Human Gene Module / Chromosome 2 / BCL11A

BCL11AB-cell CLL/lymphoma 11A (zinc finger protein)

Score
2S
Strong Candidate, Syndromic Criteria 2.1, Syndromic
Autism Reports / Total Reports
5 / 12
Rare Variants / Common Variants
22 / 1
Aliases
BCL11A, BCL11A-L-S, Ã‚ BCL11A-XL, Ã‚ BCL11a-M,  CTIP1,  EVI9,  HBFQTL5,  ZNF856, Ã‚ BCL11A
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation, Syndromic
Chromosome Band
2p16.1
Associated Disorders
DD/NDD, SCZ
Relevance to Autism

A de novo loss-of-function variant in the BCL11A gene has been identified in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014). This gene was also identified in an ASD whole-exome sequencing study and subsequent TADA (transmission and de novo association) analysis as a gene strongly enriched for variants likely to affect ASD risk with a false discovery rate (FDR) of <0.1 (De Rubeis et al., 2014).

Molecular Function

This gene encodes a C2H2 type zinc-finger protein by its similarity to the mouse Bcl11a/Evi9 protein that functions as a myeloid and B-cell proto-oncogene. BCL11A resides within the dyslexia susceptibility candidate region 3 (DYX3) and has been proposed to be a candidate gene in chromosome 2p16.1-p15 deletion syndrome.

Reports related to BCL11A (12 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary De novo gene disruptions in children on the autistic spectrum. Iossifov I , et al. (2012) Yes -
2 Support De novo microdeletion of BCL11A is associated with severe speech sound disorder. Peter B , et al. (2014) No DD
3 Recent recommendation Synaptic, transcriptional and chromatin genes disrupted in autism. De Rubeis S , et al. (2014) Yes -
4 Support Large-scale discovery of novel genetic causes of developmental disorders. Deciphering Developmental Disorders Study (2014) Yes -
5 Support BCL11A deletions result in fetal hemoglobin persistence and neurodevelopmental alterations. Basak A , et al. (2015) Yes SCZ
6 Support Brain malformations in a patient with deletion 2p16.1: A refinement ofthe phenotype to BCL11A. Balci TB , et al. (2015) No Dysmorphic features, brain malformations
7 Recent recommendation Bcl11a (Ctip1) Controls Migration of Cortical Projection Neurons through Regulation of Sema3c. Wiegreffe C , et al. (2015) No -
8 Recent recommendation Low load for disruptive mutations in autism genes and their biased transmission. Iossifov I , et al. (2015) Yes -
9 Recent recommendation BCL11A Haploinsufficiency Causes an Intellectual Disability Syndrome and Dysregulates Transcription. Dias C , et al. (2016) No Microcephaly
10 Support Identifying candidate genes for 2p15p16.1 microdeletion syndrome using clinical, genomic, and functional analysis. Bagheri H , et al. (2016) No -
11 Support The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies. Redin C , et al. (2016) No -
12 Support A clinical utility study of exome sequencing versus conventional genetic testing in pediatric neurology. Vissers LE , et al. (2017) No Dystonia, chorea
Rare Variants   (22)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.792_793insC p.Leu265ProfsTer3 frameshift_variant De novo - Simplex 22542183 Iossifov I , et al. (2012)
- - copy_number_loss De novo - Simplex 24810580 Peter B , et al. (2014)
c.1325delT p.Leu442ProfsTer37 frameshift_variant De novo - Simplex 25363760 De Rubeis S , et al. (2014)
c.492A>C p.Glu164Asp missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.1174C>A p.Pro392Thr missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.382G>A p.Ala128Thr missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.833C>G p.Pro278Arg missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.143G>T p.Cys48Phe missense_variant De novo - Simplex 25533962 Deciphering Developmental Disorders Study (2014)
c.198C>A p.His66Gln missense_variant De novo - Unknown 25533962 Deciphering Developmental Disorders Study (2014)
c.139A>C p.Thr47Pro missense_variant De novo - Simplex 25533962 Deciphering Developmental Disorders Study (2014)
- - copy_number_loss De novo - - 25938782 Basak A , et al. (2015)
- - copy_number_loss De novo - - 25938782 Basak A , et al. (2015)
- - copy_number_loss De novo - - 25938782 Basak A , et al. (2015)
- - copy_number_loss De novo - Simplex 25979662 Balci TB , et al. (2015)
c.529C>T p.Gln177Ter stop_gained De novo - 5+B5820:M582 27453576 Dias C , et al. (2016)
c.2035_2037delinsC p.Ser679GlnfsTer47 frameshift_variant De novo - - 27453576 Dias C , et al. (2016)
c.1545delinsGGCTTC p.Phe515LeufsTer5 frameshift_variant De novo - - 27453576 Dias C , et al. (2016)
c.1775_1776insTGGCTCAGCGG p.Glu593GlyfsTer9 frameshift_variant De novo - - 27453576 Dias C , et al. (2016)
c.154C>T p.Gln52Ter stop_gained De novo - - 27453576 Dias C , et al. (2016)
c.193G>T p.Glu65Ter stop_gained De novo - - 27453576 Dias C , et al. (2016)
- - copy_number_gain De novo - - 27841880 Redin C , et al. (2016)
c.10C>T p.Arg4Cys missense_variant De novo - - 28333917 Vissers LE , et al. (2017)
Common Variants   (1)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
c.386-22379G>A - intron_variant - - - 25938782 Basak A , et al. (2015)
SFARI Gene score
2S

