A large cohort study of prenatal exome sequencing redefines diagnosis in fetal corpus callosum anomalies

Delphine Héron¹, Anna Gerasimenko¹, Lisa Frugère¹, Jade Ducourneau¹, Capucine Rossi¹, Caroline Nava², Jean-Madeleine de Sainte-Agathe², Cyril Mignot¹, Daphné Lehalle¹, Sarah Grotto¹, Laila El-Khattabi^{2

3}, Toan Nguyen⁴, Catherine Garel⁴, Eleonore Blondiaux⁴, Mathieu Milh⁵, Béatrice Desnous⁵, Nadine Girard⁶, Vincent des Portes⁷, Laurent Guibaud⁸, Isabelle Sabatier⁸, Olivier Patat⁹, Sophie Julia⁹, Alexandra Benachi¹⁰, Alexandre Vivanti¹⁰, Olivier Picone¹¹, Agnès Guet¹¹, Mathilde Nizon¹², Marie Vincent¹², Solène Conrad¹², Claudine Le Vaillant¹³, Thierry Billette de Villemeur¹⁴, Sébastien Moutton¹⁵, Vassilis Tsatsaris¹⁶, Lucie Guilbaud¹⁷, Jean-Marie Jouannic¹⁷, Stéphanie Valence¹⁴, Boris Keren², Solveig Heide¹

Affiliations

¹ Clinical Genetics Unit, Referral Centers for Rare Diseases "Intellectual Disabilities of Rare Causes" and "Developmental Anomalies and Malformative Syndromes", APHP.Sorbonne University, Pitié Salpêtrière Hospital, APHP, Paris, 75013, France.
² Developmental and Reproductive Genomics Unit, Medical Genetics Department, APHP.Sorbonne University, Pitié-Salpêtrière Hospital, APHP, Paris, 75013, France.
³ Paris Brain Institute, Sorbonne Université, Inserm U1127, CNRS UMR 7225, Hôpital Pitié-Salpêtrière, Paris, 75013, France.
⁴ Department of Pediatric Radiology, Trousseau Hospital, AP-HP.Sorbonne University, Paris, 75012, France.
⁵ Pediatric Neurology Department, Timone Enfant, APHM, Marseille, 13005, France.
⁶ Department of Radiology, University Hospital Timone, Aix Marseille University, Marseille, 13005, France.
⁷ Department of child neurology, Referral Centers for Rare Diseases "Intellectual Disabilities of Rare Causes", Lyon Hospital, and University Claude Bernard Lyon1, Lyon, 69500, France.
⁸ Department of Fetal and Pediatric Imaging, Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Bron, 69500, France.
⁹ Department of Medical Genetics, Purpan Hospital, CHU de Toulouse, Toulouse, 31200, France.
¹⁰ 10Obstetrics and Gynaecology Department. Antoine Béclère Hospital, APHP, Paris Saclay University, Clamart, 92140, France.
¹¹ Neonatal and Pediatric Units, Louis-Mourier Hospital APHP, Colombes, 92025, France.
¹² Medical Genetics Unit, Nantes Hospital and University, Nantes, 44000, France.
¹³ Department of Obstetrics and Gynecology, CHU Nantes, Nantes, 44000, France.
¹⁴ Pediatric neurology department, Referral Centers for Rare Diseases "Intellectual Disabilities of Rare Causes", APHP.Sorbonne University, Armand Trousseau Hospital, APHP, Paris, 75012, France.
¹⁵ CPDPN, Pôle mère enfant, Maison de Santé Protestante Bordeaux Bagatelle, Talence, 33522, France.
¹⁶ Department of Obstetric, Cochin Hospital, APHP, Université Paris Cité, Paris, 75014, France.
¹⁷ Fetal Medicine Department, Armand Trousseau University Hospital, DMU Origyne, Sorbonne University, Paris, 75012, France.

PMID: 40905141
DOI: 10.1093/brain/awaf311

A large cohort study of prenatal exome sequencing redefines diagnosis in fetal corpus callosum anomalies

Delphine Héron et al. Brain. 2025.

. 2025 Sep 4:awaf311.

doi: 10.1093/brain/awaf311. Online ahead of print.

