basics of clinical genetics Flashcards
what does the triangle of disease aetiology represent?
for any condition, the balance between environmental and genetic factors can be represented by a point somewhere on the triangle
are strokes genetic or environmental?
they have environmental factors but also polygenic factors or a single gene making them multifactorial
which diseases are on each end of the genetic/environmental spectrum?
genetic - duchenne muscular dystrophy
in the middle there is spina bifida and pyloric stenosis and completely environmental - scurvy
what are the characteristics of genetic and environmental diseases?
genetic are rare - they have simple genetics and are unifactorial. They have a high recurrence rate. However, environmental have complex genetics, are multifactorial, have a low recurrent rate and are common.
what is the definition of multifactorial?
the interaction of multiple genes and environmental factors causing a condition
what mode of inheritance is common for single gene disorders?
these are mutations in single genes and therefore Mendelian inheritance is common - AD, AR, XL or mitochondrial
what is a chromosomal condition?
the rearrangement or imbalance in chromosome structure
what are somatic mutations?
mutation in a gene in a defined population of cells that results in a disease
what do gametes contain?
23 chromosomes - 1 copy of each
what is autosomal dominant inheritance?
when a trait or disease runs from one generation to the next. Affected individuals are heterozygous for the mutation. The chance that offspring are affected or unaffected is both 50%. These mutations tends to alter the structure of proteins.
define penetrance?
the frequency with which a specific genotype is expressed in those individuals affected by it - presented as a percentage. It can alter with age or there can be incomplete penetrance whereby not every member of the family that inherits the mutation develops the disease.
what is the term for variation in expression? and describe it?
expressivity - extent to which a heritable trait is manifested by an individual. This may be 100% but there are different expressions.
what is anticipation?
the symptoms of a genetic disorder appear earlier as it is passed down through generations and usually an increase in severity of symptoms too
what is a de novo mutation?
it is a new dominant mutation that has occurred during gametogenesis or early in embryonic development - not inherited but can be passed on
what is autosomal recessive inheritance?
it is when disease is seen in one generation and does not tend to pass to the next as the parents are generally unaffected. The affected individuals are homozygous or compound heterozygous for the mutation. The risk to offspring is 25% to have the disorder and to be a carrier is 2/3.
what is the cause of milder phenotypes?
it is when some people have different mutations on different point of their genes and therefore it makes a compound heterozygous mutation
what are haemochromatosis, sickle cell, CF and many other metabolic disorders examples of?
autosomal recessive inheritance
who is affected in X linked disorders and what are they?
males (some females - less severe), it cannot have male to male transmission however all daughters will have the mutation. It can be gene and chromosome related.
what is the risk of offspring being affected by a XL disease?
with a carrier mother: 25% for both affected boys and carrier girls and 25% not affected for boys and girls. With a carrier father: no chance for boys and all daughters are carriers (most asymptomatic or have mild symptoms)
what are examples of XL diseases?
duchenne muscular dystrophy, Fragile X syndrome, red and green colour blindness, haemophilia
what affects the expression of the phenotype of XL diseases in females?
X inactivation and XL dominant or XL recessive
what is lyonisation?
X inactivation. The process of random inactivation of one of the X chromosomes in cells that have more than one X chromosome. All daughter cells have the same X chromosome switched off. It occurs early in embryogenesis and remains inactive throughout the whole lifetime of cell and all of it’s descendants. Most but not all of the genes will be switched off on the inactivated X. The inactivated one is the Barr Body.
what is skewed X inactivation?
the random preference for normal X chromosome to be inactivated - therefore resulting in a significant phenotype - the preference usually has preference for the mutated in a certain tissue group. It may not be same throughout the whole body.
what is XL dominant expression?
it is rare where most carrier women are fine but could have a full disorder. Examples are Rett and Fragile X syndromes.
what is XL recessive?
this is not uncommon but requires an affected father and carrier mother which is uncommon. Examples are Duchenne, haemophilia and red green colour blindness.
how many genes roughly are in the mitochondria?
around 30 - 27 genes within the mitochondrial DNA
who do we inherit our mitochondria from?
the mother
what are the sources of mitochondrial disease?
there can be mutations in ths genes that are in the nucleus that direct the mitochondrial function or in the mitochondrial themselves
how do you build a pedigree?
you build up from the bottom starting with the affected child and their relatives. You need names and DOBs. The proband is the first person to present with the disorder whereas the consultand is the person infront of you
what are the signs for an abortion/ still born?
a small triangle is a miscarriage (spontaneous abortion), a triangle with a line through is an abortion (therapeutic) and a diamond with a line through and SB is a still born with unknown sex,
what are the patterns in AD inheritance?
you have vertical transmission with M:F = 1:1, it is across multiple generations with male to male transmission
what are the pedigree symbols for each gender
circle is female and square is male - filled in is affected and line through has died
What is the symbol for identical / non identical twins?
identical is the branches off same origin with line connecting them, where non has no line
what does a double line represent?
a consanguineous union
what is the pattern for autosomal recessive inheritance?
the M:F ratio is again 1:1 but is often just seen in a single generation - consanguinity can be a clue and there is a horizontal pattern
what is the pattern for XL recessive inheritance?
only males are affected and females are carriers - diagonal pattern with no male to male transmission
what is the pattern for XL dominant inheritance?
both males and females are affected and sometimes males more severely. Again there is no male to male transmission.
what is the pattern for mitochondrial inheritance?
male to female = 1. It always comes from the mum an there is variable severity.
what is the pattern for chromosomal translocations inheritance?
there are multiple miscarriages in the family and many of the liveborns have multiple congenital abnormalities and learning difficulties
