title: Genetic and phenotypic dissection of 1q43q44 microdeletion syndrome and neurodevelopmental phenotypes associated with mutations in ZBTB18 and HNRNPU.
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.
authors.affiliation: IGBMC, CNRS UMR 7104/INSERM U964/Université de Strasbourg, 67400, Illkirch, France. depiennc@igbmc.fr.|Laboratoires de Génétique, Institut de Génétique médicale d'Alsace, Hôpitaux Universitaires de Strasbourg, 67000, Strasbourg, France. depiennc@igbmc.fr.|INSERM, U 1127, CNRS UMR 7225, Institut du Cerveau et de la Moelle épinière, ICM, Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, 75013, Paris, France. depiennc@igbmc.fr.|AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Département de Génétique, 75013, Paris, France. depiennc@igbmc.fr.|EuroEPINOMICS RES consortium, . depiennc@igbmc.fr.
authors.forename: Christel
authors.initials: C
authors.lastname: Depienne
authors.affiliation: INSERM, U 1127, CNRS UMR 7225, Institut du Cerveau et de la Moelle épinière, ICM, Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, 75013, Paris, France.|AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Département de Génétique, 75013, Paris, France.|EuroEPINOMICS RES consortium.
authors.forename: Caroline
authors.initials: C
authors.lastname: Nava
authors.affiliation: INSERM, U 1127, CNRS UMR 7225, Institut du Cerveau et de la Moelle épinière, ICM, Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, 75013, Paris, France.|AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Département de Génétique, 75013, Paris, France.
authors.forename: Boris
authors.initials: B
authors.lastname: Keren
authors.affiliation: AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Département de Génétique, 75013, Paris, France.|Groupe de Recherche Clinique (GRC) "déficience intellectuelle et autisme" UPMC, Groupe Hospitalier Pitié-Salpêtrière, 75013, Paris, France.
authors.forename: Solveig
authors.initials: S
authors.lastname: Heide
authors.affiliation: INSERM, U 1127, CNRS UMR 7225, Institut du Cerveau et de la Moelle épinière, ICM, Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, 75013, Paris, France.
authors.forename: Agnès
authors.initials: A
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authors.affiliation: AP-HP, Department of Child Neurology, Hôpital Robert Debré, Paris, France.|AP-HP, Department of Genetics, Hôpital Robert Debré, Paris, France.|INSERM UMR U1141, Hôpital Robert Debré, Université Paris-Diderot, Sorbonne Paris Cité, Paris, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Passemard
authors.affiliation: AP-HP, Département de Génétique Médicale, Unité fonctionnelle de Génétique Chromosomique, CHU Paris Est, Hôpital d'Enfants Armand-Trousseau, 75571, Paris, France.
authors.forename: Sandra
authors.initials: S
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authors.affiliation: AP-HP, Service de Neuropédiatrie, Hôpital Trousseau, 75012, Paris, France.|UPMC, GRC ConCer-LD, Sorbonne Université, Paris, France.|Centre de Référence des Maladies Neurogénétiques de l'Enfant et de l'Adolescent, Paris, France.
authors.forename: Marie-Laure
authors.initials: ML
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authors.affiliation: Divisions of Genetics and Genomics and Newborn Medicine, Manton Center for Orphan Disease Research, Boston Children's Hospital and Harvard Medical School, Boston, MA, 02115, USA.
authors.forename: Pankaj B
authors.initials: PB
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authors.affiliation: Divisions of Genetics and Genomics and Newborn Medicine, Manton Center for Orphan Disease Research, Boston Children's Hospital and Harvard Medical School, Boston, MA, 02115, USA.
authors.forename: Grace
authors.initials: G
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authors.affiliation: Divisions of Genetics and Genomics and Newborn Medicine, Manton Center for Orphan Disease Research, Boston Children's Hospital and Harvard Medical School, Boston, MA, 02115, USA.
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authors.initials: JM
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authors.affiliation: Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, VIC, 3052, Australia.|Department of Paediatrics, University of Melbourne, Parkville, VIC, 3052, Australia.
