Flashcards in 7. Inheritance Patterns Deck (19):
Key for pedigree drawing
• Males are squares
• Females are circles
• Partners have a line between them
• Siblings have a line above them
• Line down for children
• Affected people are shaded
• Carriers have dots in
• Double line joins union of consanguineous couple (share the same blood)
• Unknown sex are diamonds
• P stands for pregnant
• SB stands for stillborn
• Non-identical twins have an incomplete triangle above them - identical twins have a complete triangle above them
• Triangle shows miscarriage
• Triangle with a line through it shows therapeutic abortion
What are the 4 ways of inheritance?
1) Autosomal dominant
2) Autosomal recessive
Autosomal dominant inheritance. Main points.
• Manifest in HETEROZYGOUS form
• Multiple generations affected
• Both sexes affected
• Male to female & female to male transmission
• Most will have an affected parent
• 50% risk to offspring
What are the characteristics of inheritance patterns autosomal dominant (AD)?
• Most individuals have an affected parent (not everybody due to cases of new mutations or incomplete penetrance).
• Males and females are equally likely to inherit the allele and be affected.
• Risk for each child of an affected parent is ½.
• If an affected individual’s siblings/children are not affected, and they do not carry the mutation they cannot pass it on to their own offspring.
Features of autosomal dominant inheritance
• Many dominant disorders show age-dependant penetrance
• Variable expressivity
• de novo mutation rate varies considerably between AD conditions
• Somatic mosaicism is present in only some tissues/cells
• Mutation present in variable proportion of gametes; can be transmitted to offspring
• Anticipation characteristically occurs in triplet repeat disorders (e.g. Huntington’s)
What is penetrance?
Percentage of individuals who carry the mutation AND develop symptoms of the disorder
What is variable expressivity?
Variation in severity/symptoms of disorder between individuals ( or within the family) with same mutation
What is somatic and germ-line mosaicism (gonadal mosaicism)?
• Somatic mosaicism: new mutn arising at early stage in embryogenesis
• Germ-line mosaicism (gonadal mosaicism): new mutn arises during oogenesis or spermatogenesis
What is anticipation of a disease?
Worsening of disease severity in successive generations
Autosomal recessive inheritance. Main points.
• Manifest in HOMOZYGOUS/ COMPOUND HETEROZYGOUS form
• Carriers (heterozygote) not affected
• Both sexes affected
• Male to female and female to male transmission
• Usually one generation affected
• May be consanguinity - e.g. cousin marriages
• 25% affected, whilst 50% carriers
What is the difference between compound heterozygote and homozygote?
• In homozygote, there are 2 identical mutations in the same gene
• In compound heterozygote, there are 2 different mutation in the same gene.
- The outcome is the same as both copies are still not functioning properly. e.g. in cystic fibrosis.
- This is seem more often than homozygous
Features of autosomal recessive inheritance
• Trait often found in clusters of siblings but not in parents & offspring.
• Recurrence risk = 1/4 for each sibling of affected person.
• Carrier probability =2/3 for unaffected siblings of affected person.
• All offspring of affected person are obligate carriers.
• Women have two X chromosomes
- Two copies of X-linked genes
- Can be homozygous or heterozgous
• Men have one X and a Y
- Only a single copy of X-linked genes
• Can be recessive (mostly)
- Women are carriers + unaffected
- No male to male transmission
• Can be dominant
- Women are affected
- Males more severely affected/lethal
Aspects of x-linked recessive inheritance
• X-linked genes never passed from father to son.
• All daughters of affected males are obligate carriers.
• Children of carrier females have a 50% chance of inheriting mutant allele.
• SKEWED X-INACTIVATION: normally the majority of genes on one of a woman’s X-chromosomes are inactivated
- the active mutated X chromosome is the one expressing all the proteins
• MANIFESTING CARRIERS: some women have some symptoms in X-linked recessive conditions e.g. cardiomyopathy in DMD.
Always and only passed from fathers to sons
What is a mutation? What are the different types? and where are they found?
• Mutation: a change in the genetic material
• A pathogenic mutation (pathogenic variant) results in an alteration of the function of the gene product and can cause a disease phenotype
• Depending on the type of mutation – can present as dominant or recessive
- Substitutions (point mutations)
• Found in:
- Coding DNA
- Non-coding DNA (such as promoters and introns)
What is a missense and nonsense mutation?
• Missense = a point mutation with leads to a change in AA (a type of nonsynonymous substitution)
• Nonsense = when the codon is changed into a stop codon
Impact of amino acid substitution
• Physicochemical similarity between the two aminoacids
• Functional role of the specific domain of the protein
• Phylogenetic conservation of original aminoacid amongst diverse species