OC06.01: Single cell sequencing of circulating extravillous trophoblasts for non‐invasive fetal copy number variant screening

Pathogenic microdeletions/duplications (pCNVs) account for a significant perinatal morbidity/mortality and have a 1/100-200 prevalence in the general prenatal population. Cell-free DNA non-invasive testing (cfNIPT) shows significant limitations for comprehensive profiling of pCNVs <7Mb in size. A proof-of-concept study demonstrated the feasibility of a novel cell-based NIPT (cbNIPT) for circulating extravillous trophoblasts (cEVTs) isolation and single cell sequencing for fetal CNV detection down to ~800kb. The scope of the study is to demonstrate cbNIPT scientific validity in a large blinded prospective performance study comparing the fetal genomic result with that of cEVTs screening. 1388 high-risk pregnancies were enrolled to obtain a statistically significant pCNV/aneuploidies number. Blood was collected from pregnant women at 11-22+6 wg before invasive diagnostic procedure and processed with proprietary laboratory workflow not optimised for recovery rate. 1070 had CMA ± karyotype and the remainders with karyotype only. Screen positive rate for aneuploidies and pCNV was 18.9% and 11.2%, respectively. Totally 203 pCNVs ≥ 1Mb were detected and 84.2% of them (171/203) were 1-7 Mb in size. Of note, pCNVs < 1 Mb were also detected. Examples of pCNV are: 22q11.2del (7 spanning 600Kb-3Mb), 22q11dup (1 of 3Mb), 2q37del (2 of 2.1Mb and 3.9Mb), 8q24.3del (2 of 600kb), 7q22.3del (1 of 800Kb), 1q21.1del (1 of 800kb), Wolf-Hirschhorn Sy (1 of 2.9Mb) and 1 Williams Beuren Sy (1 of 1Mb). At the time of submission, the clinical database was locked and confirmatory clinical data analysis was ongoing. Analysis of cEVTs from maternal blood offers the detection of genome wide pCNV < 1 Mb, below the resolution of cell-free DNA screening. In the general pregnancy population, this would allow the opportunity for a significant reduction of residual risk for pCNV at early gestational weeks. CbNIPT clinical performance data will be provided together with an estimated rate of detection compared to cfNIPT.

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Publication Details

Journal
Ultrasound in Obstetrics and Gynecology
Published
2024-09-01
DOI
https://doi.org/10.1002/uog.27754
Primary Topic
Prenatal Screening and Diagnostics
Type
article
Field-Weighted Citation Impact
0.00

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article

OC06.01: Single cell sequencing of circulating extravillous trophoblasts for non‐invasive fetal copy number variant screening

Genny Buson, Emma Bertucci, Isabella Fabietti, Claudia Izzi et al.
Ultrasound in Obstetrics and Gynecology
Prenatal Screening and Diagnostics
article

OC06.01: Single cell sequencing of circulating extravillous trophoblasts for non‐invasive fetal copy number variant screening

Genny Buson, Emma Bertucci, Isabella Fabietti, Claudia Izzi, Antonio Novelli, Thomas J. Musci, Camilla Amadesi, N. Volpe, A. Doffini, Lucia Pasquini, Chiara Bolognesi, Leonardo Caforio, Anna Locatelli, E. Giovannone, Fabrizia Restaldi, M. Signorelli, Felice Petraglia, Claudio Forcato, D. Lattuada, Francesca Romana Grati, G. Rembouskos, Alessandra Sponzilli, Lorenzo Monasta, Domizia Pasquetti, Ester Del Signore, R. Foti, T. Ghi, D. Paladini, Pietro Bagolan, Sara Ornaghi, Elisa Bevilacqua, C. Fregona, I. Molinaro, M. Iannitiello, Pedro L.O. Volpe, T. Stampalija, Enrico Maria Ferrazzi
article en

Abstract

Pathogenic microdeletions/duplications (pCNVs) account for a significant perinatal morbidity/mortality and have a 1/100-200 prevalence in the general prenatal population. Cell-free DNA non-invasive testing (cfNIPT) shows significant limitations for comprehensive profiling of pCNVs <7Mb in size. A proof-of-concept study demonstrated the feasibility of a novel cell-based NIPT (cbNIPT) for circulating extravillous trophoblasts (cEVTs) isolation and single cell sequencing for fetal CNV detection down to ~800kb. The scope of the study is to demonstrate cbNIPT scientific validity in a large blinded prospective performance study comparing the fetal genomic result with that of cEVTs screening. 1388 high-risk pregnancies were enrolled to obtain a statistically significant pCNV/aneuploidies number. Blood was collected from pregnant women at 11-22+6 wg before invasive diagnostic procedure and processed with proprietary laboratory workflow not optimised for recovery rate. 1070 had CMA ± karyotype and the remainders with karyotype only. Screen positive rate for aneuploidies and pCNV was 18.9% and 11.2%, respectively. Totally 203 pCNVs ≥ 1Mb were detected and 84.2% of them (171/203) were 1-7 Mb in size. Of note, pCNVs < 1 Mb were also detected. Examples of pCNV are: 22q11.2del (7 spanning 600Kb-3Mb), 22q11dup (1 of 3Mb), 2q37del (2 of 2.1Mb and 3.9Mb), 8q24.3del (2 of 600kb), 7q22.3del (1 of 800Kb), 1q21.1del (1 of 800kb), Wolf-Hirschhorn Sy (1 of 2.9Mb) and 1 Williams Beuren Sy (1 of 1Mb). At the time of submission, the clinical database was locked and confirmatory clinical data analysis was ongoing. Analysis of cEVTs from maternal blood offers the detection of genome wide pCNV < 1 Mb, below the resolution of cell-free DNA screening. In the general pregnancy population, this would allow the opportunity for a significant reduction of residual risk for pCNV at early gestational weeks. CbNIPT clinical performance data will be provided together with an estimated rate of detection compared to cfNIPT.

Ultrasound in Obstetrics and GynecologyVol. 64(S1)
Università Cattolica del Sacro Cuore (IT), University of Modena and Reggio Emilia (IT), University of Parma (IT), University of Trieste (IT), IRCCS Materno Infantile Burlo Garofolo (IT), Istituto Giannina Gaslini (IT), Agostino Gemelli University Polyclinic (IT), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (IT), Menarini Group (Italy) (IT), Azienda Ospedaliera San Gerardo (IT), Azienda Ospedaliero-Universitaria Careggi (IT), Bambino Gesù Children's Hospital (IT), University of Florence (IT), University of Milano-Bicocca (IT), University of Brescia (IT)
Università Degli Studi di Modena e Reggio Emila, Università degli Studi di Milano, Menarini Silicon Biosystems, Università degli Studi di Firenze, Università degli Studi di Parma, Università degli Studi di Brescia, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico
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