new maladies rares et génomique : introduction générale - defidiag · 2019. 2. 8. · 10ème...
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10ème journée ITS – 6 & 7 novembre 2018 – Strasbourg – https://its.aviesan.fr
Maladies rares et Génomique : introduction générale - DEFIDIAG
Hélène Dollfus – HUS et UMRS_1112 Strasbourg
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Les Maladies Rares: un enjeu de santé publique
• >7000 maladies rares >80 % génétiques
• 1 personne sur 20 : • 30 millions d’Européens • 5 millions de Français • ≈ 300 000 dans GRAND-EST • ≈ 120 00 en Alsace
• Tous les âges (début enfance >60 %)
• > 80% entraînent un (POLY) handicap chronique
• Réduction de la qualité et l’espérance de vie
• TRANSDISCIPLINAIRE : Médecine Générale et toutes les spécialités médicales sont concernées
• => PNMR (1-3) (3 CRMR – 6 CCMR- 1 FSMR)
• => PFMG 2025 (HUS PI du projet pilote DEFIDIAG)
• => ERN (coord d’un des 24 ERNs)
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UMRS_1112: Laboratoire de Génétique Médicale Evaluation HCERES 02/02/2017
Service de génétique médicale et
CRMR, CCMR, FSMR, ERN, …
Expertise Clinique aux HUS : Maladies Rares Génétiques • Service de Génétique Médicale • CRMR : coordinateurs – constitutifs –
compétences : Oph, Ano Dev, DI • Filière SENSGENE (coord), FSMR ANDI-rare, … • Réseau Européen de Référence: ERN-EYE (coord)
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UMRS_1112: Laboratoire de Génétique Médicale Evaluation HCERES 02/02/2017
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UMRS_1112: Laboratoire de Génétique Médicale Evaluation HCERES 02/02/2017
De la MALADIE RARE à la MALADIE COMMUNE
PATIENT GENE-
MUTATION
GENETIQUE TRANSLATION
NELLE
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Capture required
(biais C-G rich)
High Density coverage
10’-100’ genes
99% completeness
Limited CNVs
detection
No SV detection
« Cheap » – « Easy »
« Unique shot »
Need sufficient
number of patients
One disease group
Low incidental
findings
Capture required
(biais C-G rich)
Moderate high density
1% genome
97% completeness
Limited CNVs
detection
No SV detection
Weak on non coding
region ( 3’-5’UTR)
Reinterperetation
Re-use possible
Incidental findings
No capture required
More complete &
uniform coverage
97% genome
SVs detection :
Better CNVs, balanced
SV, Breakpts….
Non coding: deep in
intronic /3’-5’UTR/
promotors, …
Reinterperetation
Re-use possible
Cost - Data analysis
Interpretation
and storage
Incidental findings
PANEL EXOME GENOME
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UMRS_1112: Laboratoire de Génétique Médicale Evaluation HCERES 02/02/2017
AII-3
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Ex7: c.[579dupT];[=]
Ex7:[=];[=]
Ex7:[=];
[=]
Ex7:
c.[579dupT];[=]
Ex7:
c.[579dupT];[=]
Ex16:
c.[1746G>T];[=]
Ex16:
c.[1746G>T];[=]
Ex16:
c.[1746G>T];[=]
Ex16:[=];
[=]
Ex16:[=
];[=]
1 2
1 2 3
I
II
SYNDROME ALZIAL: microcéphalie - rétinopathie
Whole exome sequencing (Illumina HiSeq 2500, GATK, VaRank) TUBGCP4 (Tubulin Gamma Complex Associated Protein)
c.579dupT (p.Gly194Trpfs*8): frameshift variant EVS 1/11597 and ExAC 14/120608 (MAF 0.0001161) c.1746G>T (p.Leu582Leu) : synonymous variant predicted to have a local splice effect as a strong cryptic acceptor site (Alamut) EVS 6/12096 and ExAC 24/66538 (MAF 0.00036)
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UMRS_1112: Laboratoire de Génétique Médicale Evaluation HCERES 02/02/2017
Pr Uwe Strahle, Dr C Etard, KIT, Karlsruhe, Allemagne
Etape 1: Validation autres familles
Pr Tony Moore, UCL, London Dr Annick Toutain, CHU Tours
Etape 2: Validation fonctionnelle in vitro sur cellules de patients
Collaboration avec A Merdes
CNRS - Université Toulouse
Fibroblastes des patients
Altération de la nucléation
et organisation microtubulaire
Etape 3: Validation in vivo sur morpholinos zebrafish
Mutations in TUBGCP4 alter microtubule organization via the -tubulin ring complex TuRC in autosomal recessive microcephaly with chorioretinopathy. Sophie Scheidecker*, Christelle Etard*, Laurence Haren*, Corinne Stoetzel, Sarah Hull, Arno Gavin, Vincent Plagnol, Séverine Drunat, Sandrine Passemard, Annick Toutain, Cathy Obringer, Meriem Koob, Véronique Geoffroy, Vincent Marion, Uwe Strahle, Pia Ostergard, Alain Verloes, Andreas Merdes, Anthony T. Moore and Hélène Dollfus. American Journal of Human Genetics 2015
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UMRS_1112: Laboratoire de Génétique Médicale Evaluation HCERES 02/02/2017
