Human Gene Module / Chromosome 2 / BCL11A

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

SFARI Gene Score
1S
High Confidence, Syndromic Criteria 1.1, Syndromic
Autism Reports / Total Reports
14 / 29
Rare Variants / Common Variants
40 / 2
EAGLE Score
9.15
Moderate Learn More
Aliases
BCL11A, BCL11A-L-S, BCL11A-XL, BCL11a-M,  CTIP1,  EVI9,  HBFQTL5,  ZNF856, BCL11A
Associated Syndromes
Dias-Logan syndrome
Chromosome Band
2p16.1
Associated Disorders
SCZ, DD/NDD, ID, EPS, ASD
Genetic Category
Rare Single Gene Mutation, Syndromic, Genetic Association, Functional
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.

External Links
Gene CardOpen Targets PlatformgnomAD browserSynGO portalPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
Mouse
Entrez GeneMouse Genome InformaticsAllen Brain Atlas
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to BCL11A (29 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 of the 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
13 Support Molecular and clinical delineation of 2p15p16.1 microdeletion syndrome Lvy J , et al. (2017) No Hypotonia
14 Support Hotspots of missense mutation identify neurodevelopmental disorder genes and functional domains Geisheker MR , et al. (2017) Yes -
15 Support Identification of novel mutations in the HbF repressor gene BCL11A in patients with autism and intelligence disabilities Cai T , et al. (2017) Yes -
16 Support BCL11A frameshift mutation associated with dyspraxia and hypotonia affecting the fine, gross, oral, and speech motor systems Soblet J , et al. (2017) No Childhood apraxia of speech, dyspraxia, hypotonia
17 Support Autism risk in offspring can be assessed through quantification of male sperm mosaicism Breuss MW , et al. (2019) Yes -
18 Support Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism Satterstrom FK et al. (2020) Yes -
19 Support Utility of clinical exome sequencing in a complex Emirati pediatric cohort Mahfouz NA et al. (2020) No -
20 Support A Novel de novo Frameshift Mutation in the BCL11A Gene in a Patient with Intellectual Disability Syndrome and Epilepsy Korenke GC et al. (2020) No DD, ID, epilepsy/seizures, autistic behavior
21 Support - Alonso-Gonzalez A et al. (2021) Yes -
22 Support - Tolve M et al. (2021) No -
23 Support - Hu C et al. (2022) Yes -
24 Support - Zhou X et al. (2022) Yes -
25 Positive Association - Wang S et al. (2022) No -
26 Support - Sheth F et al. (2023) Yes DD, ID, epilepsy/seizures
27 Support - Isabelle Schrauwen et al. (2024) No -
28 Support - Siavash Fazel Darbandi et al. () Yes -
29 Support - Axel Schmidt et al. (2024) No -
Rare Variants   (40)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss De novo - - 28573701 Lvy J , et al. (2017)
- - copy_number_loss De novo - - 25938782 Basak A , et al. (2015)
- - copy_number_gain De novo - - 27841880 Redin C , et al. (2016)
- - copy_number_loss De novo - Simplex 24810580 Peter B , et al. (2014)
- - copy_number_loss De novo - Simplex 25979662 Balci TB , et al. (2015)
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)
c.529C>T p.Gln177Ter stop_gained De novo - - 27453576 Dias C , et al. (2016)
c.2230+26G>T - missense_variant De novo - - 31873310 Breuss MW , et al. (2019)
c.295G>A p.Val99Met missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.*1094del - frameshift_variant Unknown - Simplex 28891213 Cai T , et al. (2017)
c.644C>G p.Pro215Arg stop_gained De novo - Simplex 28891213 Cai T , et al. (2017)
c.*612del - frameshift_variant De novo - Simplex 28960836 Soblet J , et al. (2017)
c.10C>T p.Arg4Cys missense_variant De novo - - 28333917 Vissers LE , et al. (2017)
c.56C>T p.Pro19Leu missense_variant Unknown - Simplex 28891213 Cai T , et al. (2017)
c.103C>T p.Pro35Ser missense_variant Unknown - - 28628100 Geisheker MR , et al. (2017)
c.142T>C p.Cys48Arg missense_variant Unknown - - 28628100 Geisheker MR , et al. (2017)
c.241G>A p.Val81Met missense_variant Unknown - - 28628100 Geisheker MR , et al. (2017)
c.1092A>T p.Gln364His missense_variant De novo - - 39039281 Axel Schmidt et al. (2024)
c.1173C>G p.Asn391Lys missense_variant De novo - - 39039281 Axel Schmidt et al. (2024)
c.2036_2037del p.Ser679Ter frameshift_variant De novo - - 27453576 Dias C , et al. (2016)
c.691_692del p.Leu231ValfsTer2 frameshift_variant De novo - - 35741772 Hu C et al. (2022)
c.2366dup p.Met789IlefsTer15 frameshift_variant De novo - - 35982159 Zhou X et al. (2022)
c.*1043_*1044insTGGCTCAGCGG - frameshift_variant De novo - - 27453576 Dias C , et al. (2016)
c.317C>T p.Thr106Met missense_variant De novo - Simplex 32382396 Mahfouz NA et al. (2020)
c.1459G>T p.Glu487Ter stop_gained De novo - Simplex 31981491 Satterstrom FK et al. (2020)
- - copy_number_loss Unknown Not maternal Simplex 38755281 Isabelle Schrauwen et al. (2024)
c.833C>G p.Pro278Arg missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.1307T>C p.Val436Ala missense_variant Familial Paternal Simplex 37543562 Sheth F et al. (2023)
c.271del p.Glu91ArgfsTer2 frameshift_variant De novo - Simplex 32903878 Korenke GC et al. (2020)
c.1096G>C p.Ala366Pro missense_variant De novo - Simplex 33431980 Alonso-Gonzalez A et al. (2021)
c.1547_1548insCTTGG p.Ser518GlyfsTer2 frameshift_variant De novo - - 27453576 Dias C , et al. (2016)
c.793dup p.Leu265ProfsTer3 frameshift_variant De novo - Simplex 22542183 Iossifov I , et al. (2012)
c.382G>A p.Ala128Thr missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.492A>C p.Lys164Asn missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.1174C>A p.Leu392Met missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.1325del p.Leu442ProfsTer37 frameshift_variant De novo - Simplex 25363760 De Rubeis S , et al. (2014)
c.139A>C p.Thr47Pro missense_variant De novo - Simplex 25533962 Deciphering Developmental Disorders Study (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)
Common Variants   (2)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
c.385+13359C>A - intron_variant - - - 36568279 Wang S et al. (2022)
c.386-22379G>A - intron_variant - - - 25938782 Basak A , et al. (2015)
SFARI Gene score
1S

