diagnosis for the undiagnosed

1. ERN ITHACA; Diagnosis For The
Undiagnosed
Jill Clayton-Smith
Manchester Centre For Genomic Medicine
Coordinator, ERN ITHACA

2. Learning Objectives
• To increase knowledge of the prevalence and types of congenital
malformations and intellectual disability
• To examine the benefits of syndrome diagnosis for patients/parents and
professionals
• To gain awareness of the clinician’s framework for the diagnosis of a rare
malformation/intellectual disability syndrome
• To gain information about how ERN ITHACA plans to facilitate diagnosis and
management of rare congenital malformations and intellectual disability
syndromes
• To consider the part that patients/parents have to play in furthering
knowledge and research into rare congenital malformation and intellectual
disability syndromes.

3. Congenital Malformations
• Affect 2-3% of livebirths
• Account for high proportion of
hospital admissions and deaths in
childhood
• When multiple often occur together
with other problems e.g. of growth of
development as part of a “syndrome”
• Genetic, environmental and
multifactorial causes
• Syndromic disorders often difficult to
diagnose
• Birth of a child with congenital
malformations poses many questions
for both parents and professionals
From National Foundation For Ectodermal
Dysplasias Website

4. Intellectual Disability
Impairment of:
• intellectual abilities (reasoning,
learning, problem solving) IQ>70
• adaptive behaviour (communication,
interaction, organisational skills)
• apparent before the age of 18
Affects 1-3% of population
85% mild IQ 55-69
10% moderate IQ 40-54
5% severe IQ 25-39
1% profound IQ <25
May be associated with other features as
part of a syndrome
Genetic, environmental and multifactorial
causes
www.downs-syndrome.org.uk

5. Why Is Syndrome Diagnosis Useful?
Consider the following scenario:
Lynda and Pete are first-time parents. Their daughter Poppy has been born following a
difficult pregnancy as Lynda was troubled by recurrent urinary tract infections and
needed several courses of antibiotics. Unfortunately Poppy has been noted to have
several problems after birth including a congenital heart defect, cleft palate and some
unusual facial features. Lynda and Pete are shocked; no-one else in the family has had
identical problems although Lynda’s younger sister, currently eight weeks pregnant
had a heart murmur as a child.
1. What questions might Lynda and Pete have?
2. What questions might the paediatric doctors have?

6. Lynda and Pete’s Questions
• What is the diagnosis?
• What caused it?
• Am I to blame? What about the antibiotics I
took?
• What does it mean for our child?
• Can it be treated/cured?
• Will it happen again?
• Where can I find out more information?
• Does it have any implications for Lynda’s sister?

7. The Neonatologist’s Questions
• What is the diagnosis?
• How shall we treat this baby?
• What is the long term prognosis?
• What investigations do we need to do?
• Do we need to screen for any other
complications?
• What shall we tell the parents?
• Where can we find more information? Is there
literature or a local expert?

8. The Ease Of Diagnosis Varies
From Bramswig et al Hum Genet 2017
TRIP12 phenotype

9. The Ease Of Diagnosis Varies
Physical features are less distinctive
Impossible to think of a single gene to
target
Distinctive physical features
Clinician has seen similar patients before
Can make a guess at diagnosis
Possible to target causative genes
Good chance of identifying mutation
De Lange Syndrome

10. Strategy For Diagnosis
• First line tests, usually carried out by paediatrician. These will
include basic blood count, biochemical tests, urine tests and a
chromosome microarray test
• If normal, referral to a clinical geneticist for further clinical opinion
and further, second line tests
• Assessment may include sharing information with colleagues, and
researching literature and databases
• Targetted test if a specific diagnosis suspected
• Tests may include X-Rays and other tests as well as genetic tests
• If no diagnostic ideas, broader test of genetic make up, e.g. panel
test, exome sequence or genome sequence

11. Tom’s Diagnostic Journey
learning problems
noted Visits family doctor
Referred to paediatrician
Battery of tests including
microarray
Seen in genetic
clinic
more tests
Case discussion DIAGNOSIS!