I
II
1
1
2
2
Mutations récurrentes BBS BBS1: p.M390R
BBS10: p.Cys91Leufs* Pas de mutation
Targeted Exome Sequencing BBS1-BBS21, ALMS1 (58 gènes de ciliopathies)
IFT140
Whole Exome Sequencing
Pas de mutation
Whole Genome Sequencing
Pas de mutation
Genome: ~5 millions variants
Jeune, Mainzer-Saldino, Early-onset retinal dystrophy, Non syndromic retinitis pigmentosa
Exome: ~100,000 variants
39 mutations bialléliques rapportées
Labex GENMED , JF Deleuze
IFT140: duplication en tandem révélée par le WGS
Rétinopathie pigmentaire Anomalies rénales
Brachydactylie (mains et pieds) Anomalies osseuses, petite taille
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UMRS_1112: Laboratoire de Génétique Médicale Evaluation HCERES 02/02/2017
I.1
I.2
II.1
II.2
IFT140 : a recurrent duplication missed by whole exome sequencing
Confirmation: - 7 other families (heterozygous et homozygous)
Tandem duplication of 4 exons (6.7kb)
One ancestral event mediated by Alu elements
Whole-genome sequencing in patients with ciliopathies uncovers a novel recurrent tandem duplication in IFT140. Geoffroy V, Stoetzel C, Scheidecker S, Schaefer E, Perrault I, Bär S, Kröll A, Delbarre M, Antin M, Leuvrey AS, Henry C, Blanché H, Decker E, Kloth K, Klaus G, Mache C, Martin-Coignard D, McGinn S, Boland A, Deleuze JF, Friant S, Saunier S, Rozet JM, Bergmann C, Dollfus H, Muller J. Hum Mutat. 2018 Jul;39(7):983-992.
https://www-ncbi-nlm-nih-gov.gate2.inist.fr/pubmed/29688594https://www-ncbi-nlm-nih-gov.gate2.inist.fr/pubmed/29688594https://www-ncbi-nlm-nih-gov.gate2.inist.fr/pubmed/29688594https://www-ncbi-nlm-nih-gov.gate2.inist.fr/pubmed/29688594https://www-ncbi-nlm-nih-gov.gate2.inist.fr/pubmed/29688594https://www-ncbi-nlm-nih-gov.gate2.inist.fr/pubmed/29688594https://www-ncbi-nlm-nih-gov.gate2.inist.fr/pubmed/29688594https://www-ncbi-nlm-nih-gov.gate2.inist.fr/pubmed/29688594https://www-ncbi-nlm-nih-gov.gate2.inist.fr/pubmed/29688594https://www-ncbi-nlm-nih-gov.gate2.inist.fr/pubmed/29688594https://www-ncbi-nlm-nih-gov.gate2.inist.fr/pubmed/29688594https://www-ncbi-nlm-nih-gov.gate2.inist.fr/pubmed/29688594https://www-ncbi-nlm-nih-gov.gate2.inist.fr/pubmed/29688594https://www-ncbi-nlm-nih-gov.gate2.inist.fr/pubmed/29688594https://www-ncbi-nlm-nih-gov.gate2.inist.fr/pubmed/29688594https://www-ncbi-nlm-nih-gov.gate2.inist.fr/pubmed/29688594https://www-ncbi-nlm-nih-gov.gate2.inist.fr/pubmed/29688594https://www-ncbi-nlm-nih-gov.gate2.inist.fr/pubmed/29688594https://www-ncbi-nlm-nih-gov.gate2.inist.fr/pubmed/29688594https://www-ncbi-nlm-nih-gov.gate2.inist.fr/pubmed/29688594
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CEA CHRU CNRS CPU INRA INRIA INSERM INSTITUT PASTEUR IRD
ARIIS EFS INERIS INSTITUT CURIE INSTITUT MINES-TELECOM UNICANCER IRBA IRSN CIRAD FONDATION MERIEUX
DEFIDIAG
DEFICIENCE INTELLECTUELLE DIAGNOSTIC
INVESTIGATEUR PRINCIPAL : PR HELENE DOLLFUS
INVESTIGATEUR ASSOCIÉ : PR THIERRY FREBOURG
COORDINATION : INSERM
11
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Patient/doctor dialogue Shared decisions
Request for exam Agreement
Pre-analytic sampling
National database of
Clinico-biological
Meta-data
Technical validation
Sequences analyzed
Support for the therapeutic decision
Clinical data Genomic
data
“Diagnostic Laboratory”
Support tools for analysis
Biological validation and interpretation
Support for the diagnostic decision
Research
AMBITION OF THE FRENCH GENOMIC
MEDICINE PLAN 2025 PFMG 2025
INTEGRATE SEQUENCING INTO A
GENERIC HEALTHCARE PATHWAY
DEVELOP A NATIONAL
GENOMIC MEDICINE SECTOR
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Standardized
procedures &
processes
Sampling Sequencing CAD
Reference
center
(CRefIX)
Sample
transfer
Variant Call File (VCF)
transfer
CREATION OF A NETWORK OF
SEQUENCING PLATFORMS
Deployment of 10 other
platforms starting in 2019
CAD
ACTION ①
2018
*Projet Pilote
DEFIDIAG
CNRGH
-
Medical and Economical Evaluation of
Whole GENOME Sequencing in Healthcare
Pathway of Patients with Rare Diseases
The Intellectual Deficiency Paradigm => the DEFIDIAG « PILOT »:
Frequency ID 1-3% - Most common cause of referral in clinical genetics -
High need to cut down patient odyssee - Highly heterogeneous (clinical
presentation, numerous genes)
DEFIDIAG OPERATIONAL Steering COMMITTEE
Christine Binquet (INSERM CIC-EC1432), Jean-François Deleuze (CNGRH, Evry), Hélène
Dollfus (CHU Strasbourg, INSERM), Hélène Esperou (PRC INSERM), Laurence Faivre
