Mendelian inheritance Flashcards
What things are obvious in an autosomal dominant pedigree?
People affected in all generations
Males and females affected
All forms of transmission can be seen including male to male transmission
What are the characteristics of an autosomal dominant condition?
Heterozygotes show pathology
What is chance of a child inheriting an autosomal dominate condition if there parent has it?
1 in 2 or 50% chance
What is variable expressivity in relation to autosomal dominate conditions
Variation in the presence and severity of clinical features
family members have different signs and symptoms of the same disease some may be severely affected others may b every mildly affected probably due to other genes modifying phenotype
Cannot predict how severely a child will experience a condition 50% chance of getting it
Give an example of variable expressivity
Neurofibromatosis type 1 cafe au lait patches on the skin
vary in severity lots of benign tumours grown around nerves
What is penetrance?
Penetrance is a measure of the proportion of individuals in a population who carry a specific gene and express the related trait
What is reduced penetrance?
reduced penetrance is when there are no abnormal clinical features even though someone has inherited an autosomal dominate disorder
therefore it appears to have ‘skipped a generation’
thought to be due to interactions of other genes as well as interaction with environmental factors
What is anticipation
In successive generations the age of onset of disease is reduced and/or the severity of the phenotype is increased
occurs due to expansion of unstable triplet repeats leading to earlier onset or more severe conditions
expansion of CAG in Huntingtons disease increases the risk of early onset
What is age related penetrance?
Age related penetrance is a delay in the onset of an autosomal dominant disease –> some people may not even develop signs
BRACA1 and Huntingtons show age related penetrance the longer the time for the onset of symptoms if they arise the less likely they are to pass onto subsequent generations
New mutations
Affected individual does not have affected parents, and wont have appeared anywhere in family history
Increased paternal age increases chances of mutation occur as there are many more divisions of th the germ cells to produce the sperm
What is mosaicism
Genetic change occurring post fertilisation leading to two cell lines
Somatic mosaicism
two different somatic cells lines can lead to single gene disorder conditions being less sever e.g. down Syndrome
Wont be passed onto offspring as not in the germ-line cells
Gonadal mosaicism
two cells lines in the gonadal cells
parents themselves are not phenotypically effected by autosomal dominate condition but offspring seem to be due to presence of mutated allele in some germ-line cells
What determines whether a condition is dominant or recessive
What gene it occurs it
mutations in genes coding for structural proteins and receptors –> lead to half the amount of functional product cannot function therefore have dominate condition and more extreme manifestation
Recessive conditions usually occur in genese codiong for enzymes or less essential receptors
one copy of the functional allele in heterozygotes is usually sufficient
however when two copies are present there is abolishment of the gene and then you get clinical signs as you cannot cope with no enzyme
Autosomal recessive conditions
Only displayed phenotypically when individual is homozygous (carrying both copies of the forty allele)
What are the characteristics of a autosomal recessive pedigree?
cant follow disease through the pedigree
Siblings tend to be affected
equal incidence in males and females
may be evidence on consanguinity parents are both blood relatives
Why can consanguinity lead to increased probability of a autosomal recessive condition?
increased probability alleles for rarer genetic diseases meeting up as they share a common heritage
How would you work out the likelihood of a woman who has had two children with one parter one with CF and then is having a child with another partner and want to know risk to the new child?
she must be a carrier (and her old partner)
need to figure out likelihood of new parter being a carrier
use Hardy Weinberg principle to calculate carrier frequency which is 1/22 for northern Europeans
then multiply both of these by the probability of child getting the disease if both the parents are carriers ie
1 X 1/22 X 1/4 = 1/88
X linked recessive inheritance
mutation in a gene carried in the X chromosome and usually only manifests in males
What are the common signs on a pedigree for an X linked recessive condition?
more than one generation affected
no direct male to male transmission affected males make all there daughters obligate carriers sons unaffected but daughters sons may then get condition known as knights move or horizontal transmission
usually only males affected
Can females be affected
Yes females can be affected but more rarely due to:
may be homozygous. for two mutated alleles (effected farther and carrier mother)
Due to Skewed X inactivation
Turners syndrome only one X chromosome
What are the outcomes of a woman carrier and normal farther having children
1 in 2 chance of each son the condition (if she was heterozygous) 1 in 4 in total
1 in 2 chance of each daughter being a carrier 1 in 4 in total
How can skewed X inactivation lead to affected females in X linked recessive diseases?
usually equal inactivation and activation of maternal and paternal x chromosomes
but this can be skewed e.g a heterozygous female carrying the mutate allele is differentially expressed leading to some mild symptoms of the disease
Give an example of an x linked ressecive disease that differential affects males and explain therefore why it is rare for males to pass on there mutated X chromosome to all there daughters
most X linked recessive diseases are fatal to males in the long run (haemophilia being a notable exception)
e.g Duchenne muscular dystrophy muscle weakness often die in teenage years
as death is common in many diseases males don’t reach reproductive age
X linked dominant inheritance
how to spot it on a pedigree
Rare
High male lethality
No male to male transmission
Excess of females affected as affected males transmit trait to all of his daughters and they are directly affected as its dominant
Give an example of an X linked dominant condition
Vitamin D resistant rickets
Rickets occurs even through there is an adequate intake of dietary vitamin D
Y linked Inheritance how to spot it on a pedigree?
Give an example
Only Males infected
Males pass on trait to all of sons but to no daughters
H-y histocompatability antigen and genes involved in spermatogenesis
Mitochondrial inheritance how to recognise it on a pedigree and why does it occur?
Mitochondrial inherited exclusively from mother sperms mitochondria much fewer and are actively expelled from oocyte
males never pass on the condition
affected females always pass on the condition to all of her offspring
