Implementation of fetal clinical exome sequencing: Comparing prospective and retrospective cohorts

Martina Marangoni; Guillaume Smits; Gilles Ceysens; Elena Costa; Robert Coulon; Caroline Daelemans; Caroline De Coninck; Sara Derisbourg; Kalina Gajewska; Giulia Garofalo; Caroline Gounongbe; Meriem Guizani; Anne Holoye; Catherine Houba; Jean Makhoul; Christian Norgaard; Cecile Regnard; Stephanie Romée; Jamil Soto; Aurore Stagel-Trabbia; Michel Van Rysselberge; An Vercoutere; Siham Zaytouni; Sarah Bouri; Nicky D'Haene; Dominique D'Onle; Christian Dugauquier; Marie-Lucie Racu; Laureen Rocq; Valérie Segers; Camille Verocq; Ephraim Freddy Avni; Marie Cassart; Anne Massez; Bettina Blaumeiser; Elise Brischoux-Boucher; Saskia Bulk; Thomy De Ravel; Guillaume Debray; Boyan Dimitrov; Sandra Janssens; Kathelijn Keymolen; Marie Laterre; Kim van Berkel; Lionel Van Maldergem; Isabelle Vandernoot; Catheline Vilain; Catherine Donner; Laura Tecco; Dominique Thomas; Julie Désir; Marc Abramowicz; Isabelle Migeotte

doi:10.1016/j.gim.2021.09.016

Implementation of fetal clinical exome sequencing: Comparing prospective and retrospective cohorts

Martina Marangoni, Guillaume Smits, Gilles Ceysens, Elena Costa, Robert Coulon, Caroline Daelemans, Caroline De Coninck, Sara Derisbourg, Kalina Gajewska, Giulia Garofalo, Caroline Gounongbe, Meriem Guizani, Anne Holoye, Catherine Houba, Jean Makhoul, Christian Norgaard, Cecile Regnard, Stephanie Romée, Jamil Soto, Aurore Stagel-TrabbiaMichel Van Rysselberge, An Vercoutere, Siham Zaytouni, Sarah Bouri, Nicky D'Haene, Dominique D'Onle, Christian Dugauquier, Marie-Lucie Racu, Laureen Rocq, Valérie Segers, Camille Verocq, Ephraim Freddy Avni, Marie Cassart, Anne Massez, Bettina Blaumeiser, Elise Brischoux-Boucher, Saskia Bulk, Thomy De Ravel, Guillaume Debray, Boyan Dimitrov, Sandra Janssens, Kathelijn Keymolen, Marie Laterre, Kim van Berkel, Lionel Van Maldergem, Isabelle Vandernoot, Catheline Vilain, Catherine Donner, Laura Tecco, Dominique Thomas, Julie Désir, Marc Abramowicz, Isabelle Migeotte

Research output: Contribution to journal › Article › peer-review

16 Citations (Scopus)

Abstract

PURPOSE: We compared the diagnostic yield of fetal clinical exome sequencing (fCES) in prospective and retrospective cohorts of pregnancies presenting with anomalies detected using ultrasound. We evaluated factors that led to a higher diagnostic efficiency, such as phenotypic category, clinical characterization, and variant analysis strategy.

METHODS: fCES was performed for 303 fetuses (183 ongoing and 120 ended pregnancies, in which chromosomal abnormalities had been excluded) using a trio/duo-based approach and a multistep variant analysis strategy.

RESULTS: fCES identified the underlying genetic cause in 13% (24/183) of prospective and 29% (35/120) of retrospective cases. In both cohorts, recessive heterozygous compound genotypes were not rare, and trio and simplex variant analysis strategies were complementary to achieve the highest possible diagnostic rate. Limited prenatal phenotypic information led to interpretation challenges. In 2 prospective cases, in-depth analysis allowed expansion of the spectrum of prenatal presentations for genetic syndromes associated with the SLC17A5 and CHAMP1 genes.

CONCLUSION: fCES is diagnostically efficient in fetuses presenting with cerebral, skeletal, urinary, or multiple anomalies. The comparison between the 2 cohorts highlights the importance of providing detailed phenotypic information for better interpretation and prenatal reporting of genetic variants.