(CHU Dijon), Thierry Frebourg (CHU Rouen) , Bénédicte Gérard (CHU Strasbourg) ,
Delphine Héron (AP-HP Paris) , Catherine Lejeune (INSERM CIC-EC1432), Stanislas
Lyonnet (AP-HP, IMAGINE), Sylvie Odent (CHU Rennes), Damien Sanlaville (CHU Lyon,
Plateforme AURAgene)
PFMG 2025 PILOT STUDY:
14
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CONTEXT
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Ministry of Health and
Solidarity
Ministry of
Higher Education
and Research
French population : 65 million citizens => 3.5 million with RARE DISEASES
PNMR 1 PNMR2
PNMR3 announced
THE FRENCH PLANS FOR RARE DISEASES
PNMR: SINCE 2004 SERVING PATIENTS WITH RARE DISEASES
CONTEXT
http://www.mediatoroscope.com/2011/04/03/affaire-tapie-un-mauvais-coup-pour-larbitrage-un-prejudice-pour-la-mediation/http://www.mediatoroscope.com/2011/04/03/affaire-tapie-un-mauvais-coup-pour-larbitrage-un-prejudice-pour-la-mediation/
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FRENCH RARE DISEASES NETWORKS
1. Developmental anomalies and malformations
(AnDDI-Rare)
2. Rare motor impairment of central nervous system
and rare dementias (Brain-Team)
3. Rare diseases of brain development and rare
intellectual disabilities (DefiScience)
4. Rare inherited heart diseases (Cardiogen)
5. Rare auto-immune and auto-inflammatory diseases
(FAI2R)
6. Rare multisystemic vascular diseases (Fava-Multi)
7. Rare liver diseases (Filfoie)
8. Rare neuromuscular diseases (Filnemus)
9. Rare dermatological diseases (Fimarad)
10. Rare malformations of abdomen and thorax
(Fimatho)
11. Rare endocrine diseases (Firendo)
12. Rare bleeding disorders (Mhemo)
13. Rare hereditary diseases of metabolic
origin (G2M)
14. Rare immuno-haematological Diseases
(Marih)
15. Rare diseases of red cells and of
erythropoïesis (MCGRE)
16. Cystic fibrosis and CFTR-related
disorders (Muco/CFTR)
17. Neurologic and sphincter complications
of rare ano-rectal and
medullarymalformations (Neurosphinx)
18. Rare kidney diseases (Orkid)
19. Rare diseases of calcium metabolism
with bone and/or renal impact (Oscar)
20. Rare respiratory diseases (Respifil)
21. Rare sensory diseases (Sensgene)
22. Amyotrophic Lateral Sclerosis (FilSAN)
23. Head, neck and teeth: rare malformations
(Tetecou)
Since 2014: 23 networks accredited by the French Ministry of Health
=> 12 Clinical sites for recruitement
-
56 Certified Molecular Genetics Laboratories
in Health Care Providers
National Association
of Molecular Geneticists
2012 :
PNMR2
NGS for gene panels
Ministry of Health and Solidarity
FRENCH RARE DISEASES NETWORKS
6 University Hospital (CHU) laboratories
will participate to DEFIDIAG
http://www.mediatoroscope.com/2011/04/03/affaire-tapie-un-mauvais-coup-pour-larbitrage-un-prejudice-pour-la-mediation/
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Patient
NGS analyses of gene panels
ID panels (ID 44) 22%
Array CGH 10%
47 % Whole Exome Sequencing
(WES)
Whole Genome Sequencing
WGS 59 %
ID DIAGNOSTIC YIELD
Identification of
causal CNVs :
-
DESIGN
• Prospective multicenter diagnostic study
• Compared strategies applied to all the patients without
obvious diagnosis, consecutively included
WGS Blind
interpretation
of each
strategy Reference strategy
Non inclusion criteria: parents with ID; patients with isolated learning disabilities
− Patients with ID
− Without any obvious diagnosis
− Signed consent
− Parents sampling is possible
-
Evaluation of WGS as a first line tool to improve diagnostic performance
for ID
DEFIDIAG aims to :
1° Show the feasibility of WGS implementation in France with ID as a paradigm for Rare diseases
2° Identify the best strategy for optimal and efficient genetic diagnosis for ID
3° Demonstrate the cost effectiveness and cost benefit of WGS for ID
4° Show the benefits on the outcome of patients /parents ( including SF)
5° Cut down the diagnostic odyssey
DEFIDIAG A PILOT PROJECT FOR PFGM2025
-
OBJECTIVES
Causal diagnostic Identification of at least one class 4 or 5 variant explaining the symptoms of the
patient
• Validated during the multidisciplinary meeting (MDM) for the WGS and the
44GPS
• Validated through the standard routine circuit for array CGH
Main steps of WGS – trio analysis
Analysis of all the variants detected in the OMIM genes
Enlarged analysis of
- other known genes (SV, CNV, SNV)
- non coding regions preserved during evolution
When negative
-
• Secondary objectives : Efficacy
Compare the percentage of genetic causal diagnosis
