ISTH Advanced Training Course
Dubai, UAE
ISTH Advanced Training Course
Genetic Counselling in
relation to genetic testing
Dr Julie Vogt
Consultant Geneticist
West Midlands Regional Genetics Service
September 2016
ISTH Advanced Training Course
Dubai, UAE
Disclosures for
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Research Support/P.I. No relevant conflicts of interest to declare
Employee No relevant conflicts of interest to declare
Consultant No relevant conflicts of interest to declare
Major Stockholder No relevant conflicts of interest to declare
Speakers Bureau No relevant conflicts of interest to declare
Honoraria No relevant conflicts of interest to declare
Scientific Advisory
BoardNo relevant conflicts of interest to declare
ISTH Advanced Training Course
Dubai, UAE
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Outline of presentation
Availability of genetic investigations
Value of genetic testing
Ordering genetic investigations
Interpreting genetic results
Communicating genetic results
ISTH Advanced Training Course
Dubai, UAE
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Availability of genetic investigations
Karyotyping
Microarrays
Single gene tests
Gene panels
Exome and genome sequencing (100K)
ISTH Advanced Training Course
Dubai, UAE
Standard karyotype
• Microscopic• Low resolution• Labour intensive• Subjective
ISTH Advanced Training Course
Dubai, UAE
MicroarrayDeletion 7q31.1q31.2
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5.85-7.8Mb
• High resolution• Higher throughput• More accurate• Cost effective• 1st line testing for DD
since 2006
ISTH Advanced Training Course
Dubai, UAE
1bp >10Mb
Molecular Genetics Cytogenetics
5Mb5Kb
DNA microarray
Resolution
>5000m1mm 5 to 5,000m
ISTH Advanced Training Course
Dubai, UAE
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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
ISTH Advanced Training Course
Dubai, UAE
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
ISTH Advanced Training Course
Dubai, UAE
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.
ISTH Advanced Training Course
Dubai, UAE
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Value of genetic testing
Confirmatory genetic diagnosis
Early diagnosis and treatment
Preconception / Prenatal testing
Predictive genetic testing
Cascade carrier testing
Population screening
ISTH Advanced Training Course
Dubai, UAE
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Value of genetic testing
Stratify risk
Opportunistic screening though incidental
findings
Mechanisms of disease
Pharmocogenomics
Identify novel therapeutic targets
Effective, tailored treatments
ISTH Advanced Training Course
Dubai, UAE
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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
ISTH Advanced Training Course
Dubai, UAE
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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
ISTH Advanced Training Course
Dubai, UAE
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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
ISTH Advanced Training Course
Dubai, UAE
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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)
ISTH Advanced Training Course
Dubai, UAE
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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
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Dubai, UAE
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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
ISTH Advanced Training Course
Dubai, UAE
Clinical Examples for Discussion
Karyotyping
Microarrays
NGS
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ISTH Advanced Training Course
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Thank you for your attention
Any questions?
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