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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
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 : Thursday, January 14, 2021 - 11:29:20 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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