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

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.

Characterization ofSETD1Ahaploinsufficiency in humans andDrosophiladefines a novel neurodevelopmental syndrome

“…Clinical analysis of these patients was performed during regular consultations focusing on medical history, physical examination, and observational analysis of behavioral features. In all patients, exome sequencing and variant filtering were performed, according to the routine procedures at each institute [17][18][19][20][21][22] .…”

Single‐nucleotide polymorphism‐based chromosomal microarray analysis provides clues and insights into disease mechanisms

“…Even though we could not find any clear relationship between the non‐classical findings described and the additional genes encompassed by the 3.4 Mb deletion (17 RefSeq genes), they could be attributed to haploinsufficiency of one or more of these genes. Interestingly, haploinsufficiency of three of these genes was shown recently to cause three distinct neurodevelopmental and dysmorphism disorders involving B‐cell lymphoma/leukemia 11B ( BCL11B ), Cyclin‐K ( CCNK ) and transcriptional repressor protein YY1 ( YY1 ). In the current study, the pregnancy was terminated, and thus, the phenotype could not be determined in as much detail as is possible in the postnatal setup.…”

Mutually suppressive roles of KMT2A and KDM5C in behaviour, neuronal structure, and histone H3K4 methylation

“…Notably, genes that have established roles in central nervous system development and are genetically associated with neurodevelopmental disorders were among these restored genes in DM. These genes include Gnao1 (48, 49), Bcl11b (50), Arnt2 (51), Mkks (52-55), Arid1a (56), Rora (57), and Sez6 (58).…”