Journal Article

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

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

2021

Overview

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. Phenotyping and genetic analyses in 169 probands referred for primary microcephaly produced a molecular diagnosis in 38, with ASPM and WDR62 most prevalent in non‐consanguineous patients, and a total diagnostics rate of 67% in consanguineous patients. Our series includes 11 novel pathogenic variants and reveals epilepsy as a more frequent feature than previously reported.

• Publisher: John Wiley & Sons, Inc,Wiley Periodicals, Inc,John Wiley and Sons Inc,Wiley
• Subject: ASPM protein, human / brain developmental disorders / cell cycle protein / Cell Cycle Proteins / Cell Cycle Proteins - genetics / Child / complication / Consanguinity / Diagnosis / Diagnostic systems / DNA microarrays / Epilepsy / Epilepsy - epidemiology / Epilepsy - genetics / Epilepsy - pathology / Female / Gene Frequency / Genes / Genetic Heterogeneity / Genetic testing / genetics / Genetics & genetic processes / Genomic analysis / Genomics / Genotype / Genotypes / Génétique & processus génétiques / Heterogeneity / human / Humans / Incidence / Life Sciences / Male / Mendeliome / Microcephaly / Microcephaly - complications / Microcephaly - genetics / Microcephaly - pathology / nerve protein / Nerve Tissue Proteins / Nerve Tissue Proteins - genetics / Original / pathology / Patients / Phenotype / Phenotypes / primary microcephaly / rare disease / Sciences du vivant / Seizures / WDR62 protein, human