Genomics at Southern Health: Transforming Patient Care

Educational Opportunities:
Online course: Preparing for consent (and many others)
Online resource
MSc, full time/part time or
CPD modules
FULLY FUNDED by HEE
Face-to-face Masters
level teaching
www.southampton.ac.uk/
medicine/postgraduate/taught
_courses/msc-genomic-
medicine.page
www.futurelearn.com
www.genomicseducation.hee.nhs.uk/courses
Primer workshop
Primer in Genomic Medicine Workshop
Friday 3rd November 2017
Funding available for NHS staff via Health Education
England (HEE)
Contact PrimerGM@soton.ac.uk for more information
The Genomics Era: the Future of
Genetics in Medicine
Online resource

Dr. Shanaya Rathod
Consultant Psychiatrist & Director of Research
Southern Health NHS Foundation Trust

Julie Dawes
Interim Chief Executive

Dr Frank Ratcliff
Wessex AHSN
So what is a Genome anyway?

Contents:
1. Talking the same language
2. Basics of biology
3. Patient friendly terms; an appeal….

Public understanding of 100,000 gnomes is low.

Genetics or Genomics?
1865
1869 Miescher Discovers DNA
1953 Watson and Crick – DNA structure

Two copies of each gene (mum and dad).
Can be dominant, or recessive.
Genetics in People;
Genetics;
Study of inherited traits
Don’t need to understand the gene/DNA to diagnose or to treat conditions.

So, what does a gene do?
DNA makes RNA makes Protein….
So what’s all the fuss about?

Genomics; the study of all the DNA at once
3,088,286,401 base pairs
23 pairs of chromosomes

So, what are you made of?
Protein. E.g. Muscle and stuff made by proteins (enzymes).
<2% of your DNA encodes proteins (Coding DNA).
i.e. <2% is Exons.
Exome…..the study of all your exons – all the protein coding bits.

98% is non-coding;
• Non-coding parts of ‘genes’
• Promoters (on/off/dimmer switches)
• Introns (10-100x greater than exons)
• Pseudo-genes
• Non-coding RNA (e.g. Ribosomal RNA, Transfer-RNA, miRNA)
• Repeat regions
• Transposons and retro-viruses (about ½ our DNA, inc 50,000 active copies of Alu)
So what does the rest of it do?

…..and what makes you YOU?
Around 3,000,000 differences between individuals
• Single Nucleotide Polymorphisms (SNP)
• Copy number variation
• Insertions and deletions
• Duplication
• Aneuploidy
• Chromosomal rearrangements
• Synonymous or non-synonymous mutations
in coding regions

Where are these differences?
Germline - inherited Germline de-novo Mosaic Tumour

“use of unfamiliar scientific phrases presents a marked barrier to communication and also creates an unhelpful
power differential of expert versus other.”
“We suggest that years of sociological research be heeded, which has indicated that one way to minimise an
unequal power dynamic2 and communicate effectively is to build on language that people are already using.3 An
example could be using the word glitch instead of variant or mutation—which is for many patients, a pejorative
word. Also, germline and somatic could be discussed in terms of inherited and acquired.”
And finally…..an appeal;
Socialising the genome, The Lancet, Volume 389, No. 10079, p1603–1604, 22 April 2017
Viv Parry, Communications lead for Genomics England
Anna Middleton, Head of Society and Ethics Research, Sanger
Mutation or variant = Glitch
Germline
Somatic
= Inherited
= Acquired

The 100,000 Genomes Project:
What is the clinical need?
Catherine Mercer, Consultant Clinical Geneticist, UHS

The 100,000 Genomes Project:
Rare Disease and Cancer

Multiple
developmental
anomalies

Multiple
developmental
anomalies
Unexplained learning
disability

Multiple
developmental
anomalies
disability Immune

Multiple
developmental
anomalies
disability Immune
Familial
Psychosis

Multiple
developmental
anomalies
Inherited
Cardiac
Conditions
disability Immune
Familial
Psychosis

Multiple
developmental
anomalies
Inherited
Cardiac
Conditions
disability Immune
Familial
Diabetes
Familial
Psychosis

Multiple
developmental
anomalies
Inherited
Cardiac
Conditions
Familial
Cancers
disability Immune
Familial
Diabetes
Familial
Psychosis

Multiple
developmental
anomalies
Inherited
Cardiac
Conditions
Familial
Cancers
disability Immune
Skeletal
Dysplasias
Familial
Diabetes
Familial
Psychosis

Multiple
developmental
anomalies
Inherited
Cardiac
Conditions
Familial
Cancers
disability Immune
Skeletal
Dysplasias
Familial
Diabetes
Familial
Psychosis
..and
thousands of
others

The burden of not knowing
Why did this happen to my child?
Why did it happen to me?
Will it happen again?
Will it happen to my own children?
Is there a treatment?

