Genetic and phenotypic dissection of 1q43q44 microdeletion syndrome and neurodevelopmental phenotypes associated with mutations in ZBTB18 and HNRNPU
- PMID: 28283832
- PMCID: PMC5360844
- DOI: 10.1007/s00439-017-1772-0
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.
Conflict of interest statement
Funding
This study was financially supported by the Assistance Publique des Hôpitaux de Paris (AP-HP), PHRC (no PO81260), INSERM, Fondation Maladies Rares, Fondation de France (FdF—Engt no 15144), Agence de la Biomédecine, Agence Nationale de la Recherche (ANR Blanc CILAXCAL), and the “Investissements d’Avenir” programme ANR-10-IAIHU-06 (IHU-A-ICM). Dr Solveig Heide was supported by a master grant from the Fondation pour la Recherche Médicale (FRM). CD and CN are members of the Biopsy labex.
Conflict of interest
The authors declare no conflict of interest.
Ethical approval
The study received approval from local ethical standards committees on human experimentation.
Informed consent
Informed written consent was obtained from each individual or their parents or legal representatives before blood sampling.
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