5.8 - Phenotypic Variability

Question 1

What is the issue with classifying genetic diseases?

Answer 1

• 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

Question 2

What is muscular dystrophy?

Answer 2

• 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

Question 3

How can the environment affect genetic disease?

Answer 3

• 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

Question 4

How does the environment affect multiple endocrine neoplasia type I (MEN1)?

Answer 4

• 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

Question 5

How does the environment affect hereditary haemochromatosis?

Answer 5

• 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

Question 6

How does the environment affect sickle cell disease?

Answer 6

• 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

Question 7

How can an individual’s sex affect genetic disease?

Answer 7

• 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

Question 8

How does sex affect hereditary haemochromatosis?

Answer 8

• 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

Question 9

How does sex affect congenital long-QT syndrome?

Answer 9

• 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

Question 10

How do other genes affect eye colour?

Answer 10

• 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

Question 11

What are cystic fibrosis modifiers?

Answer 11

• 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

Question 12

What are Von Hippel-Lindau (VHL) syndrome modifiers?

Answer 12

• 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

Question 13

How do different mutations in the same gene lead to different phenotypes? e.g. MD

Answer 13

• 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

Question 14

What are unstable mutations?

Answer 14

• 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

Question 15

Unstable mutations in Huntington’s disease

Answer 15

• 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

Question 16

SUMMARY - how do you know which cause of phenotypic variability it is?

Answer 16

• if individuals genetically identical = environmental
• if non-identical individuals with same mutation e.g. family members = environment or existence of variation in other genes which interact with disease-causing mutation
• unrelated individuals = different mutations or different disease-causing genes
• if it gets worse per generation, then unstable mutation/trinucleotide expansion
• every patient is an individual, so even if two patients are affected by the same disease and mutation, their experience and response will be different and can change with time and circumstance