PFMG2025-integrating genomic medicine into the national healthcare system in France

Abstract

Integrating genomic medicine into healthcare systems is a health policy challenge that requires continuously transferring scientific advances into clinics and ensuring equal access for patients. France was one of the first countries to integrate genome sequencing into clinical practice at a nationwide level, with the ambition to provide more accurate diagnostics and personalized treatments. Since 2016, the French government has invested €239M in the 2025 French Genomic Medicine Initiative (PFMG2025) which has so far focused on patients with rare diseases (RD), cancer genetic predisposition (CGP) and cancers. PFMG2025 has addressed numerous challenges to set up an operational organizational framework. As of December the 31st 2023, 12,737 results were returned to prescribers for RD/CGP patients (median delivery time: 202 days, diagnostic yield: 30.6%) and 3109 for cancer patients (median delivery time: 45 days). PFMG2025's future priorities encompass ensuring economic sustainability, strengthening links with research, empowering patients and practitioners, and fostering collaborations with European partners.

Funding: As of December the 31st 2023, €239M have been invested by the French government.

Keywords: Cancer predisposition; Cancers; French genomic medicine initiative; Genome sequencing; Genomic medicine; PFMG2025; Rare diseases.

Fig. 1

Major hallmarks of the framework for genomic medicine in France. (A) PFMG2025 organization: Overview of the PFMG2025 initiative in a research-care continuum (left). The interactions between the 3 main specific infrastructures are illustrated, with diagnostic reports sent from the two first FMGlabs (AURAGEN and SeqOIA) to patients for diagnosis and/or personalized treatment, data transfer to the national facility for secure data storage and intensive calculation (Collecteur Analyseur de Données–CAD) for research with the technical support of the reference center for innovation, assessment, and transfer (CRefIX). Several working groups dedicated to ethical, legal and society issues, medico-economic evaluation, training and education, industries, communication, international affairs were set up. Four pilot research projects were launched, in research settings. The genomic healthcare pathway from prescription to delivery of the result to the patient (right). The genomic healthcare pathway has various successive stages: an initial medical consultation to inform the patient, an upstream multidisciplinary meeting (MDM) for rare diseases and cancer genetic predisposition (RD/CGP) or multidisciplinary tumor board (MTB) for oncology to validate the medical prescription, a medical consultation to collect the patient’s consent and to perform an electronic prescription, sample preparation and dispatch to FMGlabs, exome/genome/transcriptome sequencing, bioinformatics analysis, clinico-biological interpretation with the drafting of the report sent to the prescribers, a medical consultation to report the results to the patient. As an option, a clinico-biological interpretation support meeting and/or a downstream MDM can be set up to discuss complex cases before drawing-up the diagnostic report and/or the treatment proposal, respectively. (B) Geographical distribution of prescriptions dated 12/31/2023/100,000 inhabitants for RD/CGP (top left) and for cancers (top right), as well as geographical distribution of biologists for RD/CGP and cancers dated 12/31/2023 (bottom). (C) Genome sequencing (GS) results in RD/CGP: histogram showing the number of “complete” RD/CGP prescriptions per semester, with a breakdown of positive diagnoses (purple), inconclusive results (mauve), negative results (light mauve) and analyses in progress (grey), as well as the diagnostic yield (purple dotted line) with little change between 31.6% for the prescriptions performed in 2021 (94.6% completeness), 30.8% for the prescriptions performed in 2022 (76.8% completeness), and 31.3% for the prescriptions performed in 2023 (42.5% completeness). (D) Delivery time between receiving the prescription at FMGlabs and returning the report to the prescribers (grey box), as well as percentage of analyses in progress (purple line), by semester, from 01/31/2020 to 12/31/2023: progressive decrease in the median time between the 1st semester of 2020 and the 2nd semester of 2023 for the 12,737 returned results in RD/CGP (left) and for the 3109 returned results in cancers (right). (E) Prescription and medical reporting activities from 03/31/2019 to 12/31/2023 for RD/CGP (left), with genomic prescriptions validated in MDM (dark purple), “complete” prescriptions with samples received by FMGlabs (purple) and medical reports (mauve), and for cancers (right), with genomic prescriptions validated in MTB (dark purple), “complete” prescriptions with samples received by FMGlabs (purple) and medical reports (mauve).