Accurate diagnosis paves the way to treatment

2013 UK Strategy for Rare Disease:
'ensure no one gets left behind just
because they have a rare disease'.

Genomics at Southern Health:
Transforming Patient Care
Overview of the 100K Genomes Project
Professor Tony Williams
Co-Clinical Director Wessex Genomic Medicine Centre
20/09/2017

Announced by David
Cameron in
December 2012
An Olympic Legacy
The 100,000 Genomes Project - origins
Announced by SoS
NHS 65th
anniversary July
2013
1. To bring
benefit to NHS
patients
2. To enable
new scientific
discovery and
medical
insights
3. To create
an ethical and
transparent
programme
based on
consent
4. To kick start
the
development of
a UK genomics
industry

The 100,000 Genomes Project in numbers

• 13 NHS Genomic Medicine Centres covering England
• Responsible for identifying and recruiting participants and for clinical care
following results
How it works

Wessex Genomic Medicine Centre
-Progress so far

RD
Solent
Southern Health

RD
UHS
Q1 2015-16

RD
PHT
Q2 2016-17
 Outreach
Salisbury
 Outreach
IOW
 Outreach
Dorchester

RD
HHFT
Q3 2016-17

RD
Southern Health
Q4 2016-17

RD
Solent
Q1 2017-18

RD
RBCH
Q2 2017-18

RD

RD

RD

RD

RD Outreach
 Outreach
 Outreach
2016-2017
 Outreach

Wessex Genomic Medicine Centre
-Progress so far

Ca
UHS
Q4 2015-16

Ca

Ca
RBCH
Q3 2016-17

Ca

Ca

Ca
HHFT
Q2 2017-18

Ca
PHT
Q3 2017-18

Ca

Ca
Dedicated Informatic team who are connecting the Data exchange between
Regional partners to support the sequencing and result interpretation

Rare Disease – Inclusive of all Specialities
Charcot-Marie-Tooth disease
Diabetes
Combined B and T cell defect
Cystic kidney disease
Dilated cardiomyopathy
Epileptic encephalopathy
Familial breast cancer
Familial colon cancer
Familial Genetic Generalised Epilepsies
Hereditary ataxia
Intellectual disability
Brugada syndrome
Long QT syndrome
Multiple endocrine tumours
Proteinuric renal disease
Renal tubular acidosis
Rod-cone dystrophy
Skeletal muscle channelopathies
Limb girdle muscular dystrophy
Multiple bowel polyps
Neuro-endocrine Tumours-
Periodic fever syndromes
IUGR and IGF abnormalities
Ketotic hypoglycaemia
A- or hypo-gammaglobulinaemia
Congenital hearing impairment
Non-CF bronchiectasis
Pulmonary atresia
Noonan syndrome plus other features
Hypertrophic cardiomyopathy
Hyperinsulinism
Osteogenesis imperfecta
Ultra-rare undescribed monogenic disorders
Significant early-onset obesity
Non-Fanconi anaemia
Epidermolysis bullosa

Cancer
 9 Cancer Pathways active with the
Haematological Cancers targeted for
Q2 2017_18
 Fresh Frozen Material taken from each
of these sites for optimised DNA
assessments
 Mutational and Structural Map of
cancer derived trough ‘subtraction’ of
germline Whole Genome Sequencing
 Genetic predisposition to come cancers
also reported (E.G Breast, Colon)
 Fast track sequencing service being
developed to support clinical timelines
 Opportunities to characterise cancer at
molecular level and support targeted
clinical trial that rely upon
stratification (Personalised Medicine)

Patient and Public
Involvement
 Research being carried out ‘with’ or
‘by’ members of the public, rather
than ‘to’, ‘about’ or ‘for’ them.
 ‘Public’ includes patients, potential
patients, carers and people who and
represent Health and Social Care
services.
 Members of patients on advisory
groups, commenting on research
materials, information sheets and
interviews with research participants
 Participant Panel
 Engagement is the two way process
between the public and research
community, involving listening and
interaction, for mutual benefit
Patient and Public
Engagement
mailto:info@genomicsengland.co.uk

