S3: Patterns of Inheritance Flashcards
What is the value of taking family history?
The family tree helps establish the family agenda and dynamics, helps narrow down a differential diagnosis and help target and interpret genetic investigations.
- Even a limited family history may have helped reach the diagnosis earlier.
- Genetic test result directly impacted patients management.
- It has the ability to offer cascade testing to family members to reassure them and reduces the recurrence risk.
- It allows family planning.
Define Allele, Autosome, Phenotype and Genotype
Allele - the alternative form of a gene.
Autosome - relating to the 22 chromosomes that are not sex chromosomes.
Phenotype - the observable characteristics of an organism resulting from the interaction of its genetic constitution and the enviroment.
Genotype - the genetic constitution of an organism. at one or more genetic loci
Describe the keys for a pedigree drawing
A pedigree is the recorded ancestry or lineage of a person or family.
- Males are squares.
- Females are circles.
- Partners have a line between them.
- Line down for children.
- Siblings have a line above them. Oldest left.
- Affected people are shaded.
- Carriers have dots.
- No offsprint is a short horizontal line at end of vertical.
- P in diamond means pregnant person.
- Diamond is full term stillborn baby.
- Triangle for spontaneous abortion or miscarriage.
- Line through symbol means the individual is deceased.
What are the 3 types of mendalian inheritance?
X linked
Autosomal recessive
Autosomal dominant
Described x linked inheritance
- Alterations on the X chromosome.
- It is more likely to affect men as they only have one X chromosome.
- X linked inheritance can be recessive where women are carriers.
- There is no male to male transmission as a man cannot pass an X chromosome onto his sons.
- All daughters of affected males are obligate carriers.
- X linked dominant conditions women are affected but men are more severely affected (can be lethal).
- In X linked recessive, women are carriers and men are affected. The mother can either pass on the normal copy or mutant X gene to her gametes. There are 4 different outcomes:
1. and 2. Normal male and female.
3. Mutated and male X chromosome to make a female carrier.
4. Mutates and male y chromosome to give an affected male.
Can carrier females (x linked recessive) be affected by the condition?
Yes.
- Some women can manifest in X linked conditions because in most cells women switch of one of the X chromosomes by random X-inactivation/skewed X inactivation. So if the normal X chromosome is randomly inactivated and the cell only expresses the mutant copy of the gene, the carrier will manifest symptoms.
- This is called manifesting carriers when some women have symptoms in X-linked recessive conditions e.g. cardiomyopathy in DMD. This may be due to unfavourable skewing of X inactivation.
Describe autosomal recessive inheritance
- Both alleles need to be mutated to express the condition e.g. cystic fibrosis so you have no functioning of a specific protein leading to a condition.
- Carriers (one normal copy and one mutated copy of the gene) are not affected because 50% of the protein is normal.
- Usually one generation is affected when two parent carriers come together.
- Males and females are equally affected.
- The more rare a trait in the general population, the greater the chance it was due to consanguineous mating.
- 2/3 unaffected siblings (of two carrier parents) will be carriers.
- All offspring of an affected person are obligate carriers.
Describe autosomal dominant inheritance
- A dominant disorder is where there is a genetic alteration in one copy of a gene (one of the alleles) and this is enough to cause a problem. Each one of us carries two copies of every gene, so in a dominant disorder you only need one allele to cause disease.
- This can be because the genetic alteration in the allele changes the function of the whole gene or protein making it disease causing or because you need two copies of the correct gene to function properly and having half the protein being altered is enough to cause disease.
- Usually in an autosomal dominant disorder, we see multiple generations affected.
- If affected, there is an 50% chance of passing the allele onto your offspring.
- Most individuals have an affected parent (not everybody because of cases of new mutations or incomplete penetrance).
What is penetrance in autosomal dominance inheritance?
It is the proportion of individuals with the genotype that express the phenotype.
- The top is 100% penetrance so everyone who carries the disorder will express it to some degree.
- If penetrance is less, you would see less affected individuals and that an unaffected individual goes on to have an affected child, because she carries the mutation but herself doesn’t express it.
- For example, Huntington’s is age dependent penetrance where the affected does not express any symptoms until older age where penetrance increases.
What is penetrance in autosomal dominance inheritance?
This is the variability in the degree/severity to which the phenotype is expressed. Not everyone with the phenotype e.g. polydactyl will express to to the same degree e.g. some may have a tiny extra flat of skin whereas others may have a fully functioning extra digit.
What is anticipation in autosomal dominance inheritance?
It is worsening of disorder as you go down subsequent generations e.g. offspring begin to be affected younger and younger.
- It characteristically occurs in triplet repeat disorders e,g. Huntingtons - generally the more repeats, the worse the disorder and earlier its manifestation and if a father passes it on to son, he is more likely to have the disorder at an earlier age.
What is new mutation rate in autosomal dominance inheritance?
Some autosomal dominant disease can occur for the first time in a particular individual (de novo mutation rate), so it can’t be seen in previous generations but springs up in one person and then can be passed on. This rate varies between AD conditions.
What is reproductive fitness in autosomal dominance inheritance?
In some AD disorders, the mutation carriers are unable to reproduce. Hence the disorder is maintained in the population by new mutations.
What is somatic mosaicism in autosomal dominance inheritance?
This is a new mutation arising at an early stage in embryogenesis, NOT at conception. So the mutation is not present in all cells/tissues, only some. Reduced risk of being passed on as occurring only in certain tissues, as long as not in germ cells won’t be passed on.
What is germ-line mosaicism in autosomal dominance inheritance?
A new mutation arising during oogenesis or spermatogenesis in the parent. So the parent isn’t affected but child is. The mutation is present in a variable proportion of the gametes and can be transmitted to the offspring. Low recurrence rate.