Strong Candidate, Syndromic

A de novo LoF variant in the BCL11A gene was identified in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014), while a second de novo LoF variant in this gene was identified in an ASD proband from 2,270 trios screened by the Autism Sequencing Consortium (De Rubeis et al., 2014). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified BCL11A as a gene meeting high statistical significance with a 0.01< FDR ?0.05, meaning that this gene had a ?95% chance of being a true autism gene (De Rubeis et al., 2014). Three de novo missense variants in BCL11A were identified in patients from the Deciphering Developmental Disorders (DDD) study that presented with developmental delay/intellectual disability; one of these patients also presented with autism (Fitzgerald et al., 2015). Functional characterization of these missense variants in Dias et al., 2016 showed deleterious effects on multiple aspects of BLC11A function, including localization, dimerization, and transcription regulation. Dias et al., 2016 also identified six new patients with de novo loss-of-function BCL11A variants; phenotypic characterization of these six patients, the ASD probands from Iossifov et al., 2012 and De Rubeis et al., 2014, and the three DDD cases from Fitzgerald et al., 2015 led the authors to conclude that BCL11A haploinsufficiency results in a syndromic form of intellectual disability. BCL11A haploinsufficiency in mice resulted in cognitive impairment, abnormal social behavior, and microcephaly, mirroring the human phenotype (Dias et al., 2016). BCL11A resides within the dyslexia susceptibility candidate region 3 (DYX3) candidate region on chromosome 2 and has been proposed as a candidate gene in 2p16.1-p15 deletion syndrome. Peter et al., 2014 identified a de novo deletion containing only the BCL11A gene in an 11-year-old male proband presenting with a severe speech disorder (childhood apraxia of speech, dysarthria in the presence of general oral and gross motor dyspraxia and hypotonia, expressive language delay, and mild intellectual delay), while Basak et al., 2015 identified three patients with 2p16.1-p15 deletions that presented with autism, developmental delay, and fetal hemoglobin persistence. Functional analysis of candidate genes for 2p16.1-p15 microdeletion syndrome in zebrafish found that knockdown of bcl11aa, one of the two copies of BCL11A in zebrafish, resulted in significant microcephaly, otic vesicle reduction, and reduction in size (Bagheri et al., 2016).

2

Strong Candidate

See all Category 2 Genes

We considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.

The syndromic category includes mutations that are associated with a substantial degree of increased risk and consistently linked to additional characteristics not required for an ASD diagnosis. If there is independent evidence implicating a gene in idiopathic ASD, it will be listed as "#S" (e.g., 2S, 3S, etc.). If there is no such independent evidence, the gene will be listed simply as "S."