Original language	English
Pages (from-to)	344-363
Number of pages	20
Journal	Genetics in Medicine : Official Journal of the American College of Medical Genetics
Volume	24
Issue number	2
DOIs	https://doi.org/10.1016/j.gim.2021.09.016
Publication status	Published - Feb 2022

Bibliographical note

Keywords

Fetal clinical exome sequencing
Prenatal diagnosis
Ultrasound abnormalities

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10.1016/j.gim.2021.09.016

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Marangoni, M., Smits, G., Ceysens, G., Costa, E., Coulon, R., Daelemans, C., De Coninck, C., Derisbourg, S., Gajewska, K., Garofalo, G., Gounongbe, C., Guizani, M., Holoye, A., Houba, C., Makhoul, J., Norgaard, C., Regnard, C., Romée, S., Soto, J., ... Migeotte, I. (2022). Implementation of fetal clinical exome sequencing: Comparing prospective and retrospective cohorts. Genetics in Medicine : Official Journal of the American College of Medical Genetics, 24(2), 344-363. https://doi.org/10.1016/j.gim.2021.09.016

Marangoni, Martina ; Smits, Guillaume ; Ceysens, Gilles ; Costa, Elena ; Coulon, Robert ; Daelemans, Caroline ; De Coninck, Caroline ; Derisbourg, Sara ; Gajewska, Kalina ; Garofalo, Giulia ; Gounongbe, Caroline ; Guizani, Meriem ; Holoye, Anne ; Houba, Catherine ; Makhoul, Jean ; Norgaard, Christian ; Regnard, Cecile ; Romée, Stephanie ; Soto, Jamil ; Stagel-Trabbia, Aurore ; Van Rysselberge, Michel ; Vercoutere, An ; Zaytouni, Siham ; Bouri, Sarah ; D'Haene, Nicky ; D'Onle, Dominique ; Dugauquier, Christian ; Racu, Marie-Lucie ; Rocq, Laureen ; Segers, Valérie ; Verocq, Camille ; Avni, Ephraim Freddy ; Cassart, Marie ; Massez, Anne ; Blaumeiser, Bettina ; Brischoux-Boucher, Elise ; Bulk, Saskia ; De Ravel, Thomy ; Debray, Guillaume ; Dimitrov, Boyan ; Janssens, Sandra ; Keymolen, Kathelijn ; Laterre, Marie ; van Berkel, Kim ; Van Maldergem, Lionel ; Vandernoot, Isabelle ; Vilain, Catheline ; Donner, Catherine ; Tecco, Laura ; Thomas, Dominique ; Désir, Julie ; Abramowicz, Marc ; Migeotte, Isabelle. / Implementation of fetal clinical exome sequencing : Comparing prospective and retrospective cohorts. In: Genetics in Medicine : Official Journal of the American College of Medical Genetics. 2022 ; Vol. 24, No. 2. pp. 344-363.

@article{6cf7642ad0d743ff9036fe486ac923c6,

title = "Implementation of fetal clinical exome sequencing: Comparing prospective and retrospective cohorts",

abstract = "PURPOSE: We compared the diagnostic yield of fetal clinical exome sequencing (fCES) in prospective and retrospective cohorts of pregnancies presenting with anomalies detected using ultrasound. We evaluated factors that led to a higher diagnostic efficiency, such as phenotypic category, clinical characterization, and variant analysis strategy.METHODS: fCES was performed for 303 fetuses (183 ongoing and 120 ended pregnancies, in which chromosomal abnormalities had been excluded) using a trio/duo-based approach and a multistep variant analysis strategy.RESULTS: fCES identified the underlying genetic cause in 13% (24/183) of prospective and 29% (35/120) of retrospective cases. In both cohorts, recessive heterozygous compound genotypes were not rare, and trio and simplex variant analysis strategies were complementary to achieve the highest possible diagnostic rate. Limited prenatal phenotypic information led to interpretation challenges. In 2 prospective cases, in-depth analysis allowed expansion of the spectrum of prenatal presentations for genetic syndromes associated with the SLC17A5 and CHAMP1 genes.CONCLUSION: fCES is diagnostically efficient in fetuses presenting with cerebral, skeletal, urinary, or multiple anomalies. The comparison between the 2 cohorts highlights the importance of providing detailed phenotypic information for better interpretation and prenatal reporting of genetic variants.",

keywords = "Fetal clinical exome sequencing, Prenatal diagnosis, Ultrasound abnormalities",

