Inheritance patterns Flashcards
Autosomal dominant
- 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
Characteristics of inheritance patterns autosomal dominant
- 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
• Penetrance - Percentage of individuals who carry the mutation AND develop symptoms of the disorder
– many dominant disorders show age-dependant penetrance
• Variable Expressivity: variation in severity/symptoms of disorder between individuals with same mutn
• New mutation rate: de novo mutation rate varies considerably between AD conditions
• Somatic mosaicism: new mutn arising at early stage in embryogenesis
• Present in only some tissues/cells
• Germ-line mosaicism (gonadal mosaicism): new mutn arises during oogenesis or spermatogenesis
• mutn present in variable proportion of gametes; can be transmitted to offspring
• Anticipation: worsening of disease severity in successive generations
• characteristically occurs in triplet repeat disorders
Autosomal recessive inheritance
• 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
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.
X linked inheritance
• 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 – Hemizygous • Recessive – Women are carriers + unaffected – No male to male transmission • 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: generally random but ~10% of women have uneven or skewed X-inactivation.
- Manifesting carriers: some women have some symptoms in X-linked recessive conditions e.g. cardiomyopathy in DMD.
Y linked inheritance
Always and only passed from fathers to sons
Mutations
- 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
- What types of mutations are there?
- What happens when the amino acid sequence of a protein isn’t what it should be?
Types of mutations
• Substitutions (point mutations) • Deletions • Insertions Found in • Coding DNA • Non-coding DNA (such as promoters and introns)
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
Insertion of a base (or more)
– In-frame (multiple of three) or frameshift (not multiple of three)
Deletion of a base
– In-frame (multiple of three) or frameshift (not multiple of three)
Point mutation
Mutation in a stop codon