04-01-2017
2S

Initial score established: 2S

Description

A de novo LoF variant in the BCL11A gene was identified in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014), while a second de novo LoF variant in this gene was identified in an ASD proband from 2,270 trios screened by the Autism Sequencing Consortium (De Rubeis et al., 2014). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified BCL11A as a gene meeting high statistical significance with a 0.01< FDR ?0.05, meaning that this gene had a ?95% chance of being a true autism gene (De Rubeis et al., 2014). Three de novo missense variants in BCL11A were identified in patients from the Deciphering Developmental Disorders (DDD) study that presented with developmental delay/intellectual disability; one of these patients also presented with autism (Fitzgerald et al., 2015). Functional characterization of these missense variants in Dias et al., 2016 showed deleterious effects on multiple aspects of BLC11A function, including localization, dimerization, and transcription regulation. Dias et al., 2016 also identified six new patients with de novo loss-of-function BCL11A variants; phenotypic characterization of these six patients, the ASD probands from Iossifov et al., 2012 and De Rubeis et al., 2014, and the three DDD cases from Fitzgerald et al., 2015 led the authors to conclude that BCL11A haploinsufficiency results in a syndromic form of intellectual disability. BCL11A haploinsufficiency in mice resulted in cognitive impairment, abnormal social behavior, and microcephaly, mirroring the human phenotype (Dias et al., 2016). BCL11A resides within the dyslexia susceptibility candidate region 3 (DYX3) candidate region on chromosome 2 and has been proposed as a candidate gene in 2p16.1-p15 deletion syndrome. Peter et al., 2014 identified a de novo deletion containing only the BCL11A gene in an 11-year-old male proband presenting with a severe speech disorder (childhood apraxia of speech, dysarthria in the presence of general oral and gross motor dyspraxia and hypotonia, expressive language delay, and mild intellectual delay), while Basak et al., 2015 identified three patients with 2p16.1-p15 deletions that presented with autism, developmental delay, and fetal hemoglobin persistence. Functional analysis of candidate genes for 2p16.1-p15 microdeletion syndrome in zebrafish found that knockdown of bcl11aa, one of the two copies of BCL11A in zebrafish, resulted in significant microcephaly, otic vesicle reduction, and reduction in size (Bagheri et al., 2016).

CNVs associated with BCL11A(1 CNVs)
2p16.1 15 Deletion-Duplication 29  /  206
Animal Models associated with BCL11A(2 Models)
BCL11A_1_KI_HT Genetic
BCL11A_2_KO_HM Genetic
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
ACTC1 ARHGAP15 Human Protein Binding 70 B3KPP5
CDCA3 cell division cycle associated 3 Human Protein Binding 83461 B2R749
CDK4 cyclin-dependent kinase 4 Human Protein Modification 1019 P11802
CDK6 cyclin-dependent kinase 6 Human Protein Modification 1021 A4D1G0
CHD4 chromodomain helicase DNA binding protein 4 Human Protein Binding 1108 Q14839
GMCL1P1 germ cell-less, spermatogenesis associated 1 pseudogene 1 Human Protein Binding 64396 Q8NEA9
HOXA1 homeobox A1 Mouse Direct Regulation 15394 P09022
MBD3 methyl-CpG binding domain protein 3 Human Protein Binding 53615 O95983
MBD3L1 methyl-CpG binding domain protein 3-like 1 Human Protein Binding 85509 Q8WWY6
MTA1 metastasis associated 1 Human Protein Binding 9112 Q13330
MTA2 metastasis associated 1 family, member 2 Human Protein Binding 9219 O94776
NR2E1 Nuclear receptor subfamily 2 group E member 1 Human Protein Binding 7101 Q9Y466
NR2E3 Photoreceptor-specific nuclear receptor Human Protein Binding 10002 Q9Y5X4
NR2F2 nuclear receptor subfamily 2, group F, member 2 Human Protein Binding 7026 P24468
NR2F6 nuclear receptor subfamily 2, group F, member 6 Human Protein Binding 2063 F1D8R3
PHF20L1 PHD finger protein 20-like 1 Human Protein Binding 51105 A8MW92
RBBP7 retinoblastoma binding protein 7 Human Protein Binding 5931 Q16576
SIRT3 sirtuin 3 Human Protein Binding 23410 Q9NTG7
SUMO3 SMT3 suppressor of mif two 3 homolog 3 (S. cerevisiae) Human Protein Binding 6612 P55854
TSC1 tuberous sclerosis 1 Human Protein Binding 7248 Q92574
ZBTB24 zinc finger and BTB domain containing 24 Human Protein Binding 9841 O43167
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