Monogenic diseases Flashcards
Why are pedigree diagrams important?
- Identify genetic diseases in a family
- Identify inheritance patterns
- Aid in diagnosis
Identify the mendelian inheritance patterns
- Autosomal dominant
- Autosomal recessive
- X linked dominant (rare)
- X linked recessive
- Mitochondrial
Explain the mechanism of an autosomal dominant condition
At least one parent is affected, transmitted/affected by M or F, vertical transmission
HUNTINGTON’S DISEASE
-Motor, cognitive + psychiatric dysfunction (hyperkinesia - muscle spasms)
-Survival = 15-18 yrs
-Cell death to basal ganglia
-Caused by instable CAG triplet repeats (27-35 risk for child, 35-40 sometimes, 40-120 affected)
Down generation
Age of onset decreases and severity increases
Provide an example for an autosomal recessive condition
No affected parent, affects/transmitted by M or F, usually no family history
Congenital absence of vas deferens (CAVD) = infertility
CYSTIC FIBROSIS
-Chromic and life threatening
-Mucus affecting lung function, blockages in pancreas
-Treatment = daily enzymes + physio
-Mutation in CFTR gene on Ch 7 (Disruption of NaCl/H2O regulation = thick mucus)
Provide an example of an X-Linked recessive condition
No affected parents, transmitted by carrier F and only M are affected
HAEMOPHILIA
-Easy bruising, heavy bleeding
-Haemophili A + B (rarer)
-A = mutation in F8 = Coagulation factor 8
-B = mutation in F9 = coagulation factor 9
-Treatment = clotting factor injections
Incomplete penetrance
Symptoms are not always present in someone with a disease causing mutation
Variable expressivity
Disease severity may vary between people with the same disease causing mutation
Phenocopy
Having the same disease but with a different underlying cause
Epistasis
Interaction between disease gene mutations and other modifier genes can affect phenotype
Genetic Heterogeneity: Same gene, different mutations, different symptoms
CF and CAVD are both caused by mutations in the CFTR gene
Genetic Heterogeneity: Same disease, different genes
Haemophilia A + B
Genetic Heterogeneity: Same disease, different genes, different inheritance patterns
Epidermolysis bullosa can be autosomal dominant or autosomal recessive
Explain the mechanisms of dominance and treatments
-Mutation causes a production in a toxic protein
-Effects of the mutated gene masks the normal copy (Huntingtins)
TREATMENT = neutralise toxic protein or switch off mutant gene
Explain the mechanism of recessive conditions and its treatments
-Caused by absence of normal functional protein (CF and Haemophilia) TREATMENT = restore activity of missing protein by replacing the gene/products/affected tissue
Explain the mechanism of codominance
-Effects of both mutated and normal genes are present (Sickle cell trait)
Outline the differences between monogenic and complex disorders
Monogenic
- clear inheritance
- No environmental influence
- Rare
- HD, CF, haemophilia
Complex Disorders
- No clear inheritance
- Environment is essential
- Common
- Type II Diabetes, schizophrenia, crohn’s disease
Mutation vs Polymorphism
Mutation = any heritable change in the DNA sequence Polymorphism = a mutation at a >1% frequency in a population, can contribute to complex diseases
What are the types of mutations?
Missense = (Point mutation) codon changes, different amino acid Nonsense = (Point mutation) ends prematurely due to stop codon Insertion = (Frame-shift mutation) extra code will shift code Deletion = (Frame-shift mutation) deletion of a base
Explain the mechanism of Huntington’s disease
- Inherit a mutated form of HTT gene on Chr 4
- encode a toxic form of huntingtin = form clumps
- Cell death in basal ganglia of the brain
Explain the mechanism of Cystic Fibrosis
- CFTR gene on Ch7 = CF transmembrane conductance regulator (2 copies of mutated gene)
- x functional CFTR gene affects cl- function in epithelial cells
- disrupt salt/water regulation = thick mucus
- deletion affects folding of protein = affects movement
Uniparental (iso)disomy
Receives 2 copies of a chromosome, or part of a chromosome from 1 parent and none from the other
- caused by non-disjunction in meiosis II
e. g. Prader Willi syndrome, Angelman syndrome
Genomic Imprinting
In some cases 1 of the 2 chromosomes are turned on. The chromosome that is active is dependent on the parent of origin
Chr 15 imprinting disorders
Prader - Willi syndrome (loss of paternal)
SYMPTOMS: -hyperphagia = obesity -mental impairment -behavioural problems -Muscle hypotonia -Short stature, small hands and feet -Delayed/incomplete puberty, infertility MANAGEMENT: -Obesity = diest restriction -exercise = ↑ muscle mass -GH for short stature -hormone replacement at puberty