WGMC – Returning Results
Implications
of this much
information

WGMC – Returning Results
Tier 1 Tier 2 Tier 3
Singletons 0.2 0.8 497
Duos 0.3 0.5 184
Trios 0.3 0.5 29
Larger 0.4 0.8 27
Every 10
cases Tier 1 Tier 2 Tier 3
Singletons 2 8 4970
Duos 3 5 1840
Trios 3 5 290
Larger 4 8 270
~25% diagnostic rate (SNV)

Wessex GMC – results
• 154 results from 51 rare disease families
• 67 results for cancer patients
Category Number of patients Comment
Tier 1 variant 6 (4 also had Tier 2)
Tier 2 variant 19 (range 1 – 4)
Tier 3 variants 3
No variant returned 23

Wessex – Connecting for Genomic Medicine
>80
Different
Disorders
Reporting
~100 RD
results by
June
Up to 1000 genes
analysed for
some disorders
Each result is 200 of these
in letters-spot
the spelling error!
>1000
DNA, RNA,
Protein,
Metabolites
samples
20M
Supporting
>50% of
recruitment
from
Mainstream
1 of 11
National
Programmes
-Certificate
-Diploma
-Master
>1500
RD
participants
>750
Cancer
patients
1000’s of
data items sent
100’s of Regional
Staff involved
Covering
every
corner
Labs

Playing Your Part
Jazz Ruttle
100,000 Genome Project Coordinator

We Need Your Help!
Engagement of wide range of clinicians and clinical services is crucial
We will take on majority of workload

Project Pathway
Identification Approach Clinic Post Clinic
Potentially eligible
pt
R&D confirm
eligibility
Introduce study &
let R&D know
R&D contact pt,
provide
information
Book clinical
appointment
Obtain consent
Collection of blood
sample & health
data
Phenotyping
Phenotyping
Feedback of results
Collection of blood
sample & health
data
Collection of blood
sample & health
data
Phenotyping

Any questions please contact us.
Project co-ordinators:
Jazz.Ruttle@southernhealth.nhs.uk
Charity.Chakanetsa@southernhealth.nhs.uk

Dr. Peter Phiri
R&D Manager

100,000 Genomes Project
A Clinician’s Perspective
Dr Ian Glass
GP & Associate Specialist in Diabetes

What is the relevence?
10% GP consultations have genetic aspect
Frequent illnesses will often have a genetic component
– IHD, Asthma, Alzheimer, DM, or single gene disorders (Huntingdons, CF)
Reproductive issues
Pharmacogenetics is the future
The link with learning disabilities
– Often no diagnosis

When to think genetics?
Known family history
Multiple affected individuals
No FHx does not mean not genetic (neurofibromatosis)
More congenital abnormalities means most likely genetic link
Atypical clinical patterns
– high cholesterol at young age
– early dementia (under 55)
– regression in a child (neurodegenerative - mitochondrial cause)
– unexpected death in apparently health individuals (under 40) and PM negative - often familial
arrhythmic cause.

When to think genetics?
Clustering of conditions within families (ovary, breast) - need increased screening
Unusual pathology - phaeochromocytoma - 25% risk of genetic
Cytogenetics - gone from looking down microscope, to array comparative genomic
hybridisation (CGH) - looks for chunks of DNA present or missing. Rapid and in 10%
of people with learning disability the diagnosis is made using this method.

The Project
Aim for genetics to be more accessible
Cost for the screening is coming down
Project started in 2012 - government funded (£550 million)
England wide with 13 hub hospitals
70,000 patients
Two arms to the project - Rare disease and cancer
1 in 17 have a rare disease and many have genetic component to them.
Using routine channels has prevented it from being found

How it will work
Concentrate on rare diseases
Identified patient will be fully consented, medical files reviewed, genomes
sequenced by blood samples, symptoms reviewed, other family members
encouraged to be recruited.
If you think there is a possibility of genetic component speak to us.
Jazz will detail referral details.

Resources
100,00 Genome Project website
Health education England have lots off info and short videos.
Primary care genetics useful resource and e-learning for general practice.

Genomics at Southern Health: Transforming Patient Care

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