Format

Send to

Choose Destination
Hum Genet. 2017 Apr;136(4):463-479. doi: 10.1007/s00439-017-1772-0. Epub 2017 Mar 10.

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

Author information

1
IGBMC, CNRS UMR 7104/INSERM U964/Université de Strasbourg, 67400, Illkirch, France. depiennc@igbmc.fr.
2
Laboratoires de Génétique, Institut de Génétique médicale d'Alsace, Hôpitaux Universitaires de Strasbourg, 67000, Strasbourg, France. depiennc@igbmc.fr.
3
INSERM, U 1127, CNRS UMR 7225, Institut du Cerveau et de la Moelle épinière, ICM, Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, 75013, Paris, France. depiennc@igbmc.fr.
4
AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Département de Génétique, 75013, Paris, France. depiennc@igbmc.fr.
5
EuroEPINOMICS RES consortium, . depiennc@igbmc.fr.
6
INSERM, U 1127, CNRS UMR 7225, Institut du Cerveau et de la Moelle épinière, ICM, Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, 75013, Paris, France.
7
AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Département de Génétique, 75013, Paris, France.
8
EuroEPINOMICS RES consortium.
9
Groupe de Recherche Clinique (GRC) "déficience intellectuelle et autisme" UPMC, Groupe Hospitalier Pitié-Salpêtrière, 75013, Paris, France.
10
AP-HP, Department of Child Neurology, Hôpital Robert Debré, Paris, France.
11
AP-HP, Department of Genetics, Hôpital Robert Debré, Paris, France.
12
INSERM UMR U1141, Hôpital Robert Debré, Université Paris-Diderot, Sorbonne Paris Cité, Paris, France.
13
AP-HP, Département de Génétique Médicale, Unité fonctionnelle de Génétique Chromosomique, CHU Paris Est, Hôpital d'Enfants Armand-Trousseau, 75571, Paris, France.
14
AP-HP, Service de Neuropédiatrie, Hôpital Trousseau, 75012, Paris, France.
15
UPMC, GRC ConCer-LD, Sorbonne Université, Paris, France.
16
Centre de Référence des Maladies Neurogénétiques de l'Enfant et de l'Adolescent, Paris, France.
17
Divisions of Genetics and Genomics and Newborn Medicine, Manton Center for Orphan Disease Research, Boston Children's Hospital and Harvard Medical School, Boston, MA, 02115, USA.
18
Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, VIC, 3052, Australia.
19
Department of Paediatrics, University of Melbourne, Parkville, VIC, 3052, Australia.
20
Centre de Référence "déficiences intellectuelles de causes rares", Paris, France.
21
INSERM U1163, Laboratory of Embryology and Genetics of Congenital Malformations, Sorbonne Paris Cité and Imagine Institute, Paris Descartes University, 75015, Paris, France.
22
AP-HP, Département de Génétique, Hôpital Necker-Enfants Malades, 75015, Paris, France.
23
INSERM U1163, Laboratory of Molecular and Physiopathological bases of osteochondrodysplasia, Sorbonne Paris Cité and Imagine Institute, Paris Descartes University, 75015, Paris, France.
24
AP-HP, GHUEP, Service de Radiologie, Hôpital Armand-Trousseau, 75012, Paris, France.
25
Laboratoires de Génétique, Institut de Génétique médicale d'Alsace, Hôpitaux Universitaires de Strasbourg, 67000, Strasbourg, France.
26
IGBMC, CNRS UMR 7104/INSERM U964/Université de Strasbourg, 67400, Illkirch, France.
27
Pediatric Neurology Department, Hautepierre Hospital, Strasbourg University Hospital, Strasbourg, France.
28
Medical and Surgical Epilepsy Unit, Hautepierre Hospital, Strasbourg University Hospital, Strasbourg, France.
29
Département de l'Enfant et de l'Adolescent, Neuropédiatrie, Hôpitaux Universitaires de Genève, Geneva, Switzerland.
30
Service de Médecine génétique, Hôpitaux Universitaires de Genève, Geneva, Switzerland.
