Intellectual disabilityGene: BCL11B Green List (high evidence)
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.
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
Gene: bcl11b has been classified as Green List (High Evidence).
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
BCL11B was added to Intellectual disability panel. Sources: Literature
BCL11B was created by Konstantinos Varvagiannis
If promoting or demoting a gene, please provide comments to justify a decision to move it.
Genes included in a Genomics England gene panel for a rare disease category (green list) should fit the criteria A-E outlined below.
These guidelines were developed as a combination of the ClinGen DEFINITIVE evidence for a causal role of the gene in the disease(a), and the Developmental Disorder Genotype-Phenotype (DDG2P) CONFIRMED DD Gene evidence level(b) (please see the original references provided below for full details). These help provide a guideline for expert reviewers when assessing whether a gene should be on the green or the red list of a panel.
A. There are plausible disease-causing mutations(i) within, affecting or encompassing an interpretable functional region(ii) of this gene identified in multiple (>3) unrelated cases/families with the phenotype(iii).
B. There are plausible disease-causing mutations(i) within, affecting or encompassing cis-regulatory elements convincingly affecting the expression of a single gene identified in multiple (>3) unrelated cases/families with the phenotype(iii).
C. As definitions A or B but in 2 or 3 unrelated cases/families with the phenotype, with the addition of convincing bioinformatic or functional evidence of causation e.g. known inborn error of metabolism with mutation in orthologous gene which is known to have the relevant deficient enzymatic activity in other species; existence of an animal model which recapitulates the human phenotype.
D. Evidence indicates that disease-causing mutations follow a Mendelian pattern of causation appropriate for reporting in a diagnostic setting(iv).
E. No convincing evidence exists or has emerged that contradicts the role of the gene in the specified phenotype.
(i)Plausible disease-causing mutations: Recurrent de novo mutations convincingly affecting gene function. Rare, fully-penetrant mutations - relevant genotype never, or very rarely, seen in controls. (ii) Interpretable functional region: ORF in protein coding genes miRNA stem or loop. (iii) Phenotype: the rare disease category, as described in the eligibility statement. (iv) Intermediate penetrance genes should not be included.
It’s assumed that loss-of-function variants in this gene can cause the disease/phenotype unless an exception to this rule is known. We would like to collect information regarding exceptions. An example exception is the PCSK9 gene, where loss-of-function variants are not relevant for a hypercholesterolemia phenotype as they are associated with increased LDL-cholesterol uptake via LDLR (PMID: 25911073).
If a curated set of known-pathogenic variants is available for this gene-phenotype, please contact us at [email protected]
We classify loss-of-function variants as those with the following Sequence Ontology (SO) terms:
Term descriptions can be found on the PanelApp homepage and Ensembl.
If you are submitting this evaluation on behalf of a clinical laboratory please indicate whether you report variants in this gene as part of your current diagnostic practice by checking the box
Standardised terms were used to represent the gene-disease mode of inheritance, and were mapped to commonly used terms from the different sources. Below each of the terms is described, along with the equivalent commonly-used terms.
A variant on one allele of this gene can cause the disease, and imprinting has not been implicated.
A variant on the paternally-inherited allele of this gene can cause the disease, if the alternate allele is imprinted (function muted).
A variant on the maternally-inherited allele of this gene can cause the disease, if the alternate allele is imprinted (function muted).
A variant on one allele of this gene can cause the disease. This is the default used for autosomal dominant mode of inheritance where no knowledge of the imprinting status of the gene required to cause the disease is known. Mapped to the following commonly used terms from different sources: autosomal dominant, dominant, AD, DOMINANT.
A variant on both alleles of this gene is required to cause the disease. Mapped to the following commonly used terms from different sources: autosomal recessive, recessive, AR, RECESSIVE.
The disease can be caused by a variant on one or both alleles of this gene. Mapped to the following commonly used terms from different sources: autosomal recessive or autosomal dominant, recessive or dominant, AR/AD, AD/AR, DOMINANT/RECESSIVE, RECESSIVE/DOMINANT.
A variant on one allele of this gene can cause the disease, however a variant on both alleles of this gene can result in a more severe form of the disease/phenotype.
A variant in this gene can cause the disease in males as they have one X-chromosome allele, whereas a variant on both X-chromosome alleles is required to cause the disease in females. Mapped to the following commonly used term from different sources: X-linked recessive.
A variant in this gene can cause the disease in males as they have one X-chromosome allele. A variant on one allele of this gene may also cause the disease in females, though the disease/phenotype may be less severe and may have a later-onset than is seen in males. X-linked inactivation and mosaicism in different tissues complicate whether a female presents with the disease, and can change over their lifetime. This term is the default setting used for X-linked genes, where it is not known definitately whether females require a variant on each allele of this gene in order to be affected. Mapped to the following commonly used terms from different sources: X-linked dominant, x-linked, X-LINKED, X-linked.
The gene is in the mitochondrial genome and variants within this can cause this disease, maternally inherited. Mapped to the following commonly used term from different sources: Mitochondrial.
Mapped to the following commonly used terms from different sources: Unknown, NA, information not provided.
For example, if the mode of inheritance is digenic, please indicate this in the comments and which other gene is involved.