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authors.initials: DJ
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authors.affiliation: INSERM UMR U1141, Hôpital Robert Debré, Université Paris-Diderot, Sorbonne Paris Cité, Paris, France.|AP-HP, Service de Neuropédiatrie, Hôpital Trousseau, 75012, Paris, France.|UPMC, GRC ConCer-LD, Sorbonne Université, Paris, France.|Centre de Référence "déficiences intellectuelles de causes rares", Paris, France.
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authors.affiliation: AP-HP, Service de Neuropédiatrie, Hôpital Trousseau, 75012, Paris, France.|Centre de Référence des Maladies Neurogénétiques de l'Enfant et de l'Adolescent, Paris, France.
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authors.affiliation: INSERM U1163, Laboratory of Embryology and Genetics of Congenital Malformations, Sorbonne Paris Cité and Imagine Institute, Paris Descartes University, 75015, Paris, France.|AP-HP, Département de Génétique, Hôpital Necker-Enfants Malades, 75015, Paris, France.
authors.forename: Caroline
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authors.affiliation: INSERM U1163, Laboratory of Molecular and Physiopathological bases of osteochondrodysplasia, Sorbonne Paris Cité and Imagine Institute, Paris Descartes University, 75015, Paris, France.|AP-HP, Département de Génétique, Hôpital Necker-Enfants Malades, 75015, Paris, France.
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authors.affiliation: IGBMC, CNRS UMR 7104/INSERM U964/Université de Strasbourg, 67400, Illkirch, France.|Pediatric Neurology Department, Hautepierre Hospital, Strasbourg University Hospital, Strasbourg, France.
authors.forename: Anne
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authors.affiliation: IGBMC, CNRS UMR 7104/INSERM U964/Université de Strasbourg, 67400, Illkirch, France.|Medical and Surgical Epilepsy Unit, Hautepierre Hospital, Strasbourg University Hospital, Strasbourg, France.
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authors.affiliation: Service de Génétique Médicale, CHU de Nantes, Nantes, France.|Faculté de Médecine, INSERM, UMR 957, Physiopathologie de la résorption osseuse et des tumeurs osseuses primitives, Université, Nantes, France.
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authors.affiliation: Department of Clinical Genetics, Lund University Hospital, 221 85, Lund, Sweden.
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authors.forename: Nienke E
authors.initials: NE
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authors.affiliation: Department of Genetics, University Medical Center Utrecht, Utrecht, 3584 CX, The Netherlands.
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authors.forename: Tania
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authors.lastname: Attié-Bitach
authors.affiliation: INSERM U1163, Laboratory of Embryology and Genetics of Congenital Malformations, Sorbonne Paris Cité and Imagine Institute, Paris Descartes University, 75015, Paris, France.|AP-HP, Département de Génétique, Hôpital Necker-Enfants Malades, 75015, Paris, France.
authors.forename: Lucile
authors.initials: L
authors.lastname: Boutaud
authors.affiliation: AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Département de Génétique, 75013, Paris, France.|Groupe de Recherche Clinique (GRC) "déficience intellectuelle et autisme" UPMC, Groupe Hospitalier Pitié-Salpêtrière, 75013, Paris, France.|Centre de Référence "déficiences intellectuelles de causes rares", Paris, France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Héron
authors.affiliation: AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Département de Génétique, 75013, Paris, France. cyril.mignot@aphp.fr.|Groupe de Recherche Clinique (GRC) "déficience intellectuelle et autisme" UPMC, Groupe Hospitalier Pitié-Salpêtrière, 75013, Paris, France. cyril.mignot@aphp.fr.|Centre de Référence "déficiences intellectuelles de causes rares", Paris, France. cyril.mignot@aphp.fr.|EuroEPINOMICS RES consortium, . cyril.mignot@aphp.fr.
authors.forename: Cyril
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mesh_terms: D002872:Chromosome Deletion; D002878:Chromosomes, Human, Pair 1; D034441:Heterogeneous-Nuclear Ribonucleoproteins / Q000235:genetics*; D006801:Humans; D009154:Mutation; D065886:Neurodevelopmental Disorders / Q000235:genetics*; D010641:Phenotype; D012097:Repressor Proteins / Q000235:genetics*
chemical_list: D034441:Heterogeneous-Nuclear Ribonucleoproteins; D012097:Repressor Proteins; C115048:ZBTB18 protein, human