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Genetic and phenotypic dissection of 1q43q44 microdeletion syndrome and neurodevelopmental phenotypes associated with mutations in ZBTB18 and HNRNPU

Christel Depienne 1, 2, 3 Caroline Nava 4, 2 Boris Keren 4, 2 Solveig Heide 5 Agnès Rastetter 2 Sandrine Passemard 6, 7 Sandra Chantot-Bastaraud 8 Marie-Laure Moutard 9, 8 Pankaj B. Agrawal Grace Vannoy Joan M. Stoler David J. Amor Thierry Villemeur 6 Diane Doummar 9 Caroline Alby 10 Valérie Cormier-Daire 10 Catherine Garel 11 Pauline Marzin Sophie Scheidecker Anne de Saint-Martin 3 Edouard Hirsch 12, 3 Christian Korff 13 Armand Bottani 14 Laurence Faivre 15 Alain Verloes 16, 17 Christine Orzechowski Lydie Burglen 18, 8, 6 Bruno Leheup 19 Joëlle Roume 20 Joris Andrieux 21 Frenny Sheth Chaitanya Datar Michael J. Parker Laurent Pasquier 22 Sylvie Odent 23, 22 Sophie Naudion Marie-Ange Delrue 24 Cédric Le Caignec 25 Marie Vincent 26 Bertrand Isidor 26, 27 Florence Renaldo 28, 6 Fiona Stewart Annick Toutain 29, 30 Udo Koehler Birgit Häckl Celina Stülpnagel Gerhard Kluger 31, 32 Rikke S. Møller Deb Pal Tord Jonson Maria Soller 33 Nienke E. Verbeek Mieke M. Haelst Carolien Kovel Bobby Koeleman Glen Monroe Gijs Haaften Ddd Study Tania Attie-Bitach 34, 10 Lucile Boutaud 34, 10 Delphine Héron 35, 5 Cyril Mignot 35, 5
1 Service de génétique, cytogénétique, embryologie [Pitié-Salpétrière]
2 ICM - Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute
3 IGBMC - Institut de Génétique et de Biologie Moléculaire et Cellulaire
4 Service de Génétique et Cytogénétique [CHU Pitié-Salpêtrière]
5 GRC - Groupe de Recherche Clinique : Déficience Intellectuelle et Autisme
6 PROTECT - Neuroprotection du Cerveau en Développement / Promoting Research Oriented Towards Early Cns Therapies
7 Unité de Neurologie, Hôpital Robert Debré
8 Service de Génétique et d'Embryologie Médicale
9 CHU Trousseau [APHP]
10 IMAGINE - U1163 - Imagine - Institut des maladies génétiques
11 Service de Radiologie Pédiatrique
12 Service de Neurologie [Strasbourg]
13 Dpt de l'Enfant et de l'Adolescent, Neuropédiatrie [Genève]
14 Génétique médicale
15 GAD - Génétique des Anomalies du Développement
16 Physiopathologie et neuroprotection des atteintes du cerveau en développement
17 Département de génétique
18 Service de neuropédiatrie et pathologie du développement
19 Service de Génétique Médicale [CHRU Nancy]
20 Service de Génétique
21 Laboratoire de Génétique Clinique
22 Service de génétique clinique [Rennes]
23 IGDR - Institut de Génétique et Développement de Rennes
24 MRGM - Maladies Rares - Génétique et Métabolisme
25 CHU Nantes - Centre hospitalier universitaire de Nantes
26 Service de génétique médicale - Unité de génétique clinique [Nantes]
27 Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives
28 Service de neurologie pédiatrique et maladies métaboliques
29 Service de génétique [Tours]
30 Imagerie et cerveau
31 Hospital for Neuropediatrics and Neurological Rehabilitation
32 PMU - Paracelsus Medizinische Privatuniversität = Paracelsus Medical University
33 Department of Clinical Genetics
34 CHU Necker - Enfants Malades [AP-HP]
35 CHU Pitié-Salpêtrière [AP-HP]
Abstract : Subtelomeric 1q43q44 microdeletions cause a syndrome associating intellectual disability, microcephaly, seizures and anomalies of the corpus callosum. Despite several previous studies assessing genotype-phenotype correlations, the contribution of genes located in this region to the specific features of this syndrome remains uncertain. Among those, three genes, AKT3, HNRNPU and ZBTB18 are highly expressed in the brain and point mutations in these genes have been recently identified in children with neurodevelopmental phenotypes. In this study, we report the clinical and molecular data from 17 patients with 1q43q44 microdeletions, four with ZBTB18 mutations and seven with HNRNPU mutations, and review additional data from 37 previously published patients with 1q43q44 microdeletions. We compare clinical data of patients with 1q43q44 microdeletions with those of patients with point mutations in HNRNPU and ZBTB18 to assess the contribution of each gene as well as the possibility of epistasis between genes. Our study demonstrates that AKT3 haploinsufficiency is the main driver for microcephaly, whereas HNRNPU alteration mostly drives epilepsy and determines the degree of intellectual disability. ZBTB18 deletions or mutations are associated with variable corpus callosum anomalies with an incomplete penetrance. ZBTB18 may also contribute to microcephaly and HNRNPU to thin corpus callosum, but with a lower penetrance. Co-deletion of contiguous genes has additive effects. Our results confirm and refine the complex genotype-phenotype correlations existing in the 1qter microdeletion syndrome and define more precisely the neurodevelopmental phenotypes associated with genetic alterations of AKT3, ZBTB18 and HNRNPU in humans.
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Journal articles
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https://hal-univ-rennes1.archives-ouvertes.fr/hal-01502135
Contributor : Laurent Jonchère <>
Submitted on : Wednesday, April 5, 2017 - 10:09:00 AM
Last modification on : Thursday, January 14, 2021 - 11:29:20 AM

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UNIV-RENNES1 | IGDR | UNIV-PARIS5 | CNRS | UNIV-PARIS7 | IGBMC | UPMC | ICM | UNIV-NANTES | UNIV-BOURGOGNE | BIOSIT | UR1-UFR-SVE | USPC | PHY-OS | UNIV-TOURS | SITE-ALSACE | UNIV-RENNES | SORBONNE-UNIVERSITE | SU-MEDECINE | IBPS | SU-SCIENCES | UNIV-PARIS | UP-SANTE | SU-TI

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Christel Depienne, Caroline Nava, Boris Keren, Solveig Heide, Agnès Rastetter, et al.. Genetic and phenotypic dissection of 1q43q44 microdeletion syndrome and neurodevelopmental phenotypes associated with mutations in ZBTB18 and HNRNPU. Human Genetics, Springer Verlag, 2017, 136 (4), pp.463-479. ⟨10.1007/s00439-017-1772-0⟩. ⟨hal-01502135⟩

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