCA-2 you inherit is responsible for 80% of eye colour, rest by other genes
- second most important gene is HERC2 - controls OCA-2 activity so even if you inherit the active form of OCA-2 you will have blue eyes if you inherit the inactive form of HERC2
- over 16 other genes that influence eye colour = wide range of eye colours
11
Q
What are cystic fibrosis modifiers?
A
- number of gene variations that interact with CF mutation to change phenotype e.g. immunoglobulin Fc-gamma receptor II, which if you have the variant can increase chance of developing P. aeruginosa infection by 4x
- great variability of pulmonary phenotype and survival in CF, even among patients who are homozygous for the most prevalent mutation, delF508
- variants of genes can modify pulmonary symptoms of CF
- patients homozygous for delF508 can be classified as having either severe or mild lung disease - TGFB1 (gene encoding transforming growth factor beta-1) variants associated with severe phenotype
12
Q
What are Von Hippel-Lindau (VHL) syndrome modifiers?
A
- VHL is a dominantly inherited familial cancer syndrome predisposing to a variety of malignant and benign neoplasms e.g. retinal, cerebellar, renal cell carcinoma, pheochromocytoma and pancreatic tumours
- variation in cyclin D1 alters phenotype - the number of retinal angiomas is significantly higher in individuals with G allele rather than AA homozygotes
- having one or more G alleles is associated with earlier diagnosis of CNS hemangioblastoma by 2x
13
Q
How do different mutations in the same gene lead to different phenotypes? e.g. MD
A
- both DMD & BMD are caused by mutations in the dystrophin gene - largest human gene
- both are similar in distribution of muscle wasting and weakness (mainly proximal), but Becker is more mild phenotype with 12 years age of onset - some patients no symptoms until later in life
- Becker - loss of ambulation varies from adolescence onward with death between 40-50 years
- opposed to DMD which is more severe and has diagnosis at 4.6 years and death at 17
- reason for differences in progression is type of mutation - both are deletions in dystrophin gene but in DMD, the mutation is a frame-shift mutation so no active dystrophin is produced; but in BMD the mutation is not a frame-shift so active dystrophin is produced albeit a shorter form which retains some activity
14
Q
What are unstable mutations?
A
- some diseases termed trinucleotide repeat disorders, caused by trinucleotide repeat expansion - mutation where region of three repeated nucleotides in genome increases in number during DNA replication
- <27 repeats in genome - these tend to be stable and protein function is normal
- as number of repeats increases, it reaches a threshold above which they are no longer stable during DNA replication = number of trinucleotide repeats increases with changes in protein function
- greater number of repeats = more severe phenotype
- these types of diseases are characterised by earlier onset and greater severity of symptoms in each succeeding generation, as number of repeats increases
15
Q
Unstable mutations in Huntington’s disease
A
- caused by expansion of region of CAG repeats in Huntington gene
- CAG = codon for glutamine, so repeats lead to chain of glutamine called a polyglutamine tract / poly Q tract
- <27 repeats - stable region, normal phenotype
- 27-35 repeats - intermediate phenotype with some minor effects, but region of DNA is no longer stable so number of repeats can increase
- 36-39 repeats - characteristic phenotype but not all carriers affected by disease
- 40+ repeats - Huntington’s in all carriers, region more unstable and more prone to expansion of CAG region
- increase in repeats occurs over generations –> children > parents > grandparents
- during DNA replication of CAG repeats, replication often pauses to allow new DNA strand to loop out and reanneal then replication proceeds = insertion of additional copies of CAG repeat
- can also result in loss of repeats but causes an increase above a stability threshold for unknown reasons
