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Development of Non-Invasive Prenatal Diagnosis for Single Gene Disorders

ConditionsInvasive PreNatal Diagnosis in a Context of Family History of Single-gene Disorders, IncludingSickle Cell DiseaseCystic FibrosisFragile X SyndromeProximal Spinal Muscular AtrophyMyotonic DystrophyMuscular Dystrophy, DuchenneMuscular Dystrophy, BeckerNeurofibromatosis-Noonan SyndromeHuntington DiseaseHemophilia AHemophilia BMODY2 DiabetesX-Linked HydrocephalusAutosomal Recessive Polycystic Kidney Disease
Trial statusRecruiting
Trial phaseNot listed
Trial typeObservational
Biological sexFemale
Age18+
SponsorAssistance Publique - Hôpitaux de Paris

About this trial

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.

Eligibility criteria

This trial does not accept healthy volunteers

Qualifiers

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

Disqualifiers

at risk of SGD involving a de novo pathogenic mutation in a previous child

woman under legal protection

Trial 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)

Trial design

Design model

Cohort

Time perspective

Prospective

Treatments tested in this trial

  • Blood sample

    Biological/Vaccine

    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.

Treatment groups

550 Participants
are divided into 2 treatment groups
Group A: pregnant women undergoing invasive PND in a context of family history of SGD1 intervention
Group B: pregnant women undergoing prenatal counselling in a context of maternal history of diabetes MODY-GCK1 intervention

Trial outcomes

Primary outcomes

1

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

respectively among conclusive results

Time frame
1 day
2

% of inconclusive results

Time frame
1 day

Secondary outcomes

1

cffDNA concentration in maternal plasma

relative concentration in % of total cell-free DNA

Time frame
1 day
2

sequencing coverage

mean number of reads in targeted locus

Time frame
1 day
3

Quality scores

block and concordance scores, evaluated from 0 to 1 as described in Pacault et al, Plos One, 2023

Time frame
1 day
4

Optimal window in terms of gestational age for maternal sampling

block and concordance scores will be compared depending on the maternal blood sampling window: * group 1 corresponds to samples between 7+0 and 7+6 weeks of gestation * group 2 corresponds to samples between 8+0 and 8+6 weeks of gestation * group 3 corresponds to samples between 9+0 and 9+6 weeks of gestation * group 4 corresponds to samples between 10+0 and 10+6 weeks of gestation * group 5 corresponds to samples between 11+0 and 11+6 weeks of gestation * group 6 corresponds to samples over 12+0 weeks of gestation

Time frame
through study completion, an average of 2 years

Other outcomes

Sponsors and contacts

Click on the lead sponsor to view all of their trials.

Assistance Publique - Hôpitaux de Paris

Lead sponsor

URC-CIC Paris Descartes Necker Cochin

Collaborator

Source ClinicalTrials.gov
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