The Generation study: exploring the use of WGS in newborns by Alice Tuff-Lacey, Programme Lead, Newborn Genomes Programme, Genomics England

1. Alice Tuff-Lacey
22/11/2023
The Generation study:
exploring the use of
WGS in newborns

2. 2
What does the Generation Study aim to do for the diagnostic odyssey?
Baby develops
symptoms
Baby gets
diagnosis
Baby referred to
specialist
Baby undergoes
tests
Newborns
Newborn baby

3. 01
Evaluating the utility and
feasibility of screening
newborns for a larger number
of childhood-onset rare
genetic conditions in the NHS
using whole genome
sequencing
3
Our research study’s focus
02
Understanding how babies’
genomic data could be
used for discovery
research, focusing on
developing new treatments
and diagnostics for NHS
patients
03
Exploring the potential
risks, benefits, and broader
implications of storing a
baby’s genome over their
lifetime
Three parts | All subject to ethics committee approval
** Key point: not just how each might be
implemented, but whether they should be
implemented.**

4. Five core questions we need to answer
Feasibility &
acceptability
Is the use of WGS as a tool for early
diagnosis of rare, childhood-onset,
actionable genetic conditions feasible and
acceptable?
Impacts
What is the impact (both positive and
negative) of the programme on
stakeholders and the wider system?
Uptake &
results
What is the clinical utility of genome-led
newborn screening as judged by the uplift
in screen-identified diagnoses compared
to standard
of care?
Cost effectiveness
What is the cost effectiveness of genome-
led newborn screening compared to
standard of care, estimated by a health
economic model developed to support the
programme?
Experiences & attitudes
What are stakeholders’ experiences and
attitudes to the use of WGS as a tool for
early diagnosis of rare, childhood-onset,
actionable genetic conditions?

5. 5
Where are we?
Implementation
into the NHS
If the evidence review
supports it,
implementation into
NHS routine care
1 2 3 4 5 6
We are
here
Vision
development
Co-design
and feasibility
Regulatory
Review
NHS-embedded
research study
Public dialogue,
engagement, NHS
Steering Group
Design, test, and
iterate how the
research study might
work
Inform research study
implementation
Begin proof-of-
concept in several
Trusts and through
NHS GMS to evaluate
benefits and
implementation
Review /
Evaluation
NHS Genomics
Medicine Service
Research
Collaborative to
coordinate
evaluation of the
research study’s
evidence to
inform decisions

6. 6
How Newborns works
• NHS Strategic Implementation Group – designed to support design study and
communicate expectations of it
• NHS England Newborn Genomes Programme Clinical Assurance Group to support
our ‘choosing conditions’ work
• Co-design with parents and healthcare professionals
• Engagement programme to work with stakeholders – including members of the
public
• Ethics engagement work: to explore ethical issues with ethical stakeholders and
the public
Expert working groups established, focusing on:
• Conditions the research study should screen for
• Recruitment
• Ethics
• Evaluation
• Education and training
• Communicating results and onward support
• Interpretation and reporting
Core in-house team

7. 7
Public, participant, and patient perspectives
Newborn
Genomes
Programme
Public dialogue and engagement Standing structures
Ethics engagement
• Newborns dialogue (2021)
• Public consultation on genes framework principles
(2022)
• Dialogue with ethnic minority community leaders,
focused on communicating the programme to different
communities (Q1, 2023)
• Dialogue on research access to data (Q1, 2023)
• Parent ethnography (2022)
• Recruitment working group (ongoing)
• Parent interviews (ongoing)
• Midwife workshops (ongoing)
• Site engagement and consultation, including with community
groups (planned)
• NHS Steering Group
• NHS Clinical Assurance Group
• Ethics Advisory Group
• Participant Panel
• Working groups
• Deliberation with experts through ethics
working group
• Ethics research, e.g., literature review
• Standing ethics group to gather views / consult on
ethical issues as they arise (Q1, 2023)
• Ethics stakeholder workshops
• Public sessions, e.g., Progress Educational Trust series
Trust
Co-design

8. 8
Participant experience
Participant
NHS
GEL + partners
In partnership with NHS

