new maladies rares et génomique : introduction générale - defidiag · 2019. 2. 8. · 10ème...

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

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)

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)


http://www.science-et-vie.net/img/illustrations/D/docteur.jpghttp://fr.dreamstime.com/register?jump_to=http://fr.dreamstime.com/images-libres-de-droits-manipulation-mutation-d-adn-image14411889


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


AII-3

30

35

40

45

50

55

0 20

Head

cir

cu

mfe

ren

ce (

cm

)

Age (Months)

AII-1

30

35

40

45

50

55

0 10 20 30

Head

cir

cu

mfe

ren

ce (

cm

)

Age (Months)

AII-1

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)


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


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


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

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

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

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



CONTEXT

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/

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/

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%


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


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






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



EFFICIENCY AND IMPACT STUDIES

(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


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 : 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



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:



OBJECTIVES AND SAMPLE SIZE



45

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



identified in patients with ID

• WGS sequential analysis - solo strategy (WGSS)

vs

• WGS sequential analysis – trio strategy (WGST)

OBJECTIVES

+7 to 10%


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


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)








OBJECTIVES

SECONDARY OBJECTIVES


=> 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






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

• 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

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)



GENOMIC TRACK

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


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


• 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


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)



• 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

(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

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)

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

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


Qualitative study assessing • Burden experienced / emotional adjustment to results/ perception of the future

new maladies rares et génomique : introduction générale - defidiag · 2019. 2. 8. · 10ème...

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