author = "Martina Marangoni and Guillaume Smits and Gilles Ceysens and Elena Costa and Robert Coulon and Caroline Daelemans and {De Coninck}, Caroline and Sara Derisbourg and Kalina Gajewska and Giulia Garofalo and Caroline Gounongbe and Meriem Guizani and Anne Holoye and Catherine Houba and Jean Makhoul and Christian Norgaard and Cecile Regnard and Stephanie Rom{\'e}e and Jamil Soto and Aurore Stagel-Trabbia and {Van Rysselberge}, Michel and An Vercoutere and Siham Zaytouni and Sarah Bouri and Nicky D'Haene and Dominique D'Onle and Christian Dugauquier and Marie-Lucie Racu and Laureen Rocq and Val{\'e}rie Segers and Camille Verocq and Avni, {Ephraim Freddy} and Marie Cassart and Anne Massez and Bettina Blaumeiser and Elise Brischoux-Boucher and Saskia Bulk and {De Ravel}, Thomy and Guillaume Debray and Boyan Dimitrov and Sandra Janssens and Kathelijn Keymolen and Marie Laterre and {van Berkel}, Kim and {Van Maldergem}, Lionel and Isabelle Vandernoot and Catheline Vilain and Catherine Donner and Laura Tecco and Dominique Thomas and Julie D{\'e}sir and Marc Abramowicz and Isabelle Migeotte",

year = "2022",

month = feb,

doi = "10.1016/j.gim.2021.09.016",

language = "English",

volume = "24",

pages = "344--363",

journal = "Genetics in Medicine",

issn = "1098-3600",

publisher = "Lippincott Williams and Wilkins",

number = "2",

}

Marangoni, M, Smits, G, Ceysens, G, Costa, E, Coulon, R, Daelemans, C, De Coninck, C, Derisbourg, S, Gajewska, K, Garofalo, G, Gounongbe, C, Guizani, M, Holoye, A, Houba, C, Makhoul, J, Norgaard, C, Regnard, C, Romée, S, Soto, J, Stagel-Trabbia, A, Van Rysselberge, M, Vercoutere, A, Zaytouni, S, Bouri, S, D'Haene, N, D'Onle, D, Dugauquier, C, Racu, M-L, Rocq, L, Segers, V, Verocq, C, Avni, EF, Cassart, M, Massez, A, Blaumeiser, B, Brischoux-Boucher, E, Bulk, S, De Ravel, T, Debray, G, Dimitrov, B, Janssens, S, Keymolen, K, Laterre, M, van Berkel, K, Van Maldergem, L, Vandernoot, I, Vilain, C, Donner, C, Tecco, L, Thomas, D, Désir, J, Abramowicz, M & Migeotte, I 2022, 'Implementation of fetal clinical exome sequencing: Comparing prospective and retrospective cohorts', Genetics in Medicine : Official Journal of the American College of Medical Genetics, vol. 24, no. 2, pp. 344-363. https://doi.org/10.1016/j.gim.2021.09.016

Implementation of fetal clinical exome sequencing : Comparing prospective and retrospective cohorts. / Marangoni, Martina; Smits, Guillaume; Ceysens, Gilles; Costa, Elena; Coulon, Robert; Daelemans, Caroline; De Coninck, Caroline; Derisbourg, Sara; Gajewska, Kalina; Garofalo, Giulia; Gounongbe, Caroline; Guizani, Meriem; Holoye, Anne; Houba, Catherine; Makhoul, Jean; Norgaard, Christian; Regnard, Cecile; Romée, Stephanie; Soto, Jamil; Stagel-Trabbia, Aurore; Van Rysselberge, Michel; Vercoutere, An; Zaytouni, Siham; Bouri, Sarah; D'Haene, Nicky; D'Onle, Dominique; Dugauquier, Christian; Racu, Marie-Lucie; Rocq, Laureen; Segers, Valérie; Verocq, Camille; Avni, Ephraim Freddy; Cassart, Marie; Massez, Anne; Blaumeiser, Bettina; Brischoux-Boucher, Elise; Bulk, Saskia; De Ravel, Thomy; Debray, Guillaume; Dimitrov, Boyan; Janssens, Sandra; Keymolen, Kathelijn; Laterre, Marie; van Berkel, Kim; Van Maldergem, Lionel; Vandernoot, Isabelle; Vilain, Catheline; Donner, Catherine; Tecco, Laura; Thomas, Dominique; Désir, Julie; Abramowicz, Marc; Migeotte, Isabelle.

In: Genetics in Medicine : Official Journal of the American College of Medical Genetics, Vol. 24, No. 2, 02.2022, p. 344-363.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Implementation of fetal clinical exome sequencing

