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Intellectual disability

Gene: BCL11B

Green List (high evidence)

BCL11B (B-cell CLL/lymphoma 11B)
EnsemblGeneIds (GRCh38): ENSG00000127152
EnsemblGeneIds (GRCh37): ENSG00000127152
OMIM: 606558, Gene2Phenotype
BCL11B is in 2 panels

2 reviews

Louise Daugherty (Genomics England Curator)

Comment on list classification: New gene added by external expert and reviewed by curation team, appropriate phenotype, sufficient cases and external expert review all support gene-disease association and relevance to this panel to rate gene to Green.
Created: 21 Feb 2019, 2:05 p.m.
Comment on phenotypes: Added phenotypes from OMIM and MIMid that indicate relevance to inclusion on the intellectual disability panel
Created: 21 Feb 2019, 2 p.m.

Konstantinos Varvagiannis (Other)

Green List (high evidence)

PMID: 27959755 reports on an individual with SCID, craniofacial, dermal anomalies and absent corpus callosum. At the age of 2 years, this individual was reported to have intellectual impairment with spastic paraplegia and seizures. Trio exome sequencing revealed a de novo heterozygous missense variant in BCL11B. Alternative causes for the immunodeficiency were eliminated. Knockdown of bcl11a in zebrafish affected T-cell development and reproduced other developmental (eg. craniofacial) abnormalities present in the patient. The authors propose a dominant negative effect as ectopic expression of the mutant allele in BCL11B-sufficient human hematopoietic progenitors / zebrafish resulted in similar anomalies to those found in the patient. In addition the mutant protein interfered with the intact BCL11B protein by forming heterodimers with altered DNA binding. The authors discuss on the possibility that this missense variant might confer new binding specificity on BCL11B. ///

PMID: 29985992 reports on 13 patients with neurodevelopmental delay as well as a (subtle) immune phenotype, all harboring heterozygous germline alterations in BCL11B. The alterations included : 6 de novo frameshift variants, 2 de novo nonsense, 1 de novo missense SNV and 2 de novo balanced chromosomal rearrangements. A further frameshift variant was found in an individual with this phenotype as well as his similarly affected mother. The chromosomal translocations disrupted a region downstream BCL11B and the relative amount of BCL11B mRNA in blood cells of these individuals was found to be approximately half the respective amount on controls. Apart from haploinsufficiency, loss of the C-terminal DNA binding zinc-finger domains could explain the pathogenicity of the premature termination variants likely escaping nonsense-mediated decay. The authors noted a more severe phenotype (with immunodefeciency in the newborn period) in the patient with the missense variant compared with individuals with mutations resulting in haploinsufficiency or truncation of the protein, none of whom was considered to be immune deficient. This was similar to the patient with a missense variant in the zinc-finger domain described in PMID: 27959755. The authors discuss the possibility that missense variants (unlike the other identified mutations) may result in acquisition of novel DNA-binding regions. ///

As a result the gene can be considered for inclusion in this panel as green (or amber).
Created: 25 Aug 2018, 3:06 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Intellectual disability

Publications

Details

Mode of Inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Expert Review Green
Phenotypes
  • Intellectual disability
  • Intellectual developmental disorder with dysmorphic facies, speech delay, and T-cell abnormalities, 618092
OMIM
606558
Clinvar variants
Variants in BCL11B
Penetrance
unknown
Publications
Panels with this gene

History Filter Activity

21 Feb 2019, Gel status: 3

Entity classified by Genomics England curator

Louise Daugherty (Genomics England Curator)

Gene: bcl11b has been classified as Green List (High Evidence).

21 Feb 2019, Gel status: 0

Set Phenotypes

Louise Daugherty (Genomics England Curator)

Phenotypes for gene: BCL11B were changed from Intellectual disability to Intellectual disability; Intellectual developmental disorder with dysmorphic facies, speech delay, and T-cell abnormalities, 618092

25 Aug 2018, Gel status: 0

Added New Source

Konstantinos Varvagiannis (Other)

BCL11B was added to Intellectual disability panel. Sources: Literature

25 Aug 2018, Gel status: 0

Created

Konstantinos Varvagiannis (Other)

BCL11B was created by Konstantinos Varvagiannis