Inheritance patterns Flashcards
What are the symbols in pedigree drawings?
Squares- Males
Circles- Females
Diamond- unknown sex
Affected people are shaded, carriers have dots (not always)
Partners line between them, siblings line above, line down for children. Double line= Consanguineous couple (same blood).Line through shape – deceased.
What is the mode of inheritance determined by?
Mode of inheritance determined by pedigrees I.e. is it autosomal dominant or recessive inheritance? Or is it sex linked?
What is a wild type allele?
When many alleles exist for the same gene, the most common phenotype is the wild type. AKA the reference allele. The wild type phenotype is not necessarily a dominant one.
What are the less common types?
When many alleles exist for the same gene, the less common types are variants. The less common alleles may be dominant or recessive to the wild type, which is most common. The wild type phenotype is not necessarily a dominant one.
What is autosomal dominant inheritance?
Only need one copy of a variant allele to actually show the disease. Approximately 50% of offspring will be affected and other half unaffected. Autosomal dominance manifests in HETEROZYGOUS form. Multiple generations are affected. Both sexes are affected.
What are the characteristics of autosomal dominant inheritance patterns?
- Most individuals have an affected parent (not 100% the case due to new mutations (de novo) or incomplete penetrance.
- Males and females are equally likely to inherit the allele be affected.
- Risk for each child of an affected parent is 50%
- If an affected individuals siblings/children are not affected, and they do not carry the mutation they cannot pass it on to their own offspring.
What are features of autosomal dominant inheritance?
- Variable expressivity: variation in severity/symptoms of disorder between individuals with same mutation.
- Penetrance: refers to the probability of a gene being expressed; expression in all of a population equals complete penetrance. A disorder that may or may not show up in a carrier is an example of penetrance
- New mutation rate: de novo mutation rate varies considerably between AD conditions
- Somatic mosaicism: new mutation arising at early stage in embryogenesis. It is present only in some tissues/cells (I.e only in daughter cells).
- Germ-line mosaicism: AKA gonadal mosaicism. New mutation arises during oogenesis or spermatogenesis. The mutation is present in variable proportion of gametes (some contain, and some don’t. Matter of chance); can be transmitted to offspring.
- Anticipation: Worsening of disease severity in successive generations. Characteristically occurs in triplet repeat orders e.g. Huntington’s.
What is penetrance? What is 100% (complete) penetrance? What is reduced penetrance?
- Penetrance is the percentage of individuals who carry the mutation AND develop symptoms of the disorder. Many dominant disorders show age-dependant penetrance (I.e. as an individual gets older, more likely to express disease).
- 100% and hence complete penetrance is expression in all of a population. The best example of complete penetrance is a gene that is expressed in all of a population with the gene.
- Reduced penetration (I.e 75%) can be as a result of genetic, environmental and lifestyle factors.
What are obligate carriers?
Heterozygous for a particular mutation, but haven’t developed disease. However they can still pass on mutation to offspring, who then does show the disease.
How do you calculate reduced penetrance?
Can be calculated based on the % of individuals who carry the mutation. Formula:
No. of individuals with disease/Total No. Of people with genotype associated with disease. = estimate of penetrance
What is autosomal recessive inheritance?
Both copies need to contain mutation for offspring to have disease. Recessive traits only display in homozygous individuals. Manifests in HOMOZYGOUS/COMPOUND HETEROZYGOUS form. Carriers (hetero) not affected. Usually, one generation affected. May be consanguinity.
What are features of Autosomal recessive inheritance?
- Trait often found in clusters of siblings but not in parents & offspring (unlike dominant inheritance)
- Recurrence risk = ¼ for each sibling of affected person.
- Carrier probability = 2/3 for unaffected siblings of affected person.
- All offspring of affected person are obligate carriers. They have to be at least heterozygous because an affected person will pass on one mutant allele (thus the offspring themselves will have at least one).
What is the difference between compound heterozygote or homozygote?
A compound heterozygote is when an individual that carries two different recessive mutations at the same locus, one on each homolog. Vast majority of recessive disorders are probably due to this.
Compound het = 2 mutants in same gene, mutants different.
Homozygote= 2 mutants in same gene, identical mutants.
Where we see homozygosity, it may suggest consanguinity. However, many individuals who are affected by recessive disorder have two different mutations in same gene (compound heterozygosity). Neither of gene is functional (Same effect as being homozygous) - one mutation in one copy of gene and other in 2nd copy of gene.
What is the genetic behind Cystic fibrosis (in both compound het and homozygote)?
Homozygote- 𐤃F508- 3BP deletion. Removal of 508th amino acid in chain (phenylalanine). Most people homozygous for CF in 𐤃F508
Compound het- 𐤃F508 - deletion on ONE copy of CFTR gene
- G542X – other copy of CFTR gene has non-sense mutation.
Both copies producing non-functional proteins thus individual gets CF. Result is same but genotype is different.
What is sex/x-linked inheritance?
When a gene mutation is present on a sex chromosome. Women have two X chromosomes, so have two copies of X-linked genes. They can be homozygous or heterozygous for any allele position.
Men have one X and a Y, so only have a single copy of X-linked genes. Thus they are HEMIZYGOUS for a sex-linked trait.