T2 - Comparing prospective and retrospective cohorts

AU - Marangoni, Martina

AU - Smits, Guillaume

AU - Ceysens, Gilles

AU - Costa, Elena

AU - Coulon, Robert

AU - Daelemans, Caroline

AU - De Coninck, Caroline

AU - Derisbourg, Sara

AU - Gajewska, Kalina

AU - Garofalo, Giulia

AU - Gounongbe, Caroline

AU - Guizani, Meriem

AU - Holoye, Anne

AU - Houba, Catherine

AU - Makhoul, Jean

AU - Norgaard, Christian

AU - Regnard, Cecile

AU - Romée, Stephanie

AU - Soto, Jamil

AU - Stagel-Trabbia, Aurore

AU - Van Rysselberge, Michel

AU - Vercoutere, An

AU - Zaytouni, Siham

AU - Bouri, Sarah

AU - D'Haene, Nicky

AU - D'Onle, Dominique

AU - Dugauquier, Christian

AU - Racu, Marie-Lucie

AU - Rocq, Laureen

AU - Segers, Valérie

AU - Verocq, Camille

AU - Avni, Ephraim Freddy

AU - Cassart, Marie

AU - Massez, Anne

AU - Blaumeiser, Bettina

AU - Brischoux-Boucher, Elise

AU - Bulk, Saskia

AU - De Ravel, Thomy

AU - Debray, Guillaume

AU - Dimitrov, Boyan

AU - Janssens, Sandra

AU - Keymolen, Kathelijn

AU - Laterre, Marie

AU - van Berkel, Kim

AU - Van Maldergem, Lionel

AU - Vandernoot, Isabelle

AU - Vilain, Catheline

AU - Donner, Catherine

AU - Tecco, Laura

AU - Thomas, Dominique

AU - Désir, Julie

AU - Abramowicz, Marc

AU - Migeotte, Isabelle

PY - 2022/2

Y1 - 2022/2

N2 - PURPOSE: We compared the diagnostic yield of fetal clinical exome sequencing (fCES) in prospective and retrospective cohorts of pregnancies presenting with anomalies detected using ultrasound. We evaluated factors that led to a higher diagnostic efficiency, such as phenotypic category, clinical characterization, and variant analysis strategy.METHODS: fCES was performed for 303 fetuses (183 ongoing and 120 ended pregnancies, in which chromosomal abnormalities had been excluded) using a trio/duo-based approach and a multistep variant analysis strategy.RESULTS: fCES identified the underlying genetic cause in 13% (24/183) of prospective and 29% (35/120) of retrospective cases. In both cohorts, recessive heterozygous compound genotypes were not rare, and trio and simplex variant analysis strategies were complementary to achieve the highest possible diagnostic rate. Limited prenatal phenotypic information led to interpretation challenges. In 2 prospective cases, in-depth analysis allowed expansion of the spectrum of prenatal presentations for genetic syndromes associated with the SLC17A5 and CHAMP1 genes.CONCLUSION: fCES is diagnostically efficient in fetuses presenting with cerebral, skeletal, urinary, or multiple anomalies. The comparison between the 2 cohorts highlights the importance of providing detailed phenotypic information for better interpretation and prenatal reporting of genetic variants.

AB - PURPOSE: We compared the diagnostic yield of fetal clinical exome sequencing (fCES) in prospective and retrospective cohorts of pregnancies presenting with anomalies detected using ultrasound. We evaluated factors that led to a higher diagnostic efficiency, such as phenotypic category, clinical characterization, and variant analysis strategy.METHODS: fCES was performed for 303 fetuses (183 ongoing and 120 ended pregnancies, in which chromosomal abnormalities had been excluded) using a trio/duo-based approach and a multistep variant analysis strategy.RESULTS: fCES identified the underlying genetic cause in 13% (24/183) of prospective and 29% (35/120) of retrospective cases. In both cohorts, recessive heterozygous compound genotypes were not rare, and trio and simplex variant analysis strategies were complementary to achieve the highest possible diagnostic rate. Limited prenatal phenotypic information led to interpretation challenges. In 2 prospective cases, in-depth analysis allowed expansion of the spectrum of prenatal presentations for genetic syndromes associated with the SLC17A5 and CHAMP1 genes.CONCLUSION: fCES is diagnostically efficient in fetuses presenting with cerebral, skeletal, urinary, or multiple anomalies. The comparison between the 2 cohorts highlights the importance of providing detailed phenotypic information for better interpretation and prenatal reporting of genetic variants.

KW - Fetal clinical exome sequencing

KW - Prenatal diagnosis

KW - Ultrasound abnormalities

UR - http://www.scopus.com/inward/record.url?scp=85123307136&partnerID=8YFLogxK

U2 - 10.1016/j.gim.2021.09.016

DO - 10.1016/j.gim.2021.09.016

M3 - Article

C2 - 34906519

VL - 24

SP - 344

EP - 363

JO - Genetics in Medicine

JF - Genetics in Medicine

SN - 1098-3600

IS - 2

ER -

Implementation of fetal clinical exome sequencing: Comparing prospective and retrospective cohorts

Abstract

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Keywords

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