12. The Genetic Assessment
• Detailed history/family history
• Detailed examination
• Search for physical anomalies,
describe them accurately and
consistently ( HPO/Orpha
terms)
• Photographs can help
• Appropriate investigation
• Put all of the above together

13. Investigations
Single gene sequencing
Whole exome/whole genome
sequencing
Clinical investigations Array CGH

14. But it may not be that easy….
• Nothing shows up on the
blood tests
• Skin biopsy
recommended and
nothing shows up on that
either
• Results of X-Rays and
scans are non-specific
• Genetic testing reveals a
change but it’s a “variant
of unknown significance”
VOUS, never seen in
anyone else before

16. Diagnostic Odyssey
• Multiple appointments
• Many investigations
• Days off school and
work
• Travel and other
expenses
• Consulting others
including Dr Google

17. What Might Help To Increase The
Chance Of Making A Diagnosis?
• Searchable databases
• Sharing information more
broadly to seek more
opinions
• Face recognition software?
• Availability of further
genetic tests e.g. testing
gene expression (how the
genes are working) From Hammond P et al.
Am J Hum Genet 2005

18. Testing tissues other than blood
• Genetic testing of skin or
other tissue is helpful if
you are considering
mosaicism, the presence
of more than one type of
cell in the body, each with
a different genetic
pattern

20. Rates of Diagnosis
• 17% of individuals with birth defects/ID have a
microarray abnormality
• Approximately 30% will be solved by whole
exome sequencing
• This rises to around 40-45% with whole genome
sequencing
• What might explain the rest?

21. Other explanations
• Technical; poor
sequencing
• Missed on analysis of
data (bioinformatics)
10-15%
• Cause is environmental
• Cause is epigenetic
• Cause is polygenic or
multifactorial and thus
harder to find
Antiepileptic drug exposure in utero
evolutionmedicine.com
Epigenetic

22. Other explanations
• Poor sequencing
• Missed on analysis of
data (bioinformatics)
• Cause is environmental
• Cause is epigenetic
• Cause is polygenic or
multifactorial
• Gene not previously known to
cause a
human disease
• Gene is actually missing in the
patient
• Change not picked out as
being significant as not
enough known about it

23. What Next?
• Look for other possibilities for investigation?
• Stop pursuing diagnosis for now and review when older
• Offer support; e.g. SWAN or relevant support group
• Seek broader opinions; present at meetings or seek
consent from parents to publish to bring to attention of
others

24. Role of parents/carers in diagnosis
• Parents are committed to finding a diagnosis for their child and may have
already done this by the time of the appointment e.g. through google
• Parents notice tiny differences in their child’s physical features or
behaviour which doctors might miss – we need to ask about these
• Bringing photos/video clips to clinic is often helpful
• Giving consent for sharing of information or diagnostic tests might be
difficult for a parent to do but can be helpful
• Parents are often in touch with other families e.g. through social media –
they will have seen more cases of syndrome X than the doctor has in many
cases and we can learn from them

25. ERN ITHACA :
Intellectual Disability, TeleHealth And Congenital
Anomalies
A European Reference Network For Rare Congenital
Malformations and Intellectual Disability
• Rare multiple anomaly syndromes
• Rare types of intellectual disability
• Rare chromosome disorders
• Undiagnosed syndromic disorders
Agreement with overlapping networks re disorders covered
Manchester chosen to coordinate ERN in view of previous experience

26. ERN ITHACA
• Aimed for good
geographical coverage
• 38 centres from 15
countries
• Plan to bring centres from
more countries on board
• Keen to encourage
patient/lay group
participation
• All needed to demonstrate
expertise
• Expectation that all will
participate in activities

27. Aims Of Our ERN
• Share information through
registers/natural history
studies
• Share expertise to improve
multidisciplinary care
• Facilitate diagnosis through
case-sharing
• Increase collaborative research
• Teaching and training
initiatives
https://ec.europa.eu/health/ern/videos_en

28. ERN ITHACA; Facilitating Diagnosis
Previous experience has shown that sharing information
and photographs of patients in a secure web space can
lead to new diagnoses, discovery of new syndromes and
new genes, as well as being useful for management and
educating the reviewers.

