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

brain developmental disorders; consanguinity; epilepsy; Mendeliome; primary microcephaly; rare disease; ASPM protein, human; cell cycle protein; nerve protein; WDR62 protein, human; child; complication; female; gene frequency; genetic heterogeneity; genetics; genotype; human; incidence; male; microcephaly; pathology; phenotype; Cell Cycle Proteins; Child; Consanguinity; Epilepsy; Female; Gene Frequency; Genetic Heterogeneity; Genotype; Humans; Incidence; Male; Microcephaly; Nerve Tissue Proteins; Phenotype

Abstract :

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

Disciplines :

Genetics & genetic processes

Author, co-author :

Duerinckx, S.; Institut de Recherche Interdisciplinaire en Biologie Humaine et moléculaire, Université Libre de Bruxelles, Brussels, Belgium

Désir, J.; Centre de Génétique Humaine, Institut de Pathologie et de Génétique, Gosselies, Belgium

Perazzolo, C.; Institut de Recherche Interdisciplinaire en Biologie Humaine et moléculaire, Université Libre de Bruxelles, Brussels, Belgium

Badoer, C.; Department of Genetics, Hôpital Erasme, ULB Center of Human Genetics, Université Libre de Bruxelles, Brussels, Belgium

Jacquemin, V.; Institut de Recherche Interdisciplinaire en Biologie Humaine et moléculaire, Université Libre de Bruxelles, Brussels, Belgium

Soblet, J.; Department of Genetics, Hôpital Erasme, ULB Center of Human Genetics, Université Libre de Bruxelles, Brussels, Belgium, Hôpital Universitaire des Enfants Reine Fabiola (HUDERF), Université Libre de Bruxelles, Brussels, Belgium

Maystadt, I.; Centre de Génétique Humaine, Institut de Pathologie et de Génétique, Gosselies, Belgium

Tunca, Y.; Department of Medical Genetics, Gülhane Faculty of Medicine & Gülhane Training and Research Hospital, University of Health Sciences Turkey, Ankara, Turkey

Blaumeiser, B.; University and University Hospital of Antwerp, Antwerp, Belgium

Ceulemans, B.; University and University Hospital of Antwerp, Antwerp, Belgium

More authors (28 more)

Language :

English

Title :

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

Publication date :

2021

Journal title :

Molecular Genetics and Genomic Medicine

eISSN :

2324-9269

Publisher :

John Wiley and Sons Inc

Volume :

Issue :

Peer reviewed :

Peer Reviewed verified by ORBi

Funding text :

This work was supported by ERA‐net E‐Rare Euromicro and the Action de Recherche Concertée (ARC) of the Belgian Fédération Wallonie Bruxelles to M.A., the Fonds de la Recherche Scientifique FRS‐FNRS Belgium and the Fonds de soutien Marguerite‐Marie Delacroix to S.D., the Fonds Erasme to M.A. and to S.D., and the Université Libre de Bruxelles to I.P.

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