identified in patients with ID
• WGS sequential analysis - solo strategy (WGSS)
vs
• WGS sequential analysis – trio strategy (WGST)
OBJECTIVES
+7 to 10%
Compare the percentage of genetic causal diagnosis
identified in ID patients with WGST vs reference strategy
and vs WGSS in the following subgroups:
− ID with major non cerebral abnormality (expected frequency in
the eligible patients = 25%)
− Moderate to severe ID (expected frequency = 50-80%)
− ID with epilepsy
-
• Secondary objectives : Efficacy
Compare the percentage of causal structural changes (CNV, translocation
inversion)
Compare the percentage of causal diagnostic in patients with ID using the 3
strategies in other clinical subgroups
• Description and compare the percentages of genetic causal diagnosis
/structural changes obtained with WGS in patients (overall population)
• Secondary findings • Number of secondary findings (class 4 or 5 variants that may improve
medical management) detected in parents wishing this active research
and having beforehand consent
• The targeted genes will be part of a pre-determined list of actionable
genes; a specific bioinformatic procedure is planned for these genes
• Efficiency (cf. C Lejeune) : Compare in terms of cost and effectiveness the three strategies (reference, WGST
et WGSs ) for the causal diagnosis of ID
OBJECTIVES
-
SECONDARY OBJECTIVES
Incidental/secondary findings
=> patient analysis : only ID genes and/or additional symptoms
only focus on genes potentially involved in his/her intellectual disability and also in
genes involved in potential additive observed symptoms (no incidental results)
=> SECONDARY FINDINGS
proposed exclusively to the parents
specific information on the initial objectives and the potential future implications.
Analysis of the 59 ACMH genes
• Individual restitution of results and ad hoc follow up Efficiency (cf. C Lejeune) : Compare in terms of cost and effectiveness the three strategies (reference, WGST et
WGSs ) for the causal diagnosis of ID
• Secondary findings • Number of secondary findings (class 4 or 5 variants that may improve
medical management) detected in parents wishing this active research
and having beforehand consent
• The targeted genes will be part of a pre-determined list of actionable
genes; a specific bioinformatic procedure is planned for these genes
-
Phenotypic evaluation
Collection of clinical data (e-CRF)
aCGH, FraX, cerebral MRI
Informed consent - Blood samples
French ID CLINICAL Networks
12 Reference Clinical Centres
French ID LAB Networks
6 Molecular Genetics LABS
DNA sample preparation
Pre-analytical certification
1 center for
Sequencing
National Center
of Genomics
(CNG/CEA) Evry
Bioinformatic
filtration
WGS
Quality reports
Base calling
Alignement
Variant calling
Trio identity control
Variant Filtrations using standard protocols
Variant interpretation (Multidisciplinary
meeting)
Reports : Causal variations / actionable
variations
DEFIDIAG INVESTIGATORS
HEALTH ECONOMIC
Study
CIC 1432 INSERM
IMPACT & QUALITATIVE
Study
University of Bourgogne
-
Studied population
Children or adults with Intellectual Disability (ID), with no
obvious clinical/genetic diagnosis, referred to a medical
geneticist for the first time or for follow-up
Inclusion criteria
Children under 6 years of age :
Enrolled on Specific criteria (severe developemental delay
including motor, language and sociability skills)
OR Above 6 years of age :
Proven ID regardless of severity, syndromic or not syndromic,
BUT without an obvious clinical diagnosis during the medical
geneticist expert consultation
Enrollment is proposed by the clinical geneticist from a DEFIDIAG center (member of the national network AndiRARE
and/or DEFISCIENCE)
ENROLLMENT OF PARTICIPANTS
-
VISIT 0 SCREENING & VISIT 1 ENROLLMENT
1°Clinical evaluation
Patient and family medical history, Clinical examination, Photos + VIDEOS
Diagnostic is obvious => no enrollment (goes back to routine care)
Local meeting presentation if needed
2° Neuropsychological evaluation and MRI if needed
3° Information given about DEFIDIAG
4° Signed Consent Forms from patient + parents
6° Blood samples collected from TRIO
•First time visit patients => Fra-X and aCGH
•Blood sent to the ad hoc DEFIDIAG LAB for WGS
•Clinical data transferred on eCRF (CleanWeb/CRT)
VISIT 1’ at Day 3 post VISIT 1
Patients/parents for qualitative study Interview 1
Multi Disciplinary Meeting (MDM)
= > RESULTS WGS+SF => contact patient and parents
