Genetic Counselling in relation to genetic testing Dr Julie Vogt Consultant Geneticist West Midlands Regional Genetics Service September 2016
Disclosures for Research Support/P.I. Employee Consultant Major Stockholder Speakers Bureau Honoraria Scientific Advisory Board No relevant conflicts of interest to declare No relevant conflicts of interest to declare No relevant conflicts of interest to declare No relevant conflicts of interest to declare No relevant conflicts of interest to declare No relevant conflicts of interest to declare No relevant conflicts of interest to declare - 2 -
- 3 - Outline of presentation Availability of genetic investigations Value of genetic testing Ordering genetic investigations Interpreting genetic results Communicating genetic results
- 4 - Availability of genetic investigations Karyotyping Microarrays Single gene tests Gene panels Exome and genome sequencing (100K)
Standard karyotype Microscopic Low resolution Labour intensive Subjective
Microarray Deletion 7q31.1q31.2 High resolution Higher throughput More accurate Cost effective 1 st line testing for DD since 2006 5.85-7.8Mb - 6 -
Resolution Molecular Genetics Cytogenetics 1bp 5Kb 5Mb >10Mb DNA microarray 1mm 5 to 5,000m >5000m
- 8 - Next-Generation Sequencing Exact order of nucleotides in a given DNA or RNA sequence Whole Exome Sequencing (WES/ WGS) Targets the coding regions (exons) of the genome 1% of total genome (25,000 genes) Incidental / secondary findings ~1% in WES WES cheaper than Whole Genome Sequencing
recruited over 12 600 families from around the UK and Ireland Completed array-cgh Exome sequencing ongoing 80 000 variants were identified from exome sequencing and microarray analysis in each individual average 400 were rare and predicted to be protein altering de novo and segregating variants in known developmental disorder genes a diagnostic yield of 27% in 1133 undiagnosed children with developmental disorders
GENOMICS ENGLAND AND THE 100,000 GENOMES PROJECT Genomics England, with the consent of participants and the support of the public, is creating a lasting legacy for patients, the NHS and the UK economy, through the sequencing of 100,000 genomes.
- 11 - Value of genetic testing Confirmatory genetic diagnosis Early diagnosis and treatment Preconception / Prenatal testing Predictive genetic testing Cascade carrier testing Population screening
- 12 - Value of genetic testing Stratify risk Opportunistic screening though incidental findings Mechanisms of disease Pharmocogenomics Identify novel therapeutic targets Effective, tailored treatments
- 13 - Ordering genetic investigations Ordering clinician Properly trained and prepared in genetics and genomics Clinical assessment and understanding of genetic counselling essential Pedigree analysis Risk assessment Guide genetic testing Collection of most informative samples Assist with interpretation of results Clarify risk for other relatives
- 14 - Ordering genetic investigations Incidental findings Minimum list of incidental findings Disease genes, verifiable and amenable to medical intervention Categories of variants to be reported Uncertainties: penetrance, health consequences, further investigation Ethical considerations asymptomatic children with adult onset disorders genetic results may have implications for other relatives Patient autonomy versus future potential health benefit Consult a clinical geneticist
Ordering genetic investigations Laboratory responsibility for analysis, interpretation, report generation, clear summary of analysis variant (1) pathogenic, (2) likely pathogenic, (3) uncertain significance, (4) likely benign, or (5) benign Patient competent to make their own health-care decisions children or significantly impaired adults teenagers and mildly impaired adults discussion and assent - 15 -
Interpreting genetic results Definitive genetic diagnosis Pathogenic mutation Well characterised mutation Consistent with phenotype Probable genetic diagnosis Likely pathogenic mutation Consistent with clinical presentation No genetic diagnosis No genetic variant detected Genetic variants of uncertain significance (~1-5% of sequencing reports) - 16 -
Interpreting genetic results Incidental findings ~ 1% of sequencing reports Insufficient evidence of benefits, risks, and costs of disclosing Reporting incidental findings with medical benefit Sequence variation is previously reported and is a recognized cause of the disorder Sequence variation is previously unreported and is of the type which is expected to cause the disorder Confirmatory investigation - 17 -
- 18 - Communicating genetic results Responsibility of ordering clinician Interpreting and communicating results to family Re-evaluate family and medical history Contextualise findings Appropriate surveillance for at risk
Clinical Examples for Discussion Karyotyping Microarrays NGS - 19 -
Thank you for your attention Any questions? - 20 -