31
Equipe d'Accueil 4271, Génétique des Anomalies du Développement, Université de Bourgogne, 21079, Dijon, France.
32
Centre de Génétique et Centre de Référence Anomalies du Développement et Syndromes Malformatifs de l'Interrégion Est, Centre Hospitalier Universitaire Dijon, 21079, Dijon, France.
33
Service de Pédiatrie, Hôpital Saint-Camille Bry-sur-Marne, Le Chesnay, France.
34
AP-HP, Service de Génétique, Hôpital Trousseau, 75012, Paris, France.
35
Centre de Référence des Malformations et Maladies Congénitales du Cervelet, Hôpital Trousseau, 75012, Paris, France.
36
Service de génétique clinique, Hôpital de Brabois, CHU de Nancy, Nancy, France.
37
Department of Genetics, Poissy-Saint-Germain-en-Laye Hospital, Poissy, France.
38
Institut de Génétique Médicale, CHRU de Lille, Lille, France.
39
Department of Cytogenetics and Molecular Cytogenetics, FRIGE's Institute of Human Genetics, FRIGE House, Satellite, Ahmedabad, India.
40
Sahyadari Medical Genetics and Tissue engineering facility (SMGTEF), Pune, 411005, India.
41
Sheffield Clinical Genetics Service, OPD2, Northern General Hospital, Herries Road, Sheffield, S5 7AU, UK.
42
Service de Génétique Clinique, CHU de Rennes, Rennes, France.
43
Centre de référence CLAD-Ouest, CHU Rennes, Rennes, France.
44
UMR 6290 CNRS, IGDR Institut de Génétique et développement de Rennes, Université de Rennes 1, Rennes, France.
45
Service de Génétique Médicale, Hôpital Pellegrin, CHU Bordeaux, Bordeaux, France.
46
Centre de Référence des Anomalies du Développement Embryonnaire, CHU Bordeaux, Bordeaux, France.
47
Service de Génétique Médicale, CHU de Nantes, Nantes, France.
48
Faculté de Médecine, INSERM, UMR 957, Physiopathologie de la résorption osseuse et des tumeurs osseuses primitives, Université, Nantes, France.
49
Northern Ireland Regional Genetics Service, Belfast City Hospital, Belfast, Ireland.
50
Service de Génétique Médicale, CHU Tours, Tours, France.
51
Medizinisch Genetisches Zentrum, 80335, Munich, Germany.
52
Hospital for Neuropediatrics and Neurological Rehabilitation, Epilepsy Center for Children and Adolescents, 83569, Vogtareuth, Germany.
53
PMU Salzburg, Salzburg, Austria.
54
The Danish Epilepsy Centre, Dianalund, Denmark.
55
Institute for Regional Health Services, University of Southern Denmark, Odense, Denmark.
56
Department of Clinical Neuroscience, Institute of Psychiatry, King's College London, London, UK.
57
Department of Clinical Genetics, University and Regional Laboratories, Skåne University Hospital, Lund University, Lund, Sweden.
58
Department of Clinical Genetics, Lund University Hospital, 221 85, Lund, Sweden.
59
Department of Genetics, University Medical Center Utrecht, Utrecht, 3584 CX, The Netherlands.
60
Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, 3584 CX, The Netherlands.
61
AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Département de Génétique, 75013, Paris, France. cyril.mignot@aphp.fr.
62
Groupe de Recherche Clinique (GRC) "déficience intellectuelle et autisme" UPMC, Groupe Hospitalier Pitié-Salpêtrière, 75013, Paris, France. cyril.mignot@aphp.fr.
63
Centre de Référence "déficiences intellectuelles de causes rares", Paris, France. cyril.mignot@aphp.fr.
64
EuroEPINOMICS RES consortium, . cyril.mignot@aphp.fr.

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.

PMID:
28283832
PMCID:
PMC5360844
DOI:
10.1007/s00439-017-1772-0
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Springer Icon for PubMed Central
Loading ...
Support Center