Phenotypes and genotypes in non-consanguineous and consanguineous primary microcephaly: High incidence of epilepsy

Sarah Duerinckx, Julie Désir, Camille Perazzolo, Cindy Badoer, Valérie Jacquemin, Julie Soblet, Isabelle Maystadt, Yusuf Tunca, Bettina Blaumeiser, Berten Ceulemans, Winnie Courtens, François-Guillaume Debray, Anne Destree, Koenraad Devriendt, Anna Jansen, Kathelijn Keymolen, Damien Lederer, Bart Loeys, Marije Meuwissen, Stéphanie MoortgatGeert Mortier, Marie-Cécile Nassogne, Tayeb Sekhara, Rudy Van Coster, Jenny Van Den Ende, Nathalie Van der Aa, Hilde Van Esch, Olivier Vanakker, Helene Verhelst, Catheline Vilain, Sarah Weckhuysen, Sandrine Passemard, Alain Verloes, Alec Aeby, Nicolas Deconinck, Patrick Van Bogaert, Isabelle Pirson, Marc Abramowicz

Research output: Contribution to journalArticle


BACKGROUND: Primary microcephaly (PM) is defined as a significant reduction in occipitofrontal circumference (OFC) of prenatal onset. Clinical and genetic heterogeneity of PM represents a diagnostic challenge.

METHODS: We performed detailed phenotypic and genomic analyses in a large cohort (n = 169) of patients referred for PM and could establish a molecular diagnosis in 38 patients.

RESULTS: Pathogenic variants in ASPM and WDR62 were the most frequent causes in non-consanguineous patients in our cohort. In consanguineous patients, microarray and targeted gene panel analyses reached a diagnostic yield of 67%, which contrasts with a much lower rate in non-consanguineous patients (9%). Our series includes 11 novel pathogenic variants and we identify novel candidate genes including IGF2BP3 and DNAH2. We confirm the progression of microcephaly over time in affected children. Epilepsy was an important associated feature in our PM cohort, affecting 34% of patients with a molecular confirmation of the PM diagnosis, with various degrees of severity and seizure types.

CONCLUSION: Our findings will help to prioritize genomic investigations, accelerate molecular diagnoses, and improve the management of PM patients.

Original languageEnglish
Article numbere1768
Number of pages19
JournalMolecular Genetics and Genomic Medicine
Issue number9
Early online date17 Aug 2021
Publication statusPublished - Sep 2021

Bibliographical note

© 2021 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.


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