1. Genetics made easy: demystifying genetic testing
Dr Catherine McWilliam
Dawn O’Sullivan

2. Workshop Aims
An overview of the role of clinical and molecular genetics
How to arrange genetic testing
Interpreting results
Case examples

3. Inherited Cardiac Disease
Hypertrophic Cardiomyopathy
Around 50% maybe caused by a dominantly inherited pathogenic variant
Familial Arrhythmia
Long QT syndrome
Brugada
Arrhythmogenic right ventricular dysplasia/cardiomyopathy
Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT)
Inherited aortopathies
Marfan, Loeys Dietz
Dilated Cardiomyopathy
Fewer genetic causes but worth considering
Congenital cardiac disease

4. Genetic Testing: What are the pro’s and cons?

5. Genetic Testing: pros and cons
To allow identification of at risk relatives
Targeted screening
Allowing early diagnosis and intervention
Confirm diagnosis
At risk relatives may not wish to know
May not clarify diagnosis if variant of uncertain significance identified
Feelings of guilt if passed on to younger generation
Predictive testing may turn the ‘well’ individual into a patient
Employment/Finance/ Insurance issues

8. Consent: What do we need to think about?

9. Consent To a specific test
Information to be shared with other family members on request of their doctor
Information to be used to allow accurate testing of family members
To DNA storage
For DNA to be used for validating test (ie within the lab, anonymously)
For DNA to be used in research

10. Aug 2018 Sophia Genetics Cardio Solution
Cardiac Arrhythmia screening in Scotland
Jul 2004 KCNQ1, KCNH2, SCN5A selected exons (dHPLC +seq)
Oct 2004 NSD funding for LQTS
May 2005 LQTS: addition KCNE1 & KCNE2
Jun 2008 Complete LQTS gene screening (dHPLC + seq,
1 gene / 56 days)
Jul 2008 Trainee project: ARVC (PKP2) screening
Jul 2009 Complete LQTS gene screening (Sequencing
1 gene / 40days)
Jan 2010 Complete LQTS gene screening (5 genes / 56 days
May 2010 ARVC: addition DSG2 & DSP
Sept 2010 UKGTN additional provider: LQTS, BrS, JLNS
Dec 2010 CPVT: RYR2
Jan 2011 ARVC: Addition DSC2
Jan 2017 Cardiac Arrhythmia 50 gene NGS panel
days
Aug 2018 Sophia Genetics Cardio Solution
56 days
Long QT (LQTS) development
Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) development
Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) development
Cardiac Arrhythmia NGS

11. Cardiac Arrhythmia Subpanels

12. Variant classification
Implementation of NGS (bigger panels) results in more Variants of Uncertain Clinical Significance (VUS)
Very little evidence available in the literature / databases
Guidelines are intended for general use in classifying variants in patients with rare diseases. Disease-specific guidelines are being developed for disorders where different evidence thresholds are required, e.g. cardiac disorders
Still framework open to interpretation and need for professional judgement

13. Variant classification system
*currently under review within the Scottish Consortium

14. Variant classification
Rules where clinical input required
PS2 De novo (both maternity and paternity confirmed) in patient with the disease and no FH
PM6 Assumed de novo, but without confirmation of paternity and maternity
PP1 Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (may be used as stronger evidence with increasing segregation data)
PP4 Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology
Greater need for good clinical and laboratory communication
Regular MDTs (lab, clinical genetics, other specialists) / VUS classification meetings
Details in referral important: patient phenotype if known and what clinical tests carried out, specific relationship to the patient, segregation data
This evidence must be formally recorded rather than verbal communication
Likely to be a change in how VUS are reported but communication will still be essential

15. Cases

16. Learning point
Variant reclassification

17. Learning point Availability of genetic testing is expanding
It can be worth looking again….

18. Learning point Beware the non-informative family history
Complexities of cascade screening in a new diagnosis

19. Learning point
Cascade screening in a timely manner/as suggested by the presentation

20. Summary
Genetic testing can be very helpful to support diagnosis and target screening for family members
Molecular genetics is complex and not always easily interpretable – if in doubt please ask!
Patients and families can find this complexity difficult and it is better to make them aware of the possibility of ‘variant of unknown significance’ at the start of the journey