Development of Non-Invasive Prenatal Diagnosis for Single Gene Disorders

NCT06147414 | Recruiting

• 2 other identifiers: APHP2208092023-A00821-44
• Study Type: observational
• Target: 550
• Locations: 1 country
• Sites: 1

Brief Summary

Cell-free fetal DNA (cffDNA) is present in the maternal blood from the early first trimester of gestation and makes up 5%-20% of the total circulating cell-free DNA (cfDNA) in maternal plasma. Its presence in maternal plasma has allowed development of noninvasive prenatal diagnosis for single-gene disorders (SGD-NIPD). This can be performed from 9 weeks of amenorrhea and offers an early, safe and accurate definitive diagnosis without the miscarriage risk associated with invasive procedures. One of the major difficulties is distinguishing fetal genotype in the high background of maternal cfDNA, which leads to several technical and analytical challenges. Besides, unlike noninvasive prenatal testing for aneuploidy, NIPD for monogenic diseases represent a smaller market opportunity, and many cases must be provided on a bespoke, patient- or disease-specific basis. As a result, implementation of SGD-NIPD remained sparse, with most testing being delivered in a research setting. The present project aims to take advantage of the unique French collaborative network to make SGD-NIPD possible for theoretically any monogenic disorder and any family.

Conditions

Sickle Cell Disease; Cystic Fibrosis; Fragile X Syndrome; Proximal Spinal Muscular Atrophy; Myotonic Dystrophy; Muscular Dystrophy, Duchenne; Muscular Dystrophy, Becker; Neurofibromatosis-Noonan Syndrome; Invasive PreNatal Diagnosis in a Context of Family History of Single-gene Disorders, Including; Huntington Disease; Hemophilia A; Hemophilia B; MODY2 Diabetes; X-Linked Hydrocephalus; Autosomal Recessive Polycystic Kidney Disease

Keywords

Gene HBB; Gene CFTR; Gene FMR1; Gene SMN1; Gene DMPK; Gene DMD; Gene NF1; Gene HTT; Gene F8; Gene F9; Gene GCK; Gene L1CAM; Gene PKHD1

Outcome Measures

Primary Outcomes (2)

• % of affected/unaffected fetuses that were correctly classified as affected/unaffected

  respectively among conclusive results

  1 day

• % of inconclusive results

  1 day

Secondary Outcomes (7)

• cffDNA concentration in maternal plasma

  1 day

• sequencing coverage

  1 day

• Quality scores

  1 day

• Optimal window in terms of gestational age for maternal sampling

  through study completion, an average of 2 years

• Simplicity of implementation

  through study completion, an average of 2 years

Study Arms (2)

pregnant women undergoing invasive PND in a context of family history of SGD

SGD-NIPD will be proposed by CPDPN recruitment centres to pregnant women undergoing invasive PND in a context of family history of SGD because of parental pathogenic mutation.s in one of the following gene: HBB, CFTR, FMR1, SMN1, DMPK, DMD, NF1, HTT, F8, F9, GCK, L1CAM, PKHD1.

Biological: Blood sample

pregnant women undergoing prenatal counselling in a context of maternal history of diabetes MODY-GCK

Biological: Blood sample

Interventions

Blood sample BIOLOGICAL

A blood sample (50 ml) will be taken in care of prenatal diagnosis and 40 ml will be used for study. The 40 mL of blood needed for the research will be collected on BCT tubes (4 tubes). During the study, in centers, the plasma samples will be stored at room temperature and will be sent to the laboratory within 24 hours (no centrifugation in centers). The plasma samples will be then temporarily stored at -80°C in each co-investigating laboratory under the supervision of lab supervisor until the analysis. cfDNA will be extracted from the whole plasma sample before each sequencing run and stored à +4°C until the cfDNA sequencing.

pregnant women undergoing invasive PND in a context of family history of SGD; pregnant women undergoing prenatal counselling in a context of maternal history of diabetes MODY-GCK

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

Pregnant woman undergoing genetic counselling in a context of family history of SGD either through prenatal diagnosis by invasive sampling or through postnatal diagnosis by sampling of the newborn (for MODY-GCK)

You may qualify if:

