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What are the different classifications of genetic disorders?

Single gene disorder: mutations in single gene (often causing loss of function)

Multifactorial diseases/common complex disorders: variants in genes causing alteration of function

Chromosome disorder: chromosomal imbalance causes alteration in gene dosage

Mitochondrial disorders: generally affect organ systems with high energy requirements - genes controlling function and structure of mitochondria are found in both mitochondrial and nuclear DNA

Somatic mutations: cause cancer - inactivation of both alleles of a gene involved in growth required


What are the types of single gene disorders?

Dominant: heterozygotes with one copy of the altered genes have the condition

Recessive: homozygotes with 2 copies of the altered gene have the condition

X-linked recessive: males with one copy of the altered gene on the X-chromosome have the condition


What do the majority of mutations cause?

Autosomal dominant - Loss of function of an allele
- some can cause gain of function but this is much rarer

Autosomal recessive - majority of mutations abolish the action of the allele


In general how does the impact of a mutation in a structural protein/receptor differ from an enzyme and why?

Even with half the concentration of a gene product a structural protein/receptor tends to cause dominant clinical effects, whereas for enzymes there is a non-clinical effect as the effect is recessive

The reason why is because we tend to overproduce enzymes and therefore you may be able to cope with just 1 normal copy


What are the different types of mutations?

Missense- change in a base causing the incorrect amino acid to be coded for
Nonsense- leads to a stop codon
Frameshift - deletion/insertion of a base causing the triplet codon codes to be shifted
Duplication- more than one codon being repeated
Deletion - an entire codon being deleted
Insertion - an additional codon being added in

These have varying effects on the health of a person, depending upon where they occur and whether they alter the function of essential proteins


What is neurofibromatosis type 1?

Autosomal dominant
Skin cafe au lait patches (freckles)


What does it mean by variation in expression of autosomal dominant conditions and how does this relate to neurofibromatosis?

It is important clinically to see how an autosomal dominant condition varies in its expression throughout a family
- this is caused by other genes modifying its phenotypes
NF1 = shows variation in expression but is completely penetrant


What does it mean by Huntington's dhows age related penetrance?

Autosomal dominant inheritance
- progressive neurological disorder (involuntary movements, dementia, psychiatric disturbance)
- onset is delayed - 50% of people with the mutation have developed signs by 50


What factors can make a person appear not to have an autosomal condition when in fact they have the genotype?

- incomplete penetrance
- age dependent penetrance
- variation in expression


What causes achondroplasia?

New mutations cause the disorder in 80% of people - increases with paternal age = higher mutation rates likely to be due to greater number of germ cell divisions
- bone growth disorder that causes disproportionate dwarfism


What is myotonic dystrophy?

Autosomal dominant disorder
Muscle weakness
Impaired muscle contraction after relaxation (myotonia)
Usual age of onset is 20s-30s

Congenital myotonic dystrophy - infants are severely affected with infants have significant respiratory problems


What does it mean by anticipation?

in successive generations:
- age of onset is reduced and/or the severity of the phenotype is increased
Unstable expanding triplet nucleotide repeat
Severity/age of onset may correlate with number of repeats


What are some examples of intragenic triplet repeats causing dominant diseases?

CTG repeat - myotonic dystrophy
CAG repeat - huntington's disease
CGG repeat - fragile X syndrome


When does the CAG repeat lead to huntington's disease?

Normal gene repeats = 11-34
>34 repeats = glutamine residue proteins aggregate in brain cells causing progressive cell death
these repeats expand further (esp. during male meiosis) causing earlier age of onset in children of men with HD allele


Where can mosaicism occur?

in the gonads
- possible recurrence of apparently de novo autosomal dominant condition


How can you recognise an autosomal recessive disease from a pedigree?

- can't follow the disease through the pedigree
- see siblings affects - horizontal transmission
- equal incidence of males and females
- may be evidence of consanguinity - double lines suggest this - marriage within groups


What is hardy-Weinberg equation and when does it hold true?

The relative proportions of each genotype will remain constant in subsequent generations
Holds true if:
- random mating
- infinitely large population
- no preferential selection of genotypes
- no new alleles


What determines the genotype frequency in a population?

Mutation rate
Heterozygous advantage
Medical intervention


What does CF confer resistance to?

- CF gene encodes a membrane chloride channel required by salmonella typhi to enter epithelial cells
- heterozygotes are resistant to typhoid via mutant channels


What is the difference in males and females in terms of X-linked recessive inheritance?

Males - one copy of an altered gene on the X chromosome causes the disease - hemizygotes

Females - an altered gene on one of the X chromosomes = carrier status - heterozygote

e.g. haemophilia


What pregnancy options are available in terms of risk of having a child with a genetic condition?

Postpone pregnancy
No further pregnancies - adoption
Further pregnancies - accept risk, prenatal diagnosis if available, artificial insemination by donor where appropriate, preimplantation diagnosis


What are the different types of mutations that can occur in duchenne muscular dystrophy?

point mutations
premature stop codons
altered splice site mutations
promoter mutations
- mutations altering the reading frame = absence of functional dystrophyn protein - approx. 65%
- mutations within the frame produce partially functional dystrophyn - milder phenotype known as Becker's muscular dystrophy


What is Becker's muscular dystrophy?

Less severe muscular weakness
mean onset is 11 years
Ambulant until adult life
Life expectancy only marginally reduced


What is an exciting new treatment approach for DMD?

correction of the reading frame in DMD mutations to make a milder phenotype=DMD to BMD
- exon skipping


Why do some females show X-linked recessive traits?

- Skewed X-inactivation
- Turner's syndrome (45, X)
- Homozygous for a recessive trait
- X autosome translocation = X chromosome involved in the translocation survives preferentially to maintain functional disomy of the autosomal genes