Inheritance testing

• Inherited disorder

  • chromosomal conditions
  • e.g. Down's, Edward's syndromes
  • change in number of chromosomes
  • single gene conditions
  • Huntington's, cystic fibrosis
  • smaller changes in human genome
  • often only one nucleotide base change
  • can be passed onto other family members in different ways
  • depends on function of gene/protein and where it is on the genome
  • multifactorial conditions
• Patterns of disease inheritance

  • important to know how genetic diseases are inherited in humans to allow appropriate medical advice to be given to patients and their families
  • predict risk of being affected by disease for family members of an affected individual
  • screening
  • treatment
  • predict risk of being carriers of disease for family members of an affected individual
  • risk to the unborn child
  • reproduction choices
• Autosomal dominant inheritance

  • 50% risk in offspring
  • transmission by males and females
  • males and females equally affected
  • affected individuals should have an affected parent
  • tends to occur in every generation
  • AUTOSOME not SEX CHROMOSOME therefore can be passed from either parent to child of either sex
• Huntington's disease

  • incidence 1/10000
  • autosomal dominant
  • onset typically 35-55 years old
  • movement, cognitive and psychiatric effects
  • advanced stages of the disease show involuntary movements of the face
  • caudate nucleus affected - can see in postmortem
• autosomal recessive inheritance

  • 25% risk in offspring (with 2 carrier parents)
  • males and females equally affected
  • usually no previous family history
  • most commonly affects siblings
  • have to inherit both alleles from parents
  • can have children who are affected, carriers or unaffected
• cystic fibrosis

  • commonest autosomal recessive disease affecting Caucasians
  • incidence 1/2500
  • 250 babies/year
  • carrier frequency is 1 in 25
  • mutation of the CF transmembrane conductance regulator (CFTR)
  • main defects in the lungs and pancreas caused by thickened mucus
• X-linked recessive inheritance

  • no male-to-male transmission (always pass on Y chromosome to son)
  • males affected almost exclusively
  • transmitted through unaffected female carriers
  • females have another X chromosome to balance the affected gene
• Examples of X-linked recessive inheritance

  • Haemophilia A and B - blood clotting disorders
  • duchenne muscular dystrophy - chronic muscle wasting
• X-linked dominant inheritance

  • males and females affected (often more females)
  • females usually less severely affected due to rescuing effect of second X chromosome
  • affected males can transmit to all daughters but no sons
  • affected females transmit to 50% of offspring
• 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 - this has rescuing effect
• X-linked dominant with male sparing

  • only females affected
  • mechanism unclear
• Y-linked inheritance

  • affects males only (only males have Y chromosome)
  • 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
  • mothers pass the disorder on to all their children
  • mitochondrial inheritance is maternal
  • Leber's hereditary optic neuropathy
  • Leigh syndrome
• Genetic pedigrees

  • graphical representation of a family tree - who is affected or not
  • very useful in calculating risk (of being affected or a carrier) to other family members for well-known disorders
  • for new disorders can determine mode of inheritance
  • eldest on left of diagram, eldest generation at top
• penetrance is proportion of people with a genetic change that exhibit symptoms e.g. BRCA1 mutation 80% - not all people get cancer. Other cancers also may have reduced penetrance.
• why do we consider genetic testing?

  • will the results of this test
  • confirm a diagnosis
  • allow presymptomatic testing
  • provide an accurate assessment of genetic risk
  • change a treatment plan
  • give information about prognosis and management
  • reproduction choices
  • diagnostic, carrier, prenatal, presymptomatic
• Diagnostic testing

  • to confirm or rule out a specific genetic or chromosomal condition which is suspected due to physical signs and symptoms
  • floppy babies tested for PWS, SMA and MD
  • children with learning disability tested for fragile X syndrome and have a CGH analysis
  • familiar cancer syndromes, cystic fibrosis, Huntington disease etc.
  • can be performed before birth or at any time during a person's life
  • treatment/counselling may depend on the disease and gene/type of mutation involved
• some clinical clues of genetic condition

  • there is a patient or family history of an inherited condition
  • medical test results that suggest a possible genetic or chromosomal condition may be present
  • a child presents demonstrating signs of developmental delay
  • a woman aged 35 or over is, or plans to become, pregnant
  • a woman has incurred a series of pregnancy losses or stillbirths
  • medical problems in the offspring of parents who are related by blood
• 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/lifestyle choices
  • Inherited cancer syndromes (breast and colon)
  • Neurological diseases i.e. CADASIL, HD etc.
  • Significant ethical issues, so clear guidelines for presymptomatic testing
  • Individuals should be at 50% risk for Autosomal Dominant disease
  • Usually on over the age of 18 (unless a clinical intervention possible)
• Carrier testing

  • A carrier for a genetic disorder has inherited one normal and one abnormal allele for a gene associated with the disorder which is either autosomal recessive or x-linked recessive
  • Unaffected
  • Examples of carrier testing include:
  • Mother of a boy affected with DMD
  • Siblings of a CF affected patient
  • People in certain ethnic groups with an increased risk of specific genetic conditions
  • Tay sachs disease in the Ashkenazi Jewish population
  • Carrier testing for chromosomal abnormalities also available.
• Prenatal genetic testing offered to

  • Women with increased risk of chromosome abnormality in offspring
  • Couples known to carry genetic disorder
  • Majority of prenatal tests are invasive with risk of miscarriage
  • CVS
  • Amniocentesis
  • Non-invasive prenatal diagnosis (NIPD) possible for foetal sexing and a small number of other genetic disorders
  • Need to know what will be tested for, chance of it occurring, risks of procedure, accuracy of the test and potential outcomes of testing, including the option of termination
  • No prenatal test can guarantee normality of the foetus