• pregnant woman with 9 weeks of amenorrhea or more
• singleton pregnancy
• undergoing invasive PND in a context of family history of SGD involving the following genes : HBB, CFTR, FMR1, SMN1, DMPK, DMD, NF1, HTT, F8, F9, GCK, L1CAM, PKHD1, or undergoing prenatal counselling in a context of maternal history of diabetes MODY-GCK
• germinal pathogenic paternal and/or maternal mutations previously identified
• age 18 years old or over
• signing an informed consent

You may not qualify if:

• at risk of SGD involving a de novo pathogenic mutation in a previous child
• woman under legal protection

Sponsors & Collaborators

• Assistance Publique - Hôpitaux de Paris: lead
• URC-CIC Paris Descartes Necker Cochin: collaborator

Study Sites (1)

Hôpital Cochin, Maternité Port-Royal, service de Gynécologie obstétrique

Paris, 75014, France

RECRUITING

Related Publications (1)

• Pacault M, Verebi C, Champion M, Orhant L, Perrier A, Girodon E, Leturcq F, Vidaud D, Ferec C, Bienvenu T, Daveau R, Nectoux J. Non-invasive prenatal diagnosis of single gene disorders with enhanced relative haplotype dosage analysis for diagnostic implementation. PLoS One. 2023 Apr 24;18(4):e0280976. doi: 10.1371/journal.pone.0280976. eCollection 2023.

  PMID: 37093806 BACKGROUND

Biospecimen

Retention: SAMPLES WITH DNA

plasma

MeSH Terms

Conditions

Anemia, Sickle Cell; Cystic Fibrosis; Fragile X Syndrome; Myotonic Dystrophy; Muscular Dystrophy, Duchenne; Neurofibromatosis-Noonan syndrome; Huntington Disease; Hemophilia A; Hemophilia B; Hydrocephalus, X-linked; Polycystic Kidney, Autosomal Recessive; Neurofibromatoses

Interventions

Blood Specimen Collection

Condition Hierarchy (Ancestors)

Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Anemia; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemoglobinopathies; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Pancreatic Diseases; Digestive System Diseases; Lung Diseases; Respiratory Tract Diseases; Infant, Newborn, Diseases; X-Linked Intellectual Disability; Intellectual Disability; Neurobehavioral Manifestations; Neurologic Manifestations; Nervous System Diseases; Sex Chromosome Disorders; Chromosome Disorders; Congenital Abnormalities; Genetic Diseases, X-Linked; Heredodegenerative Disorders, Nervous System; Muscular Dystrophies; Muscular Disorders, Atrophic; Muscular Diseases; Musculoskeletal Diseases; Myotonic Disorders; Neurodegenerative Diseases; Neuromuscular Diseases; Basal Ganglia Diseases; Brain Diseases; Central Nervous System Diseases; Dementia; Chorea; Dyskinesias; Movement Disorders; Cognition Disorders; Neurocognitive Disorders; Mental Disorders; Blood Coagulation Disorders, Inherited; Blood Coagulation Disorders; Coagulation Protein Disorders; Hemorrhagic Disorders; Polycystic Kidney Diseases; Kidney Diseases, Cystic; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Abnormalities, Multiple; Ciliopathies; Neurofibroma; Nerve Sheath Neoplasms; Neoplasms, Nerve Tissue; Neoplasms by Histologic Type; Neoplasms; Neoplastic Syndromes, Hereditary; Neurocutaneous Syndromes

Intervention Hierarchy (Ancestors)

Specimen Handling; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Punctures; Surgical Procedures, Operative; Investigative Techniques

Study Officials

• Juliette NECTOUX, MD,PhD

  Assistance Publique - Hôpitaux de Paris

  PRINCIPAL INVESTIGATOR

• Thierry BIENVENU

  Assistance Publique - Hôpitaux de Paris

  STUDY DIRECTOR

Central Study Contacts

Juliette NECTOUX, MD,PhD

CONTACT

01 58 41 11 86; juliette.nectoux@aphp.fr

Christelle AUGER

CONTACT

01 71 76 07 53; christelle.auger@aphp.fr

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 18, 2023
• First Posted: November 27, 2023
• Study Start: October 23, 2024
• Primary Completion (Estimated): May 1, 2027
• Study Completion (Estimated): May 1, 2027
• Last Updated: April 23, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will not share

Locations

FR (1)