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

TY - JOUR

T1 - BCL11B mutations in patients affected by a neurodevelopmental disorder with reduced type 2 innate lymphoid cells

AU - Lessel, Davor

AU - Gehbauer, Christina

AU - Bramswig, Nuria C

AU - Schluth-Bolard, Caroline

AU - Venkataramanappa, Sathish

AU - van Gassen, Koen L I

AU - Hempel, Maja

AU - Haack, Tobias B

AU - Baresic, Anja

AU - Genetti, Casie A

AU - Funari, Mariana F A

AU - Lessel, Ivana

AU - Kuhlmann, Leonie

AU - Simon, Ruth

AU - Liu, Pentao

AU - Denecke, Jonas

AU - Kuechler, Alma

AU - de Kruijff, Ineke

AU - Shoukier, Moneef

AU - Lek, Monkol

AU - Mullen, Thomas

AU - Lüdecke, Hermann-Josef

AU - Lerario, Antonio M

AU - Kobbe, Robin

AU - Krieger, Thorsten

AU - Demeer, Benedicte

AU - Lebrun, Marine

AU - Keren, Boris

AU - Nava, Caroline

AU - Buratti, Julien

AU - Afenjar, Alexandra

AU - Shinawi, Marwan

AU - Guillen Sacoto, Maria J

AU - Gauthier, Julie

AU - Hamdan, Fadi F

AU - Laberge, Anne-Marie

AU - Campeau, Philippe M

AU - Louie, Raymond J

AU - Cathey, Sara S

AU - Prinz, Immo

AU - Jorge, Alexander A L

AU - Terhal, Paulien A

AU - Lenhard, Boris

AU - Wieczorek, Dagmar

AU - Strom, Tim M

AU - Agrawal, Pankaj B

AU - Britsch, Stefan

AU - Tolosa, Eva

AU - Kubisch, Christian

PY - 2018/8/1

Y1 - 2018/8/1

N2 - 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.

AB - 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.

KW - Journal Article

U2 - 10.1093/brain/awy173

DO - 10.1093/brain/awy173

M3 - SCORING: Journal article

C2 - 29985992

VL - 141

SP - 2299

EP - 2311

JO - BRAIN

JF - BRAIN

SN - 0006-8950

IS - 8

ER -