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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 10 Caroline Alby 11 Valérie Cormier-Daire 11 Catherine Garel 12 Pauline Marzin Sophie Scheidecker Anne de Saint-Martin 3 Edouard Hirsch 13, 3 Christian Korff 14 Armand Bottani 15 Laurence Faivre 16 Alain Verloes 17, 18 Christine Orzechowski Lydie Burglen 19, 8, 6 Bruno Leheup 20 Joëlle Roume 21 Joris Andrieux 22 Frenny Sheth Chaitanya Datar Michael J. Parker Laurent Pasquier 23 Sylvie Odent 24, 23 Sophie Naudion Marie-Ange Delrue 25 Cédric Le Caignec 26 Marie Vincent 27 Bertrand Isidor 27, 28 Florence Renaldo 29, 6 Fiona Stewart Annick Toutain 30, 31 Udo Koehler Birgit Häckl Celina Stülpnagel Gerhard Kluger 32, 33 Rikke S. Møller Deb Pal Tord Jonson Maria Soller 34 Nienke E. Verbeek Mieke M. Haelst Carolien Kovel Bobby Koeleman Glen Monroe Gijs Haaften Ddd Study Tania Attie-Bitach 35, 11 Lucile Boutaud 35, 11 Delphine Héron 36, 5 Cyril Mignot 36, 5
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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Submitted on : Wednesday, April 5, 2017 - 10:09:00 AM
Last modification on : Wednesday, August 19, 2020 - 11:18:14 AM

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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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