VISIT 2
8° Medical geneticist consultation: Delivery of RESULTS
ADAPT Patient care planning (back to routine care)
IF SF for parents ad hoc referral (back to routine care)
VISIT 2’ at day 3 post VISIT 2
Patients/parents for qualitative study Interview 2 + DIARY given
VISIT 3 at 12 months post VISIT 2
Patients/parents for qualitative study Interview 3
PARTICIPANTS VISITS
-
Figure 2: Sample flow description (C: clinical centers; L: laboratory; CNRGH, centre
national de recherche en génétique humaine)
GENOMIC TRACK
-
CNRGH => variant
calling
on the entire genome
SNV
small insertion/deletions
(indels)
structural variants
(including Copy Number
Variant, CNV)
LABS => Annotations
of the called variants
common specific software
defined by the lab
bioinformatic
work group in each lab
-
Multidisciplinary meeting
MDM coordinator, 4 clinical centers, 2 involved laboratories, bioinformatician
Presentation of the variants biologically selected during WGS analysis – DI 44 extracted results from WGS dataset
– WGS simplex analysis: presentation and discussion of the variants; additional analysis that would be
necessary to conclude
– WGS trio analysis : presentation and discussion of the variants
Conclusion and variant classification
Additional tests needed to conclude
Secondary findings will be discussed separately in MDM with involved specialist
such as oncology, heart disease, metabolic disease …
GENOMIC TRACK
-
GENOMIC TRACK
reference laboratory mirror laboratory
Reception of samples
DNA extraction and qualification
Whole genome sequencing at the CNRGH
verification of the QC report
verification of the trio concordance
Analysis of the DI44 GPS
WGS Trio analysis WGS Simplex analysis
MDM : presentation and discussion
1) Simplex analysis variants ; Trio analysis variants ; Synthesis and conclusion
Additional analysis if needed
Research report => Further investigation
Secondary findings analysis in parents
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EFFICIENCY AND IMPACT STUDIES
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(1) MEDICO-ECONOMIC EVALUATION
• Cost-effectiveness analysis (current strategy, WGSTrio, WGSSolo)
• Population: − « primo-investigated » patients
− subgroups
• Time horizon: results disclosure at 12 months maximum
• Point of view: collective
• Direct medical costs:
• samples’ transports
• genetic analyses
• complementary and confirmatory medical examinations
-
(1) MEDICO-ECONOMIC EVALUATION
Declarative data (clinicians) + tariffs
Medical visit
Genetic analyses
prescription Results disclosure
complementary (imaging...)
+
confirmatory (Sanger…) examinations
12 months max
PERIOD 1 PERIOD 3 PERIOD 2
24 months
INCLUSION
-
EFFICIENCY AND IMPACT STUDIES
• Efficiency : medico-economic evaluation
• Impact studies :
Impact of WGS on the cost of the wavering research of a
diagnosis
Impact of WGS on the medical and psychosocial follow-up
of the patients
Perception of the patients and the parents / WGS
-
PROJECT 3 : QUALITATIVE IMPACT
3 interviews (sociology /psychology) – parents + mild ID patients
• Inclusion, to explore:
‒ burden experienced by the parents
‒ expectations of the parents/patients towards genomic analyses 30 interviews in sociology (15 parents-15 patients) / 30 interviews in psychology parents
(15 parents-15 patients)
• Results disclosure, whatever the results, to explore:
‒ emotional adjustment to the genetic tests results and expectations 30 interviews in sociology / 30 interviews in psychology
• 1 year after the results disclosure, to explore
− factual changes in their life
‒ changes of perpection of the futur 30 interviews in sociology / 30 interviews in psychology
-
TIMELINES
8 6 4 2
Jun
e 2
2th
20
16
No
v. 2
9th
20
16
Sep
t. 1
4th
20
17
Q2
20
18
Q3
/Q4
20
18
Mar
ch 3
0th
20
17
Mar
ch 2
2th
20
18
Q2
20
18
1rst meeting
Trial Steering Committee
Executive committee
Essential documents
1rst inclusion
FMG 2025
1rst meeting
Executive committee
1rst meeting
Scientific Advisory
Board
Submission
Publication of the French Genomic
Medicine 2025 Plan
2nd meeting
To competent authorities
-
REMERCIEMENTS
- NOMBREUX PROFESSIONNELS SOLLICITÉS POUR GTS
- MEMBRES DU COMITÉ DE PILOTAGE
- ANPGM – GROUPE NGS
- FILIERES ANDI-RARES ET DEFISCIENCE
- EQUIPE DRC INSERM
- SAB
-
08/02/2019 40
PROJET PILOTE PFMG DEFIDIAG
« DEFiscience Intellectuelle DIAGnostic »
PROMOTEUR : INSERM
Pôle de Recherche Clinique
Claire Lévy-Marchal, Héléne Espérou,
Christelle Delmas, Carine Malle
COMITE PILOTAGE
