Advanced

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

Depienne, Christel; Nava, Caroline; Keren, Boris; Heide, Solveig; Rastetter, Agnès; Passemard, Sandrine; Chantot-Bastaraud, Sandra; Moutard, Marie Laure; Agrawal, Pankaj B. and VanNoy, Grace, et al. (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.

(Less)
Please use this url to cite or link to this publication:
author
, et al. (More)
(Less)
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Human Genetics
volume
136
issue
4
pages
17 pages
publisher
Springer
external identifiers
  • scopus:85014814557
  • wos:000398730900009
ISSN
0340-6717
DOI
10.1007/s00439-017-1772-0
language
English
LU publication?
yes
id
0ad511dd-dd21-4406-92eb-78d35e193ce3
date added to LUP
2017-04-03 11:58:01
date last changed
2018-01-07 11:57:49
@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 Pal, Deb and Jonson, Tord and Soller, Maria and Verbeek, Nienke E. and van Haelst, Mieke M. and de Kovel, Carolien and Koeleman, Bobby P. and Monroe, Glen and van Haaften, Gijs and Attié-Bitach, Tania and Boutaud, Lucile and Héron, Delphine and Mignot, Cyril and , },
  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},
  volume       = {136},
  year         = {2017},
}