L9: Personalised medicine and ethics

Characteristics of personalised medicine

Definition

  • an emerging approaching for disease prevention and treatment: taking individual variability in genes, environment and lifesetyle into account

  • also known as precision medicine

How it works

  • combine pharmacology and genomics to develop effective and safe medications based on one's genetic makeup

  • utilise polygenic risk prediction for prevention treatment

    • polygenic risk score: sum of all risk-increasing and risk -decreasing variants weighted by their magnitude of effect

Advantages

  • prevent adverse drug effect

  • determine the optimal drug dosage based on one’s genetic makeup

  • More effective and precise therapies.

  • Potential for early disease detection and prevention.

Ethical Issues related to personalised medicine

Paediatric genome-wide sequencing

  • whether parents have the right to make decision regarding sequencing for child

  • whether to use exam or genome-wide or limited genetic test

  • whether parents should get the sequencing result regarding the risk of late-onset disease of their child

  • Eugenics

    • A social movement or philosophy that supports enhancing human traits by encouraging the reproduction of desired individuals and traits, while discouraging the reproduction of less desired individuals and traits.

Carrier screening

  • a genetic test on asymptomatic individual to determine if one carries a genetic variants associated with a recessive disorder

  • purpose

    • screen for daises casual genetic variants before or during pregnancy

    • provide useful info for potential parents for family planning and consider other reproductive options

      • e.g. donor gametes, preimplantation genetic diagnosis

    • provide info for public health sectors to improve prenatal diagnosis and paediatric care management

Ethnicity-specific carrier screening

  • genetic testing aimed at identifying individuals within specific ethnic groups who carry gene mutations associated with certain inherited condition

  • limitations

    • multi-ethnic background→ some couples at risk may be missed by the screening

    • collective risk posed by rare diseases may outweigh that of more common diseases

  • examples

    • cystic fibrosis and spinal muscular atrophy: many ethnics

    • hemoglobinopathies: southeast asian, African, southern European

    • familial dysautonomia: Ashkenazi Jewish

    • Tay-Sachs disease: Cajun or French Canadian

Panethmic carrier screening

  • Genetic screening regardless of one’s ethnic background

  • considerations

    • clinical severity

    • medical actionability

    • technical issues: sensitivity and specificity

    • carrier frequencies

Secondary findings in NGS

Background

  • Primary findings: pathogenic changes in a gene or genes that are relevant to the diagnostic indication for which the sequencing was ordered

  • Secondary findings (SFs): findings that are apparently not relevant to a diagnostic indication for wine the sequencing was ordered

    • Anticipated and actively sought in the study, sometimes based on recommendations from outside experts.

  • Incidental findings (IFs): anticipated or unanticipated with exam and genome sequencing

Research-based vs Clinical sequencing

  • research-based sequencing

    • participants are willing to contribute to the research

    • mostly not expected for any genetic finding

  • clinical sequencing

    • expected for genetic findings related to the disease of the proband

    • not expected for secondary findings

    • usually receive genetic counselling

Guidelines of returning SFs

  • Clinical sequencing

    • ACMG: routinely inspect a panel of 59 genes deemed medically actionable to detect pathogenic variants, which may be unrelated to the testing purpose

    • ESHG: Use a filter to avoid receiving unexpected findings or findings that cannot be interpret; unexpected findings that indicate a serious health issue should be returned

    • CCMG: use a filter to avoid incidental findings; Incidental findings with a highly penetrant condition that is medically actionable in childhood should be returned

  • Human research

    • participants should have the right to know and decide about the return of results

    • if return: mist provide results within a framework of healthcare or counselling

Main considerations of returning SFs

  • clinical actionability: the findings should be medically actionable

  • gene-disease validity

  • variant pathogenicity