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Phenotypes and genotypes in outbred and inbred Primary microcephaly: high incidence of epilepsy
  • +36
  • 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,
  • Koen Devriendt,
  • Anna Jansen,
  • Kathelijn Keymolen,
  • Damien Lederer,
  • Bart Loeys,
  • Gert Matthijs,
  • Marije Meuwissen,
  • Stéphanie Moortgat,
  • Geert Mortier,
  • Marie-Cécile Nassogne,
  • Tayeb Sekhara,
  • Rudy van Coster,
  • Jenneke  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
Sarah Duerinckx
Université Libre de Bruxelles

Corresponding Author:saduerin@ulb.ac.be

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Julie Désir
Institut de Pathologie et de Génétique asbl
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Camille Perazzolo
Université Libre de Bruxelles
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Cindy Badoer
Hôpital Erasme
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Valérie Jacquemin
Université Libre de Bruxelles
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Julie Soblet
Hôpital Erasme
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Isabelle Maystadt
Institut de Pathologie et de Genetique asbl
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Yusuf Tunca
University of Health Sciences Turkey, Gülhane Faculty of Medicine & Gülhane Training and Research Hospital
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Bettina Blaumeiser
University Hospital Antwerp
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Berten Ceulemans
University Hospital Antwerp
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Winnie Courtens
Centre hospitalier universitaire de Liège
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François-Guillaume Debray
Centre hospitalier universitaire de Liège
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Anne Destree
Institut de Pathologie et de Génétique asbl
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Koen Devriendt
KU Leuven University Hospitals Leuven
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Anna Jansen
Universitair Ziekenhuis Brussel
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Kathelijn Keymolen
Universitair Ziekenhuis Brussel
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Damien Lederer
Institut de Pathologie et de Génétique asbl
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Bart Loeys
University Hospital Antwerp
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Gert Matthijs
KU Leuven University Hospitals Leuven
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Marije Meuwissen
University Hospital Antwerp
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Stéphanie Moortgat
Institut de Pathologie et de Genetique asbl
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Geert Mortier
University Hospital Antwerp
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Marie-Cécile Nassogne
Cliniques universitaires Saint-Luc
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Tayeb Sekhara
CHIREC
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Rudy van Coster
Universitair Ziekenhuis Gent
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Jenneke  Van den Ende
University Hospital Antwerp
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Nathalie Van der Aa
University Hospital Antwerp
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Hilde Van Esch
KU Leuven University Hospitals Leuven
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Olivier Vanakker
Universitair Ziekenhuis Gent
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Helene Verhelst
Universitair Ziekenhuis Gent
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Catheline Vilain
Hôpital Universitaire des Enfants Reine Fabiola
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Sarah Weckhuysen
University Hospital Antwerp
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Sandrine PASSEMARD
APHP
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alain verloes
APHP
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Alec Aeby
Hôpital Universitaire des Enfants Reine Fabiola
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Nicolas Deconinck
Hôpital Universitaire des Enfants Reine Fabiola
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Patrick Van Bogaert
CHU Angers
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Isabelle Pirson
Université Libre de Bruxelles
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Marc Abramowicz
University of Geneva
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Abstract

Primary microcephaly (PM) is defined as a significant reduction in occipito-frontal circumference (OFC) of prenatal onset. Clinical and genetic heterogeneity of PM represents a diagnostic challenge. 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. 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 outbred patients (9%). Our series includes 15 previously unreported families and 11 novel pathogenic variants, and we identify novel candidate genes including IGF2BP3, DNAH2, and TSR1. We confirm progression of microcephaly over time in affected children. Epilepsy was an important associated feature in our PM cohort, affecting 34% of patients, with various degrees of severity and seizure types. Our findings will help to prioritize genomic investigations, accelerate molecular diagnoses and improve management of PM patients.