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

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, analysing 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 aetiology (3.2%, n = 9), associated with a favourable 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. Prenatal decision-making and care are supported by essential prognosis information provided by pES. The identification of genes associated with favourable outcomes, along with the integration of pES into prenatal diagnosis, enhances informed decision-making for parents and improves the clinical management of AnCC.

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Journal
Brain
Published
2025-09-03
DOI
https://doi.org/10.1093/brain/awaf311
Primary Topic
Fetal and Pediatric Neurological Disorders
Type
article
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article

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

Olivier Picone, Béatrice Desnous, Agnès Guët, Boris Keren et al.
1 links
Brain
Fetal and Pediatric Neurological Disorders
article

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

Olivier Picone, Béatrice Desnous, Agnès Guët, Boris Keren, Capucine Rossi, Sophie Julia, Isabelle Sabatier, Lamiae Elkhattabi, Daphné Lehalle, Cathérine Garel, Solveig Heide, Vassilis Tsatsaris, Laurent Guibaud, Caroline Nava, Éléonore Blondiaux, Sarah Grotto, Mathilde Nizon, Anna Gerasimenko, Thierry Billette de Villemeur, Solène Conrad, Toan Nguyen, Alexandre Vivanti, Claudine Le Vaillant, Lucie Guilbaud, Sébastien Moutton, Marie Vincent, Cyril Mignot, Stéphanie Valence, Mathieu Milh, Lisa Frugère, Jean-Madeleine de Sainte-Agathe, Jean‐Marie Jouannic, Delphine Héron, Vincent des Portes, Olivier Patat, Nadine Girard, Alexandra Benachi, Jade Ducourneau
article en

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, analysing 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 aetiology (3.2%, n = 9), associated with a favourable 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. Prenatal decision-making and care are supported by essential prognosis information provided by pES. The identification of genes associated with favourable outcomes, along with the integration of pES into prenatal diagnosis, enhances informed decision-making for parents and improves the clinical management of AnCC.

BrainVol. 148(12)
Université Claude Bernard Lyon 1 (FR), Centre National de la Recherche Scientifique (FR), Inserm (FR), Lyon College (US), Université Paris Cité (FR), Aix-Marseille Université (FR), Université Paris-Saclay (FR), Centre Hospitalier Universitaire de Nantes (FR), Sorbonne Université (FR), Hôpital Femme Mère Enfant (FR), Hôpital Armand-Trousseau (FR), Hôpital Louis-Mourier (FR), Sorbonne Paris Cité (FR), Hôpital Cochin (FR), Assistance Publique – Hôpitaux de Paris (FR), Institut de Myologie (FR), Pitié-Salpêtrière Hospital (FR), Centre d'Investigation Clinique de Nantes (FR), Hôpital Purpan (FR), Hôpital Antoine-Béclère (FR), Institut du Cerveau (FR), Infirmerie Protestante (FR), Hôpital de la Timone (FR), Nantes Université (FR)
Openalex Percentile: Top 67%
Fetal and Pediatric Neurological Disorders
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