o Christine BINQUET CIC Dijon
o Jean-François DELEUZE Evry CNRGH
o Hélène DOLLFUS CHU Strasbourg
o Laurence FAIVRE CHU Dijon
o Thierry FREBOURG CHU Rouen
o Bénédicte GERARD CHU Strasbourg
o Delphine HERON AP-HP
o Catherine LEJEUNE Université Bourgogne
o Stanislas LYONNET AP-HP IHU Imagine
o Sylvie ODENT CHU Rennes
GROUPES DE
TRAVAIL:
-GT
Méthodologie
-Data/
Evaluation
médico-
économique
- GT Circuit
patient / RCP
- GT Biologie –
laboratoire /
Bioinformatique
- GT Budget
Ethique et
règlementaire
ORGANISATION
&
EXECUTION
DEFIDIAG
Conception
Protocole
Rédaction CRF
Dossiers
réglementaires
(CNIL, CPP, ..)
Avis Conseil
scientifique
Evaluation
financière
Ect …
-
GOVERNANCE
Executive committee
Steering committee
WG
methodology
/ biostat
WG
data
WG
Lab
Scientific Advisory Board International experts : Genetics and genomics :
Jacques Beckmann David Fitzpatrick Gert Matthijs Lucy Raymond Olaf Riess Statistician: Michal Abrahamowicz
Economic evaluation : James Buchanan Patients representative : Clémence Désiré (UNAPEI)
WG Participant
circuit WG
Efficiency &
Impact studies
WG
Bio
informatic
WG
MDM WG
Communication
WG
Ethics & Regulatory
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STUDY PARTICIPANTS
-
Medical and Economical Evaluation of
Whole GENOME Sequencing in Healthcare
Pathway of Patients with Rare Diseases
The Intellectual Deficiency Paradigm => the DEFIDIAG « PILOT »:
Frequency ID 1-3%
Most common cause of referral in clinical genetics
High need to cut down patient odyssee
Highly heterogeneous (clinical presentation, numerous genes)
Projet réalisé en collaboration avec FSMRS
PFMG 2025 PILOT STUDY:
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CEA CHRU CNRS CPU INRA INRIA INSERM INSTITUT PASTEUR IRD
ARIIS EFS INERIS INSTITUT CURIE INSTITUT MINES-TELECOM UNICANCER IRBA IRSN CIRAD FONDATION MERIEUX
OBJECTIVES AND SAMPLE SIZE
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CEA CHRU CNRS CPU INRA INRIA INSERM INSTITUT PASTEUR IRD
ARIIS EFS INERIS INSTITUT CURIE INSTITUT MINES-TELECOM UNICANCER IRBA IRSN CIRAD FONDATION MERIEUX
45
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OBJECTIVES
Causal diagnostic Identification of at least one class 4 or 5 variant explaining the symptoms of the
patient
• Validated during the multidisciplinary meeting (MDM) for the WGS and the
44GPS
• Validated through the standard routine circuit for array CGH
Main steps of WGS – trio analysis
Analysis of all the variants detected in the OMIM genes
Enlarged analysis of
- other known genes (SV, CNV, SNV)
- non coding regions preserved during evolution
When negative
-
• Secondary objectives : Efficacy
Compare the percentage of genetic causal diagnosis
identified in patients with ID
• WGS sequential analysis - solo strategy (WGSS)
vs
• WGS sequential analysis – trio strategy (WGST)
OBJECTIVES
+7 to 10%
Compare the percentage of genetic causal diagnosis
identified in ID patients with WGST vs reference strategy
and vs WGSS in the following subgroups:
− ID with major non cerebral abnormality (expected frequency in
the eligible patients = 25%)
− Moderate to severe ID (expected frequency = 50-80%)
− ID with epilepsy
-
• Secondary objectives : Efficacy
Compare the percentage of causal structural changes (CNV, translocation
inversion)
Compare the percentage of causal diagnostic in patients with ID using the 3
strategies in other clinical subgroups
• Description and compare the percentages of genetic causal diagnosis
/structural changes obtained with WGS in patients (overall population)
• Secondary findings • Number of secondary findings (class 4 or 5 variants that may improve
medical management) detected in parents wishing this active research
and having beforehand consent
• The targeted genes will be part of a pre-determined list of actionable
genes; a specific bioinformatic procedure is planned for these genes
• Efficiency (cf. C Lejeune) : Compare in terms of cost and effectiveness the three strategies (reference, WGST
et WGSs ) for the causal diagnosis of ID
OBJECTIVES
-
SECONDARY OBJECTIVES
Incidental/secondary findings
=> patient analysis : only ID genes and/or additional symptoms
only focus on genes potentially involved in his/her intellectual disability and also in
genes involved in potential additive observed symptoms (no incidental results)
=> SECONDARY FINDINGS
proposed exclusively to the parents
specific information on the initial objectives and the potential future implications.
