genetic counselling in relation to genetic testing

ISTH Advanced Training Course

Dubai, UAE


Genetic Counselling in

relation to genetic testing

Dr Julie Vogt

Consultant Geneticist

West Midlands Regional Genetics Service

September 2016


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


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


Dubai, UAE

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Availability of genetic investigations

Karyotyping

Microarrays

Single gene tests

Gene panels

Exome and genome sequencing (100K)


Dubai, UAE

Standard karyotype

• Microscopic• Low resolution• Labour intensive• Subjective


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


Dubai, UAE

1bp >10Mb

Molecular Genetics Cytogenetics

5Mb5Kb

DNA microarray

Resolution

>5000m1mm 5 to 5,000m


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


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


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.

http://www.genomicsengland.co.uk/

http://www.genomicsengland.co.uk/


Dubai, UAE

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Confirmatory genetic diagnosis

Early diagnosis and treatment

Preconception / Prenatal testing

Predictive genetic testing

Cascade carrier testing

Population screening


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Stratify risk

Opportunistic screening though incidental

findings

Mechanisms of disease

Pharmocogenomics

Identify novel therapeutic targets

Effective, tailored treatments


Dubai, UAE

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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


Dubai, UAE

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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


Dubai, UAE

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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


Dubai, UAE

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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)


Dubai, UAE

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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


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


Dubai, UAE

Clinical Examples for Discussion

Karyotyping

Microarrays

NGS

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Dubai, UAE

Thank you for your attention

Any questions?

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