Genetic and phenotypic dissection of 1q43q44 microdeletion syndrome and neurodevelopmental phenotypes associated with mutations in ZBTB18 and HNRNPU
(2017) In Human Genetics 136(4). p.463-479- 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... (More)
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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- publishing date
- 2017
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- published
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- Human Genetics
- volume
- 136
- issue
- 4
- pages
- 17 pages
- publisher
- Springer
- external identifiers
-
- scopus:85014814557
- pmid:28283832
- wos:000398730900009
- ISSN
- 0340-6717
- DOI
- 10.1007/s00439-017-1772-0
- language
- English
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- 0ad511dd-dd21-4406-92eb-78d35e193ce3
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@article{0ad511dd-dd21-4406-92eb-78d35e193ce3,
abstract = {{<p>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.</p>}},
author = {{Depienne, Christel and Nava, Caroline and Keren, Boris and Heide, Solveig and Rastetter, Agnès and Passemard, Sandrine and Chantot-Bastaraud, Sandra and Moutard, Marie Laure and Agrawal, Pankaj B. and VanNoy, Grace and Stoler, Joan M. and Amor, David J and Billette de Villemeur, Thierry and Doummar, Diane and Alby, Caroline and Cormier-Daire, Valérie and Garel, Catherine and Marzin, Pauline and Scheidecker, Sophie and de Saint-Martin, Anne and Hirsch, Edouard and Korff, Christian and Bottani, Armand and Faivre, Laurence and Verloes, Alain and Orzechowski, Christine and Burglen, Lydie and Leheup, Bruno and Roume, Joelle and Andrieux, Joris and Sheth, Frenny and Datar, Chaitanya and Parker, Michael J. and Pasquier, Laurent and Odent, Sylvie and Naudion, Sophie and Delrue, Marie Ange and Le Caignec, Cédric and Vincent, Marie and Isidor, Bertrand and Renaldo, Florence and Stewart, Fiona and Toutain, Annick and Koehler, Udo and Häckl, Birgit and von Stülpnagel, Celina and Kluger, Gerhard and Møller, Rikke S. and Jonson, Tord and Soller, Maria}},
issn = {{0340-6717}},
language = {{eng}},
number = {{4}},
pages = {{463--479}},
publisher = {{Springer}},
series = {{Human Genetics}},
title = {{Genetic and phenotypic dissection of 1q43q44 microdeletion syndrome and neurodevelopmental phenotypes associated with mutations in ZBTB18 and HNRNPU}},
url = {{http://dx.doi.org/10.1007/s00439-017-1772-0}},
doi = {{10.1007/s00439-017-1772-0}},
volume = {{136}},
year = {{2017}},
}