Analysis of the 59 ACMH genes
• Individual restitution of results and ad hoc follow up Efficiency (cf. C Lejeune) : Compare in terms of cost and effectiveness the three strategies (reference, WGST et
WGSs ) for the causal diagnosis of ID
• Secondary findings • Number of secondary findings (class 4 or 5 variants that may improve
medical management) detected in parents wishing this active research
and having beforehand consent
• The targeted genes will be part of a pre-determined list of actionable
genes; a specific bioinformatic procedure is planned for these genes
-
OBJECTIVES
• Secondary objectives:
• Efficiency (cf. C Lejeune) : Compare in terms of cost and effectiveness the three strategies (reference, WGST
et WGSs ) for the causal diagnosis of ID
• Efficiency (cf. C Lejeune) : Compare in terms of cost and effectiveness the three strategies (reference,
WGST et WGSs ) for the causal diagnosis of ID
• Qualitative study assessing
• the burden experienced by the parents
• the patient and parents’ emotional adjustment to the genetic tests
results
• the patient and parents’ perception of the future
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SAMPLE SIZE
• Determination of the diagnostic performance of WGST vs the reference strategy (and 2ndly vs WGSs)
• Comparison in the overall population of patients coming for a first advice (– quota fixed to 50%) • + Comparisons in each subgroups
- children 5 years - mild ID associated with another sign (15%) - Moderate to severe ID (50-80%) - ID with major non cerebral abnormality (25%)
−ID associated with epilepsy (22%) • + Comparison WGST vs and WGSs on a smallest subgroup
1 main comparison in 8 populations (sample as a whole + 7 subgroups)+ WGSs vs WGST =9 comparisons
Focus on the main comparison in the subgroup with the lowest expected difference (15%) - 1% identified by the reference strategy but not by WGST - unilateral alpha for 9 comparisons =0.00278 - power=80%
Required population include given the planed quota of patients coming for a first advice (50%)
number of patients to allow the comparisons in the smallest subgroup of patients coming for a 1st advice (15%) Allow also to have the sufficient power to compare WGST vs WGSs (196 subjects coming for a first advice required)
91
607
1214
1275 Total number of patients to include (5% of unusable samples) i.e. 3825 individuals (patients+ parents)
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GENOMIC TRACK
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WGS analysis
WGS analysis will be performed with standardized
protocols for filtration and variant interpretation.
The 6 laboratories and 12 clinical centers will be gathered
in 3 independent tracks to facilitate the organization of
the multidisciplinary meetings (400 cases for each MDM,
including 2 labs and 4 clinical centers)
The same patient will be analyzed independently by 2
mirror laboratories, trio analysis in the first lab and
simplex analysis in the second one
The data for this patient will be presented in the same
meeting, simplex first, to guaranty the blindness until
clinical validation of detected variations
Incidental/secondary findings
Parents’ secondary findings will be separately analyzed
by one laboratory and specifically reported.
GENOMIC TRACK
-
OMIM genes
Other genomic
regions
STOP
Class 4-5
reported to
MDM
Class 4 -5 explaining
clinical presentation ?
yes
no
yes
Class 3 variants or no variation reported
Trio
analy
sis
Class 4 -5 explaining
clinical presentation ?
STOP
Class 4-5
reported to
MDM no
de novo variants
(CNV, SV, SNV, indel)
-Certain or de novo variants and Probable de novo variants at the vicinity OMIM genes
AR genes
pathogenic or likely pathogenic whatever their frequency
Variants with MAF
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CEA CHRU CNRS CPU INRA INRIA INSERM INSTITUT PASTEUR IRD
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EFFICIENCY AND IMPACT STUDIES
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(1) MEDICO-ECONOMIC EVALUATION
• Cost-effectiveness analysis (current strategy, WGSTrio, WGSSolo)
• Population: − « primo-investigated » patients
− subgroups
• Time horizon: results disclosure at 12 months maximum
• Point of view: collective
• Direct medical costs:
• samples’ transports
• genetic analyses
• complementary and confirmatory medical examinations
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(1) MEDICO-ECONOMIC EVALUATION
Declarative data (clinicians) + tariffs
Medical visit
Genetic analyses
prescription Results disclosure
complementary (imaging...)
