Autosomal recessive primary microcephaly due to ASPM mutations: An update

Pascaline Létard 1 Séverine Drunat 2 Yoann Vial 3 Sarah Duerinckx 4 Anais Ernault 5 Daniel Amram 6 Stéphanie Arpin 7 Marta Bertoli 8 Tiffany Busa 9 Berten Ceulemans 10 Julie Desir 11 Martine Doco-Fenzy 12 Siham Chafai Elalaoui 13 Koenraad Devriendt 14 Laurence Faivre 15 Christine Francannet 16 David Genevieve 17 Marion Gérard 18, 19 Cyril Gitiaux 20 Sophie Julia 21 Sébastien Lebon 22 Toni Lubala 23 Michele Mathieu-Dramard 24 Hélène Maurey 25 Julia Metreau 26 Sanaa Nasserereddine 27 Mathilde Nizon 28 Geneviève Pierquin 29 Nathalie Pouvreau 6 Clothilde Rivier-Ringenbach 30 Massimiliano Rossi 31 Elise Schaefer 32 Abdelaziz Sefiani 33 Sabine Sigaudy 34 Yves Sznajer 9 Yusuf Tunca 35 Sophie Guilmin Crepon 5 Corinne Alberti 36 Monique Elmaleh-Bergès 37 Brigitte Benzacken 2 Bernd Wollnick 38 C Geoffrey Woods 39 Anita Rauch 40 Marc Abramowicz 4 Vincent El Ghouzzi 1 Pierre Gressens 1 Alain Verloes 41 Sandrine Passemard 42
Abstract : Autosomal recessive microcephaly or microcephaly primary hereditary (MCPH) is a genetically heterogeneous neurodevelopmental disorder characterized by a reduction in brain volume, indirectly measured by an occipitofrontal circumference (OFC) 2 standard deviations or more below the age- and sex-matched mean (-2SD) at birth and -3SD after 6 months, and leading to intellectual disability of variable severity. The abnormal spindle-like microcephaly gene (ASPM), the human ortholog of the Drosophila melanogaster "abnormal spindle" gene (asp), encodes ASPM, a protein localized at the centrosome of apical neuroprogenitor cells and involved in spindle pole positioning during neurogenesis. Loss-of-function mutations in ASPM cause MCPH5, which affects the majority of all MCPH patients worldwide. Here, we report 47 unpublished patients from 39 families carrying 28 new ASPM mutations, and conduct an exhaustive review of the molecular, clinical, neuroradiological, and neuropsychological features of the 282 families previously reported (with 161 distinct ASPM mutations). Furthermore, we show that ASPM-related microcephaly is not systematically associated with intellectual deficiency and discuss the association between the structural brain defects (strong reduction in cortical volume and surface area) that modify the cortical map of these patients and their cognitive abilities.
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Submitted on : Wednesday, December 4, 2019 - 2:34:35 PM
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Pascaline Létard, Séverine Drunat, Yoann Vial, Sarah Duerinckx, Anais Ernault, et al.. Autosomal recessive primary microcephaly due to ASPM mutations: An update. Human Mutation, Wiley, 2018, 39 (3), pp.319-332. ⟨10.1002/humu.23381⟩. ⟨hal-02393637⟩

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