Inheritance and testing in genetic disease

Question 1

why are models of disease inheritance important?

Answer 1

to know how genetic disease are inherited to allow appropriate medical advice to be given
predict risk of being affected by disease for family members of an affected individual - screening and treatment
predict risk of being carriers of disease for family members of an affect individual - risk to unborn child, reproduction choices

Question 2

autosomal dominant inheritance

Answer 2

50% risk to offspring
transmission by males and females
males and females equally affected
affected individuals should have an affected parent 
tends to occur in every generation

Question 3

huntington disease

Answer 3

incidence = 1/10,000
onset 35-55 years of age
affects movement, cognitive and psychiatric behaviours

Question 4

autosomal recessive inheritance

Answer 4

25% risk to offspring - with 2 carrier parents
males and females equally affected
usually no previous family history
most commonly affects siblings

Question 5

cystic fibrosis

Answer 5

commonest autosomal recessive disease affecting caucasians
incidence = 1/2,500 - 250 babies a year
carrier frequency = 1/25
mutation of the CF transmembrane conductance regulator (CFTR)
main defects in the lungs and pancreas caused by thickened mucus

Question 6

example of autosomal dominant disease

Answer 6

huntington disease

Question 7

example of autosomal recessive disease

Answer 7

cystic fibrosis

Question 8

x-linked recessive inheritance

Answer 8

no male-to-male transmission
males affected almost exclusively
transmitted through unaffected female carriers

Question 9

examples of x recessive linked inherited conditions

Answer 9

haemophilia A and B

Duchenne muscular dystrophy

Question 10

x linked dominant inheritance

Answer 10

males and females affected - often more females
females less severely affected
affected males can transmit to all daughters but none of their sons
affected females transmit to 50% of her offspring
very rare
males usually more severely affected than females due to rescuing affect by second x chromosome

Question 11

examples of x-linked dominant inheritance

Answer 11

rett syndrome, incontinentia pigmenti, fragile X syndrome

Question 12

x-linked dominant inheritance with male lethality

Answer 12

male is so severely affected that survival is unusual

live born males with these conditions often have an additional x chromosome

Question 13

x-linked dominant with male sparing

Answer 13

only females affected but mechanism unclear

Question 14

y-linked inheritance

Answer 14

affected males only

affected males transmit to all their sons

Question 15

mitochondrial inheritance

Answer 15

conditions can appear in every generation of a family
can affect both males and females
fathers do not pass these disorders to their daughters or sons

Question 16

examples of mitochondrial inheritance

Answer 16

leber’s hereditary optic neuropathy

leigh syndrome

Question 17

how are identical twins represented on a pedigree diagram?

Answer 17

like a triangle, joined with a line

Question 18

how are non-identical twins represented on a pedigree diagram?

Answer 18

1 line from the parents splits into 2

Question 19

why might a genetic test be considered?

Answer 19

to confirm a diagnosis
allow presymptomatic testing
provide an accurate assessment of genetic risk
change a treatment plan
give information about prognosis and management

Question 20

what are the different categories of genetic test?

Answer 20

diagnostic
carrier
prenatal
presymptomatic

Question 21

Diagnostic testing

Answer 21

to confirm or rule out a specific genetic or chromosomal condition which is suspected due to specific physical signs and symptoms
such as floppy babies
children with learning disabilities
cancer

Question 22

when can diagnostic testing be done?

Answer 22

can be performed before birth or at any time during a person’s life, but is not available for all genes or all genetic conditions
treatment/ counselling may depend on the gene/ type of mutation involved

Question 23

what is a floppy baby a sign of?

Answer 23

Prader willi syndrome
muscular dystrophy
spinal muscular atrophy

Question 24

what genetic test could be done for children with learning disabilities?

Answer 24

fragile X syndrome and CGH analysis for ploidy

Question 25

clinical clues of a genetic condition

Answer 25

there is patient or family history of an inherited condition
medical test results that suggest a possible genetic or chromosomal condition may be present
child presents demonstrating signs of developmental delay
woman aged 35 or over is or plans to become pregnant
woman has incurred a series of pregnancy losses or stillbirths
medical problems in the offspring of parents who are related by blood

Question 26

CADASIL

Answer 26

cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy

Question 27

what is CADASIL

Answer 27

most common hereditary vascular dementia

caused by mutations in exons 3 and 4 of the NOTCH3 gene

Question 28

symptoms of CADASIL

Answer 28

migraine
recurrent minor strokes
Family history of these 2

Question 29

presymptomatic testing

Answer 29

for unaffected individuals in families with a confirmed genetic disease with a known mutation
some genetic disorders are late onset and knowledge of genetic mutation can affect screening/ treatment. life style choices
e.g. cancer syndromes (breast and colon)
late onset neurological disease (Huntingtons)
there are significant ethical issues, so there are clear guidelines

Question 30

guideline for presymptomatic testing

Answer 30

individuals should be at 50% risk for autosomal dominant disease
usually over the age of 18 - unless a clinical intervention is possible

Question 31

what mutation causes huntington’s?

Answer 31

triplet repeat expansion in IT15 Huntingtin gene and shows anticipation

Question 32

what is anticipation?

Answer 32

as a genetic disorder is passed on to the next generation the symptoms become apparent at an earlier age with each generation

Question 33

Diagnosis of Huntington disease

Answer 33

no treatment

death occurs 15-20 years after diagnosis

Question 34

what are the implications for family members after a huntington diagnosis

Answer 34

presymptomatic testing now available for siblings and offspring
prior to presymptomatic testing genetic counselling is given
implications of a positive or negative result for patient and family discussed
follow-up appointment made to receive results

Question 35

what is a carrier

Answer 35

someone who has inherited one normal and one abnormal allele for a gene associated with the disorder which is either autosomal recessive or x-linked recessive. They are unaffected

Question 36

examples of carrier testing

Answer 36

mother of a boy affected by duchenne’s muscular dystrophy
siblings of a CF affected patient
people in certain ethnic groups with an increased risk of specific genetic conditions
available for chromosomal abnormalities

Question 37

what are the mutations for CF

Answer 37

p. Phe508 mutation

p. Gly551Asp

Question 38

who is prenatal genetic testing offered to?

Answer 38

women with increased risk of chromosome abnormality in offspring
couples who are known to carry a genetic disorder

Question 39

prenatal genetic tests

Answer 39

invasive with risk of miscarriage:

• CVS - chorionic villous sampling
• amniocentesis
• NIPD - non-invasive prenatal diagnosis (possible for fetal sexing and small number of genetic disorders)

Question 40

what needs to known about prenatal genetic testing?

Answer 40

what will be tested for
chance of it occurring
risks of procedure
accuracy of test
potential outcomes of testing
option for termination 
no prenatal test can guarantee normality of the fetus - not possible to test for every disease