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Brain. 2018 Aug 1;141(8):2299-2311. doi: 10.1093/brain/awy173.

BCL11B mutations in patients affected by a neurodevelopmental disorder with reduced type 2 innate lymphoid cells.

Author information

1
Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
2
Department of Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
3
Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, Essen, Germany.
4
Service de Génétique, Hospices Civils de Lyon, Lyon, France.
5
Lyon Neuroscience Research Center, Inserm U1028 - CNRS UMR5292 - UCBLyon1, GENDEV Team, Bron, France.
6
Institute of Molecular and Cellular Anatomy, Ulm University, Ulm, Germany.
7
Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
8
Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
9
Institute of Human Genetics, Technische Universität München, Munich, Germany.
10
Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
11
Computational Regulatory Genomics Group, MRC London Institute of Medical Sciences, London, UK.
12
Divisions of Genetics and Genomics and Newborn Medicine, Boston Children's Hospital and Harvard Medical School, Boston, USA.
13
The Manton Center for Orphan Disease Research, Boston Children's Hospital and Harvard Medical School, Boston, USA.
14
Unidade de Endocrinologia do Desenvolvimento, Laboratorio de Hormonios e Genetica Molecular (LIM42), Hospital das Clinicas da Faculdade de Medicina, Universidade de São Paulo (USP), São Paulo, Brazil.
15
Institute of Immunology, Hannover Medical School, Hannover, Germany.
16
Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
17
Department of Pediatrics, University Medical Center Eppendorf, Hamburg, Germany.
18
Department of Pediatrics, St. Antonius Hospital, Nieuwegein, The Netherlands.
19
Pränatal-Medizin München, Munich, Germany.
20
Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, USA.
21
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, USA.
22
Institute of Human Genetics, University Clinic, Heinrich-Heine University, Düsseldorf, Germany.
23
Unidade de Endocrinologia Genetica (LIM25), Hospital das Clinicas da Faculdade de Medicina, Universidade de São Paulo (USP), São Paulo, Brazil.
24
Department of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes, University of Michigan, Ann Arbor, USA.
25
Institute for Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
26
Unité de Génétique Clinique, CLAD Nord de France, CHU Amiens-Picardie, Amiens, France.
27
Service de Génétique Clinique, Chromosomique et Moléculaire, CHU Hôpital Nord, Saint-Etienne, France.
28
Département de Génétique, Hôpital La Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France.
29
Département de génétique médicale, Sorbonne Université, GRC n°19, pathologies Congénitales du Cervelet-LeucoDystrophies, AP-HP, Centre de Référence déficiences intellectuelles de causes rares, Hôpital Armand Trousseau, F-75012 Paris, France.
30
Department of Pediatrics, Division of Genetics and Genomic Medicine, Washington University School of Medicin, St. Louis, MO, USA.
31
GeneDx, Gaithersburg, MD, USA.
32
Molecular Diagnostic Laboratory and Division of Medical Genetics, Department of Pediatrics, CHU Sainte-Justine, Montreal, Canada.
33
Division of Medical Genetics and Research Center, CHU Sainte-Justine and Department of Pediatrics, Université de Montréal, Montreal, Canada.
34
Department of Pediatrics, CHU Sainte-Justine and University of Montreal, Montreal, Canada.
35
Greenwood Genetic Center, Greenwood, South Carolina, USA.
36
Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, London, UK.

Abstract

The transcription factor BCL11B is essential for development of the nervous and the immune system, and Bcl11b deficiency results in structural brain defects, reduced learning capacity, and impaired immune cell development in mice. However, the precise role of BCL11B in humans is largely unexplored, except for a single patient with a BCL11B missense mutation, affected by multisystem anomalies and profound immune deficiency. Using massively parallel sequencing we identified 13 patients bearing heterozygous germline alterations in BCL11B. Notably, all of them are affected by global developmental delay with speech impairment and intellectual disability; however, none displayed overt clinical signs of immune deficiency. Six frameshift mutations, two nonsense mutations, one missense mutation, and two chromosomal rearrangements resulting in diminished BCL11B expression, arose de novo. A further frameshift mutation was transmitted from a similarly affected mother. Interestingly, the most severely affected patient harbours a missense mutation within a zinc-finger domain of BCL11B, probably affecting the DNA-binding structural interface, similar to the recently published patient. Furthermore, the most C-terminally located premature termination codon mutation fails to rescue the progenitor cell proliferation defect in hippocampal slice cultures from Bcl11b-deficient mice. Concerning the role of BCL11B in the immune system, extensive immune phenotyping of our patients revealed alterations in the T cell compartment and lack of peripheral type 2 innate lymphoid cells (ILC2s), consistent with the findings described in Bcl11b-deficient mice. Unsupervised analysis of 102 T lymphocyte subpopulations showed that the patients clearly cluster apart from healthy children, further supporting the common aetiology of the disorder. Taken together, we show here that mutations leading either to BCL11B haploinsufficiency or to a truncated BCL11B protein clinically cause a non-syndromic neurodevelopmental delay. In addition, we suggest that missense mutations affecting specific sites within zinc-finger domains might result in distinct and more severe clinical outcomes.

PMID:
29985992
PMCID:
PMC6061686
DOI:
10.1093/brain/awy173
[Indexed for MEDLINE]
Free PMC Article

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