Inheritance and testing in genetic disease Flashcards
why are models of disease inheritance important?
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
autosomal dominant inheritance
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
huntington disease
incidence = 1/10,000
onset 35-55 years of age
affects movement, cognitive and psychiatric behaviours
autosomal recessive inheritance
25% risk to offspring - with 2 carrier parents
males and females equally affected
usually no previous family history
most commonly affects siblings
cystic fibrosis
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
example of autosomal dominant disease
huntington disease
example of autosomal recessive disease
cystic fibrosis
x-linked recessive inheritance
no male-to-male transmission
males affected almost exclusively
transmitted through unaffected female carriers
examples of x recessive linked inherited conditions
haemophilia A and B
Duchenne muscular dystrophy
x linked dominant inheritance
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
examples of x-linked dominant inheritance
rett syndrome, incontinentia pigmenti, fragile X syndrome
x-linked dominant inheritance with male lethality
male is so severely affected that survival is unusual
live born males with these conditions often have an additional x chromosome
x-linked dominant with male sparing
only females affected but mechanism unclear
y-linked inheritance
affected males only
affected males transmit to all their sons
mitochondrial inheritance
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
examples of mitochondrial inheritance
leber’s hereditary optic neuropathy
leigh syndrome
how are identical twins represented on a pedigree diagram?
like a triangle, joined with a line
how are non-identical twins represented on a pedigree diagram?
1 line from the parents splits into 2
why might a genetic test be considered?
to confirm a diagnosis
allow presymptomatic testing
provide an accurate assessment of genetic risk
change a treatment plan
give information about prognosis and management
what are the different categories of genetic test?
diagnostic
carrier
prenatal
presymptomatic
Diagnostic testing
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
when can diagnostic testing be done?
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
what is a floppy baby a sign of?
Prader willi syndrome
muscular dystrophy
spinal muscular atrophy
what genetic test could be done for children with learning disabilities?
fragile X syndrome and CGH analysis for ploidy
clinical clues of a genetic condition
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
CADASIL
cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy
what is CADASIL
most common hereditary vascular dementia
caused by mutations in exons 3 and 4 of the NOTCH3 gene
symptoms of CADASIL
migraine
recurrent minor strokes
Family history of these 2
presymptomatic testing
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
guideline for presymptomatic testing
individuals should be at 50% risk for autosomal dominant disease
usually over the age of 18 - unless a clinical intervention is possible
what mutation causes huntington’s?
triplet repeat expansion in IT15 Huntingtin gene and shows anticipation
what is anticipation?
as a genetic disorder is passed on to the next generation the symptoms become apparent at an earlier age with each generation
Diagnosis of Huntington disease
no treatment
death occurs 15-20 years after diagnosis
what are the implications for family members after a huntington diagnosis
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
what is a carrier
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
examples of carrier testing
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
what are the mutations for CF
p. Phe508 mutation
p. Gly551Asp
who is prenatal genetic testing offered to?
women with increased risk of chromosome abnormality in offspring
couples who are known to carry a genetic disorder
prenatal genetic tests
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)
what needs to known about prenatal genetic testing?
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