Fig. 2

Diagnostic yield in patients with rare diseases and cancer genetics (RD/CGP) and somatic variants in cancers. (A) Diagnostic yields (purple) and VUS levels (mauve) presented per subgroup of RD/CGP pre-indications, after exclusion of subgroups with less than 100 patients; (CNS: central nervous system disorders, MND: malformations and/or neurodevelopmental disorders, IAI: immunological and autoinflammatory diseases). (B) Retrospective study of the first 2734 consecutive prescriptions for RD/CGP: Diagnostic yields (purple) and VUS levels (mauve) regarding the number of individuals sequenced in a family (solo, duo, trio and four and more). (C) Retrospective study of the first 2734 consecutive prescriptions for RD/CGP: Diagnostic yields (purple) and VUS levels (mauve) regarding the number of genetic tests requested before GS analysis (first-line, one, two, three and four and more). (D) Retrospective study of the first 2446/2734 consecutive prescriptions for RD/CGP: Diagnostic yields (purple) and VUS levels (mauve) after different combinations of genetic tests requested before GS analysis (standard chromosomal analysis and targeted genes, array comparative genomic hybridization (array-CGH) alone, targeted gene panel alone, exome sequencing with other genetic tests, and all other genetic tests without exome). (E) Retrospective study of the first 2734 consecutive prescriptions for RD/CGP: reasons why GS identified a causal diagnosis in 78 patients with negative ES. (F) Repartition of the 3367 complete prescriptions by cancers pre-indication from 04/01/2019 to 12/31/2023. (G) Types of the 18,549 somatic variants returned for discussing actionability and treatment proposition in the MTB identified in 1718 patients.

Fig. 3

Four clinical cases of interest in RD diagnosed by GS. GS identified causative variant after a normal gene panel sequencing (Case 3) or after a heterozygous variant of unknown significance in genes with autosomal recessive condition identified by gene panel sequencing (Case 4) or exome sequencing (Case 1). GS also characterized a structural variant of unknown significance previously detected by array-CGH leading to its reclassification in causative variant (Case 2). Case 1: a diagnosis of PIGN-related encephalopathy (MIM#614080) secondary to compound heterozygous variants (missense and intragenic deletion) in PIGN (MIM∗606097); main clinical features and IGV capture of both variants in proband and unaffected parents. Case 2: a diagnosis of Simpson-Golabi-Behmel syndrome (MIM#312870) secondary to complex genomic rearrangement interrupting the GPC3 gene (MIM∗300037); main clinical features and diagram explaining the rearrangement. Case 3: a diagnosis of X-linked Alport syndrome (MIM#301050) secondary to inherited deep intronic variant in COL4A5 (MIM∗303630); main clinical features, IGV capture of the variant in proband, non-affected brother, affected mother, and affected half-brother, and RT-PCR results on patient cultured fibroblasts compared with control fibroblasts, revealed the formation of an out-of-phase pseudo-exon, using the splice acceptor site enhanced by the variant and the strongest of the preexisting donor sites with a total effect on splicing. Arrows indicate the primers used for RT-PCR located in exons 31 (primer a) and 37 (primer B), as well as in the inserted 33p predicted pseudo-exon (primers a1 and b1). Case 4: a diagnosis of autosomal recessive polycystic kidney disease (MIM#263200) secondary to heterozygous composite variants (missense and deep intronic variant) in PKHD1 (MIM∗606702); main clinical features and IGV capture of both variants in proband and unaffected parents (ES: exome sequencing, MIM: Mendelian Inheritance in Man, MRI: Magnetic Resonance Imaging; US: ultrasound, WG: weeks of gestation, RT-PCR: Reverse Transcription Polymerase Chain Reaction).