Wk8 Mendelian Inheritance Flashcards
What are single gene disorders?
Mutations in single genes (often causing loss of function)
what are multi factorial diseases?
Variants in genes causing alteration of function (also called common complex disorders)
What are chromosome disorders?
Chromosomal imbalance causes alteration in gene dosage
What are mitochondrial disorders?
Generally affect organ systems with high energy requirement.
What are somatic mutations?
Cause cancer. Inactivation of both alleles (two “hits”) of a gene involved in growth required
Dominant types of single gene disorder
Heterozygotes with one copy of the altered gene have the condition
Recessive types of single gene disorder
Homozygotes with two copies of the altered gene have the condition
X-linked recessive types of single gene disorder
Males with one copy of the altered gene on the X- chromosome have the condition
What are autosomal dominant conditions?
- Dominant: describes any trait expressed in a heterozygote
- Variation in expression
- Penetrance
- New mutations
- Anticipation
What do mutations cause?
- some mutations can cause gain of function but majority of mutations in autosomal dominant disorders cause loss of function of the allele
- e.g. half the number of LDL receptors on the cell membrane in familial hypercholesterolaemia
- the majority of mutations in autosomal recessive disorders abolish action of the allele
Dominant or recessive pattern of inheritance?
Depends on how the cell copes with effectively half the amount of gene produce
Enzyme = no clinical effect (recessive)
Structural protein or receptor = clinical effect (dominant)
How to diagnose using DNA?
Is this a normal variant or pathogenic? • Synonymous/silent SNP? • Missense mutation? • Nonsense mutation? • Frameshift mutation?
Before assuming that a sequence change is the cause of a genetic condition (and not just a polymorphism) determine the likely effect on gene expression or function
What are exceptions to mendel’s rules in autosomal dominant inheritance?
Neurofibromatosis type 1 Autosomal dominant Skin café au lait patches Multiple neurofibroma
What are exceptions to mendels rules in autosomal dominant inheritance?
- Variation in expression
- Reduced/incomplete penetrance
- New mutation
- Anticipation
- Mosaicism
What does Huntington disease demonstrate?
- age related penetrance
• Autosomal dominant inheritance
• Progressive neurological disorder
– involuntary movements – dementia
– psychiatric disturbance
What is age dependent penetrance?
• A delay in the onset of a genetic disease
• Huntington disease
50% of people with the mutation have developed signs by age 50
What is myotonic dystrophy?
• Autosomal Dominant
• Muscle weakness
• Impaired muscle contraction after relaxation (myotonia)
• Usual age of onset 20’s-30s
Congenital myotonic dystrophy- severely affected infants with Respiratory problems
Why is Huntington disease a triple repeat disease?
Usual gene 11-34 CAG repeats = 11-34 glutamine residues in protein
>34 glutamine residues protein aggregates in brain cell causes progressive cell death
Runs of >34 CAG repeats in HD gene expand further (particularly during male meiosis) causing earlier age of onset in children of men with HD allele - anticipation
How to recognise an autosomal recessive disease from a pedigree?
- Can’t follow the disease through the pedigree
- See siblings affected - ‘horizontal transmission’
- Equal incidence of males and females
- May be evidence of consanguinity
What is the chance of this pregnancy being affected with CF?
Mother must be a carrier (probability = 1)
Chance of new partner being a carrier obtained from frequency of
condition in population = 1/22
Chance of an affected pregnancy is therefore 1 x 1/22 x 1x4=1/88
Determine the CFTR mutation in the affected brother
Offer carrier testing to both parents
What is hardy-Weinberg principle?
Carrier rate
2pq =2(1-q)q=2q-2q2
HW - equations
P+q = 1
P2 + 2pq + q2 = 1
What are the different letters for?
P = dominant allele Q = recessive allele P2 = homozygous dominant genotype 2pq = heterozygous genotype Q2 = homozygous recessive genotype
Why does HW hold true?
- Random mating
- Infinitely large population
- No preferential selection of genotypes
- No new alleles
What are available options with a genetic condition?
• Postpone pregnancy • No further pregnancies - adoption • Further pregnancies - accept risk - prenatal diagnosis if available - egg donation - preimplantation diagnosis if availsble
Why do some females show X-linked recessive traits?
• Skewed X-inactivation • Turner syndrome (45,X) • Homozygous for a recessive trait e.g. colour blindness • X;autosome translocations - X chromosome involved in the translocation survives preferentially to maintain functional disomy of the autosomal genes
What is a key feature of mitochondrial inheritance?
Exclusively’ maternal inheritance egg cells 100,000 mitochondria sperm cells 100 mitochondria
sperm mitochondria actively expelled from fertilized egg