basics of clinical genetics

Question 1

what does the triangle of disease aetiology represent?

Answer 1

for any condition, the balance between environmental and genetic factors can be represented by a point somewhere on the triangle

Question 2

are strokes genetic or environmental?

Answer 2

they have environmental factors but also polygenic factors or a single gene making them multifactorial

Question 3

which diseases are on each end of the genetic/environmental spectrum?

Answer 3

genetic - duchenne muscular dystrophy

in the middle there is spina bifida and pyloric stenosis and completely environmental - scurvy

Question 4

what are the characteristics of genetic and environmental diseases?

Answer 4

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.

Question 5

what is the definition of multifactorial?

Answer 5

the interaction of multiple genes and environmental factors causing a condition

Question 6

what mode of inheritance is common for single gene disorders?

Answer 6

these are mutations in single genes and therefore Mendelian inheritance is common - AD, AR, XL or mitochondrial

Question 7

what is a chromosomal condition?

Answer 7

the rearrangement or imbalance in chromosome structure

Question 8

what are somatic mutations?

Answer 8

mutation in a gene in a defined population of cells that results in a disease

Question 9

what do gametes contain?

Answer 9

23 chromosomes - 1 copy of each

Question 10

what is autosomal dominant inheritance?

Answer 10

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.

Question 11

define penetrance?

Answer 11

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.

Question 12

what is the term for variation in expression? and describe it?

Answer 12

expressivity - extent to which a heritable trait is manifested by an individual. This may be 100% but there are different expressions.

Question 13

what is anticipation?

Answer 13

the symptoms of a genetic disorder appear earlier as it is passed down through generations and usually an increase in severity of symptoms too

Question 14

what is a de novo mutation?

Answer 14

it is a new dominant mutation that has occurred during gametogenesis or early in embryonic development - not inherited but can be passed on

Question 15

what is autosomal recessive inheritance?

Answer 15

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.

Question 16

what is the cause of milder phenotypes?

Answer 16

it is when some people have different mutations on different point of their genes and therefore it makes a compound heterozygous mutation

Question 17

what are haemochromatosis, sickle cell, CF and many other metabolic disorders examples of?

Answer 17

autosomal recessive inheritance

Question 18

who is affected in X linked disorders and what are they?

Answer 18

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.

Question 19

what is the risk of offspring being affected by a XL disease?

Answer 19

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)

Question 20

what are examples of XL diseases?

Answer 20

duchenne muscular dystrophy, Fragile X syndrome, red and green colour blindness, haemophilia

Question 21

what affects the expression of the phenotype of XL diseases in females?

Answer 21

X inactivation and XL dominant or XL recessive

Question 22

what is lyonisation?

Answer 22

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.

Question 23

what is skewed X inactivation?

Answer 23

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.

Question 24

what is XL dominant expression?

Answer 24

it is rare where most carrier women are fine but could have a full disorder. Examples are Rett and Fragile X syndromes.

Question 25

what is XL recessive?

Answer 25

this is not uncommon but requires an affected father and carrier mother which is uncommon. Examples are Duchenne, haemophilia and red green colour blindness.

Question 26

how many genes roughly are in the mitochondria?

Answer 26

around 30 - 27 genes within the mitochondrial DNA

Question 27

who do we inherit our mitochondria from?

Answer 27

the mother

Question 28

what are the sources of mitochondrial disease?

Answer 28

there can be mutations in ths genes that are in the nucleus that direct the mitochondrial function or in the mitochondrial themselves

Question 29

how do you build a pedigree?

Answer 29

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

Question 30

what are the signs for an abortion/ still born?

Answer 30

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,

Question 31

what are the patterns in AD inheritance?

Answer 31

you have vertical transmission with M:F = 1:1, it is across multiple generations with male to male transmission

Question 32

what are the pedigree symbols for each gender

Answer 32

circle is female and square is male - filled in is affected and line through has died

Question 33

What is the symbol for identical / non identical twins?

Answer 33

identical is the branches off same origin with line connecting them, where non has no line

Question 34

what does a double line represent?

Answer 34

a consanguineous union

Question 35

what is the pattern for autosomal recessive inheritance?

Answer 35

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

Question 36

what is the pattern for XL recessive inheritance?

Answer 36

only males are affected and females are carriers - diagonal pattern with no male to male transmission

Question 37

what is the pattern for XL dominant inheritance?

Answer 37

both males and females are affected and sometimes males more severely. Again there is no male to male transmission.

Question 38

what is the pattern for mitochondrial inheritance?

Answer 38

male to female = 1. It always comes from the mum an there is variable severity.

Question 39

what is the pattern for chromosomal translocations inheritance?

Answer 39

there are multiple miscarriages in the family and many of the liveborns have multiple congenital abnormalities and learning difficulties