+
confirmatory (Sanger…) examinations
12 months max
PERIOD 1 PERIOD 3 PERIOD 2
24 months
INCLUSION
-
Mean cost
per patient
Mean effectiveness
per patient
=
positive diagnosis
Incremental cost-effectiveness ratio (ICER)
Cost per additional positive diagnosis
Mean cost innovation - Mean cost reference
Mean effectiveness innovation - Mean effectiveness reference
a two-steps comparison :
• Reference strategy (Fra-X, Chromosomal microarray analysis, 44GPS)
vs WGST
• WGST vs WGSS
Deterministic + probabilistic (bootstrap)
(1) MEDICO-ECONOMIC EVALUATION
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EFFICIENCY AND IMPACT STUDIES
• Efficiency : medico-economic evaluation
• Impact studies :
Impact of WGS on the cost of the wavering research of a
diagnosis
Impact of WGS on the medical and psychosocial follow-up
of the patients
Perception of the patients and the parents / WGS
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(2) IMPACT STUDIES PROJECT 1: AVOIDED WAVERING RESEARCH COST OF A DIAGNOSIS
PREVIOUS MEDICAL
INVESTIGATION:
-BIOLOGICAL TESTS
-GENETIC TESTS
-IMAGING PROCEDURES
-CONSULTATIONS WITH/WITHOUT HOSPITALISATIONS
Medical visit
Genetic analyses prescription
Results
disclosure
12 months max
PERIOD 1
24 months INCLUSION
Patients previously investigated before the inclusion:
• Sources: medical files + interviews clinicians / parents
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PROJECT 2: IMPACT ON THE MEDICAL AND PSYCHOSOCIAL
FOLLOW-UP OF THE PATIENTS
Results disclosure
MEDICAL INVESTIGATIONS
+
TREATMENTS AND DIETS +
MEDICO-SOCIAL, REEDUCATIVE
AND PSYCHOLOGICAL
FOLLOW-UP
PERIOD 1
BEFORE
• Medical files
• interviews clinicians / parents
PERIOD 3
AFTER
MEDICAL INVESTIGATIONS
+
TREATMENTS AND DIETS +
MEDICO-SOCIAL, REEDUCATIVE
AND PSYCHOLOGICAL FOLLOW-UP
• Patients’ diary
• Phone follow-up
12 months max 24 months
Medical visit
Genetic analyses prescription
INCLUSION
Previously investigated patients
Type and frequency of changes according to the results ( +, –, uncertain)
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PROJECT 3 : QUALITATIVE IMPACT
3 interviews (sociology /psychology) – parents + mild ID patients
• Inclusion, to explore:
‒ burden experienced by the parents
‒ expectations of the parents/patients towards genomic analyses 30 interviews in sociology (15 parents-15 patients) / 30 interviews in psychology parents
(15 parents-15 patients)
• Results disclosure, whatever the results, to explore:
‒ emotional adjustment to the genetic tests results and expectations 30 interviews in sociology / 30 interviews in psychology
• 1 year after the results disclosure, to explore
− factual changes in their life
‒ changes of perpection of the futur 30 interviews in sociology / 30 interviews in psychology
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TIMELINES
8 6 4 2
Jun
e 2
2th
20
16
No
v. 2
9th
20
16
Sep
t. 1
4th
20
17
Q2
20
18
Q3
/Q4
20
18
Mar
ch 3
0th
20
17
Mar
ch 2
2th
20
18
Q2
20
18
1rst meeting
Trial Steering Committee
Executive committee
Essential documents
1rst inclusion
FMG 2025
1rst meeting
Executive committee
1rst meeting
Scientific Advisory
Board
Submission
Publication of the French Genomic
Medicine 2025 Plan
2nd meeting
To competent authorities
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REMERCIEMENTS
- NOMBREUX PROFESSIONNELS SOLLICITÉS POUR GTS
- MEMBRES DU COMITÉ DE PILOTAGE
- ANPGM – GROUPE NGS
- FILIERES ANDI-RARES ET DEFISCIENCE
- EQUIPE DRC INSERM
- SAB
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OBJECTIVES
Main Objective
• Compare % of genetic causal diagnosis identified in ID patients
• Reference strategy (ANPGM recommandation) (X-fra + array CGH + 44GPS*)
vs
• « sequential analysis » of whole genome sequencing – trio strategy (WGST)
• Compare % of genetic causal diagnosis identified in patients with ID
• WGS sequential analysis - solo strategy
vs
• WGS sequential analysis – trio strategy
• Compare % of genetic causal diagnosis identified in ID patients with WGST vs
reference strategy in subgroups: non cerebral abnormality - Moderate to severe
ID - ID with epilepsy
Secondary findings • Number of secondary findings (class 4 or 5 variants that may improve medical
management) on a pre-determined list of actionable genes
Efficiency : • Compare in terms of cost and effectiveness the three strategies (reference, WGST
et WGSs ) for the causal diagnosis of ID
Qualitative study assessing • Burden experienced / emotional adjustment to results/ perception of the future
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