Authors

Affiliations

¹ Clinical Genetics Unit, Referral Centers for Rare Diseases "Intellectual Disabilities of Rare Causes" and "Developmental Anomalies and Malformative Syndromes", APHP.Sorbonne University, Pitié Salpêtrière Hospital, APHP, Paris, 75013, France.
² Developmental and Reproductive Genomics Unit, Medical Genetics Department, APHP.Sorbonne University, Pitié-Salpêtrière Hospital, APHP, Paris, 75013, France.
³ Paris Brain Institute, Sorbonne Université, Inserm U1127, CNRS UMR 7225, Hôpital Pitié-Salpêtrière, Paris, 75013, France.
⁴ Department of Pediatric Radiology, Trousseau Hospital, AP-HP.Sorbonne University, Paris, 75012, France.
⁵ Pediatric Neurology Department, Timone Enfant, APHM, Marseille, 13005, France.
⁶ Department of Radiology, University Hospital Timone, Aix Marseille University, Marseille, 13005, France.
⁷ Department of child neurology, Referral Centers for Rare Diseases "Intellectual Disabilities of Rare Causes", Lyon Hospital, and University Claude Bernard Lyon1, Lyon, 69500, France.
⁸ Department of Fetal and Pediatric Imaging, Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Bron, 69500, France.
⁹ Department of Medical Genetics, Purpan Hospital, CHU de Toulouse, Toulouse, 31200, France.
¹⁰ 10Obstetrics and Gynaecology Department. Antoine Béclère Hospital, APHP, Paris Saclay University, Clamart, 92140, France.
¹¹ Neonatal and Pediatric Units, Louis-Mourier Hospital APHP, Colombes, 92025, France.
¹² Medical Genetics Unit, Nantes Hospital and University, Nantes, 44000, France.
¹³ Department of Obstetrics and Gynecology, CHU Nantes, Nantes, 44000, France.
¹⁴ Pediatric neurology department, Referral Centers for Rare Diseases "Intellectual Disabilities of Rare Causes", APHP.Sorbonne University, Armand Trousseau Hospital, APHP, Paris, 75012, France.
¹⁵ CPDPN, Pôle mère enfant, Maison de Santé Protestante Bordeaux Bagatelle, Talence, 33522, France.
¹⁶ Department of Obstetric, Cochin Hospital, APHP, Université Paris Cité, Paris, 75014, France.
¹⁷ Fetal Medicine Department, Armand Trousseau University Hospital, DMU Origyne, Sorbonne University, Paris, 75012, France.

PMID: 40905141
DOI: 10.1093/brain/awaf311

Abstract

Anomalies of the corpus callosum (AnCC) are congenital malformations associated with highly variable neurodevelopmental outcomes. We performed prenatal Exome Sequencing (pES) on a cohort of 352 fetuses diagnosed with AnCC, analyzing the diagnostic yield, the implicated genes based on the type of anomaly (partial or complete agenesis, short corpus callosum, or callosal dysgenesis) and assessing the impact on pregnancy outcomes. The overall diagnostic yield of pES was 23%, with pathogenic or likely pathogenic variants identified in 49 different genes, most of which linked to intellectual developmental disorders. The highest diagnostic yield (46%) was observed in fetuses with callosal dysgenesis. Notably, in cases of corpus callosum agenesis, variants in the DCC gene were the most frequently identified etiology (3.2%, n=9), associated with a favorable neurodevelopmental outcome. All couples with a fetal DCC variant decided to continue the pregnancy to term. In contrast, 73% of couples with other genetic diagnoses chose pregnancy termination, compared to 17% in cases without a genetic diagnosis. pES provides essential prognosis information that supports prenatal decision-making and care. The identification of genes associated with favorable outcomes, along with the integration of pES into prenatal diagnosis, enhances informed decision-making for parents and improves the clinical management of AnCC.

Keywords: DCC; ZEB2; agenesis of the corpus callosum; anomalies of the corpus callosum; corpus callosum; prenatal exome sequencing.

© The Author(s) 2025. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.

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A large cohort study of prenatal exome sequencing redefines diagnosis in fetal corpus callosum anomalies

Affiliations

A large cohort study of prenatal exome sequencing redefines diagnosis in fetal corpus callosum anomalies

Authors

Affiliations

Abstract

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Research Materials