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

Christel Depienne*, Caroline Nava, Boris Keren, Solveig Heide, Agnès Rastetter, Sandrine Passemard, Sandra Chantot-Bastaraud, Marie Laure Moutard, Pankaj B. Agrawal, Grace VanNoy, Joan M. Stoler, David J. Amor, Thierry Billette de Villemeur, Diane Doummar, Caroline Alby, Valérie Cormier-Daire, Catherine Garel, Pauline Marzin, Sophie Scheidecker, Anne de Saint-MartinEdouard Hirsch, Christian Korff, Armand Bottani, Laurence Faivre, Alain Verloes, Christine Orzechowski, Lydie Burglen, Bruno Leheup, Joelle Roume, Joris Andrieux, Frenny Sheth, Chaitanya Datar, Michael J. Parker, Laurent Pasquier, Sylvie Odent, Sophie Naudion, Marie Ange Delrue, Cédric Le Caignec, Marie Vincent, Bertrand Isidor, Florence Renaldo, Fiona Stewart, Annick Toutain, Udo Koehler, Birgit Häckl, Celina von Stülpnagel, Gerhard Kluger, Rikke S. Møller, Deb Pal, Mieke M. van Haelst, DDD Study

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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.

Original languageEnglish
Pages (from-to)463-479
Number of pages17
JournalHuman Genetics
Volume136
Issue number4
DOIs
Publication statusPublished - 1 Apr 2017

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