29. www.dyscerne.org
and from experts…..

30. www.dyscerne.org

31. EU Case-Sharing Platform;CPMS
• CPMS developed by OpenApp
• Consent form designed by EU
Data Protection and Legal
Teams with
coordinators/patients
• Upload anonymised patient
features and images
• Discussion board and Integral
report production
• Responsibility for care lies with
the submitting clinician
• Trialled version 1 and fed back
comments, waiting for next
version

32. Research Collaborations
• Circulation of calls for
patients with rare
diseases for research
studies
• Gathering data on
cohorts of individuals
with Mowat Wilson
syndrome to construct
growth curves
• Collection of photos for
an evaluation of facial
recognition software

33. SOLVE-RD Project
• H2020 project led from
Tübingen
• 19,000 unsolved cases
who have already had
exome sequencing
• Re-analysis of data
• Further tests
• ERN-ITHACA will
contribute ~ 5000

34. Expert Patient Care
• Rare disease guidelines are
challenging to develop
• Collecting existing,
methodologically robust
guidelines
• Translated some of these
• Consensus meetings; FVS April,
Noonan syndrome
June , Pitt Hopkins syndrome
• Aiming for a user-friendly
template
• Make sure they comply with
AGREE II guidelines

35. Patient Registers
• Contain key information about
patients which can shed light
on the natural history of the
disorder
• Form a resource for
identification of patients for
future clinical trials
• Can highlight issues such as
side effects of drugs before
they would otherwise be
noted
• Costly to set up and maintain
• Currently partnered with
GenIDA and Nijmegen Human
Genetic Disease initiatives

36. Teaching and Training
• Survey of existing resources
• Upload to EU collaborative portal of high
quality teaching materials we can share
• Survey of resources we need to develop
• Trainee exchanges/bursaries
• Aim to develop an accredited Masters course
in Rare Disease

37. Reaching Out
• Interactions with other
ERNs
• Collaborative research
with other ERNs
• Engagement with
patients
• Looking wider;
Matchmaker exchange

38. Roles of Patients/Parents/Lay Groups
• Participation on ERN Board and in
Work Packages
• Active members of the guideline
groups
• Patient-entered data e.g. in
GenIDA
• Review of patient information
and consent forms
• Contribution to teaching and
training materials and to training
needs survey
• Steering committee membership
• Financial support
• Help with Patient Survey
• Advice on feasibility and design of
research studies
• Flag up research areas of interest
• Dissemination of agreed care
plans
• Lead on future publications
• Prepare content for the ERN
ITHACA website
• Increase role on patient register
work
• Completion and dissemination of
surveys
• Lobbying with higher bodies
Working within the challenges of limited resources

39. ERN ITHACA website
• Public face of our ERN
• For general public to
access
• Links to resources
• News
• Info on research and
how to access services
• www.ernithaca.org

40. Challenges and Opportunities
• Coordinating many centres
• Different languages and
legal systems
• Trying to fulfil all patient
expectations
• Limited funding
• Complex budgeting, admin
and reporting
• IT still in development and
needs improvement
• Getting centres to engage
and share
• BREXIT!
• Potential to improve
diagnosis and care of
patients
• Eligibility for EU funding
initiatives
• Good position for future
clinical trials
• Improving IT
• Opportunities for trainees
• Enhance research and
publications

41. Summary
• Congenital malformations and intellectual disability are
common
• Diagnosis has many benefits for the individual, their
family and professionals involved
• A structured approach to diagnosis with sharing of
expertise can facilitate diagnosis
• ERN ITHACA has made progress with planned goals and
achieved all Year 1 deliverables but the work is
challenging
• Patients and parents working with professionals within
ERNs play a key role in the ERN initiatives and we have
more to learn about working together

42. www.ernithaca.org
michael.smith@mft.nhs.uk Project manager