9. 9
Choosing which conditions to
screen for
The challenge: there are thousands of conditions that
could be detected through whole genome sequencing
– but we may not want to look for all of them
The programme will only screen for a specific set of
conditions, genes, and variants
Principles and criteria for screening already exist –
we are taking a bespoke approach in the context of
a UK-based research programme
Four principles…
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-
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10. 10
Overview
Principles
Principle A: there is strong evidence that the
genetic variant or variants cause the condition
and can be reliably detected
Principle B: a high proportion of individuals who
have the genetic variant or variant would be
expected to have symptoms that would have a
debilitating impact on quality of life if left
undiagnosed
Principle C: early or pre-symptomatic intervention
for the condition has been shown to lead to
substantially improved outcomes in children,
compared to intervention after the onset of
symptoms
Principle D: Conditions screened for are only
those for which the interventions are equitably
accessible for all

11. 11
Governance and timeline
Sign-off
Aware
and
consulted
Developing principles
for choosing conditions
Reviewing conditions &
genes against principles using
a standardised approach
Confirming planned pathway
and that this can be
operationalised for each
condition
Defining variant selection
and prioritisation for
each gene
Conditions framework
working group
NHS Newborn Steering
Group
NHS Clinical Assurance
Group with input from
expert groups
Conditions framework
working group
NHS Newborn Strategic
Implementation Group
Engagement with GLH
clinical scientists and NHS
England
NHS Newborn Strategic
Implementation Group
Members of public,
healthcare professionals and
rare disease communities
Sept 2021 – Aug 2022
Sept 2022 – Summer 2023
Summer 2023 – Autumn 2023
By Sept
2023
By go-
live (late
2023)
NHS Clinical Assurance
Group and Treatment and
Interventions sub-group with
input from expert groups

12. 12
Specialities in scope
Audiovestibular
Cancer
Cardiology
Dermatology
Endocrinology
Gastroenterology
Haematology
Immunology
Metabolic
Nephrology
Respiratory
Ophthalmology

13. 13
Variant Prioritisation Strategy
Inclusion list
Curated list of
disease-causing
variants
Data
refinement
ACMG classification,
Internal AF Matching
expected
inheritance
mode
Singletons, so
phase info from
sequenced read
groups
Exclusion list
Technical and
database entry
issues
Data
refinement
Transcript region-
specific, Consequence
type,
Internal AF, External AF
Predicted high
impact
variants
Protein truncating
variants,
include CNVs
Manual
variant
review
Variants
reviewed
manually before
further action
Aim: to only identify variants that have potential to reach pathogenic or likely pathogenic classification in the absence of clinical
features in the newborn.

14. Communicating results
14
Note: Why we are not saying
‘positive’ or ‘negative’
• Communicating ‘condition suspected’:
• Communicating ‘no conditions suspected’:
• ~1% of babies (~1000 expected)
• How: by phone from an NHS specialist, a few
weeks after birth
• Aim to arrange an appointment for the baby and
their families to be seen in an NHS specialist clinic
to have confirmatory testing and appropriate
further care
Communicating ‘sample failure / no results returned’:
• ~99% of babies
• How: by email/letter, a few months after birth
• Sent by Genomics England to parents, with a copy also
sent to the baby’s GP for their record
• Includes information about what to expect in the future as
a study participant
• How: by email/letter
• Sent by Genomics England to parents
• May occur if samples are not taken or the test could not
be completed

15. 15
The locations of our study recruitment
NHS sites throughout England
Factors we’re considering when choosing sites:
Site opening will be in stages
• Birth volumes
• The diversity of people who use the hospital
• Maternity department performance
• Starting with 3-5 trusts
• Increasing up to 40 trusts

16. 16
Regional approaches
Develop treatment and support pathways
Refer and coordinate 'condition suspected' results
(Regional Coordinators)
Identify senior leadership/champions
Raise awareness and engagement
Support communications and press enquiries
Support regional study initiation and delivery
Enable access to education and training
Genomic Medicine Service Alliances are regional structures,
and the study will provide dedicated funding to work with
them to:

17. Thank you
Visit: www.genomicsengland.co.uk
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