High Confidence, Syndromic

Score Delta: Score remained at 1S

criteria met
See SFARI Gene'scoring criteria
1

High Confidence

See all Category 1 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.

S

Syndromic

See all Category S Genes

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."

1/1/2021
1
icon
1

Score remained at 1

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).

Reports Added
[Exploring the biological role of postzygotic and germinal de novo mutations in ASD2021]
10/1/2020
1
icon
1

Score remained at 1

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).

Reports Added
[A Novel de novo Frameshift Mutation in the BCL11A Gene in a Patient with Intellectual Disability Syndrome and Epilepsy2020]
4/1/2020
1
icon
1

Score remained at 1

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).

Reports Added
[Utility of clinical exome sequencing in a complex Emirati pediatric cohort2020]
1/1/2020
1
icon
1

Score remained at 1

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).

Reports Added
[Autism risk in offspring can be assessed through quantification of male sperm mosaicism.2019] [Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism2020]
10/1/2019
2S
icon
1

Decreased from 2S to 1

New Scoring Scheme
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).

Reports Added
[New Scoring Scheme]
10/1/2017
2S
icon
2S

Decreased from 2S to 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).

Reports Added
[Identification of novel mutations in the HbF repressor gene BCL11A in patients with autism and intelligence disabilities.2017] [BCL11A frameshift mutation associated with dyspraxia and hypotonia affecting the fine, gross, oral, and speech motor systems.2017]
7/1/2017
2S
icon
2S

Decreased from 2S to 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).

Reports Added
[Molecular and clinical delineation of 2p15p16.1 microdeletion syndrome.2017] [Hotspots of missense mutation identify neurodevelopmental disorder genes and functional domains.2017]
4/1/2017
2S
icon
2S

Decreased from 2S to 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).

Reports Added
[De novo gene disruptions in children on the autistic spectrum.2012] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [De novo microdeletion of BCL11A is associated with severe speech sound disorder.2014] [BCL11A deletions result in fetal hemoglobin persistence and neurodevelopmental alterations.2015] [Brain malformations in a patient with deletion 2p16.1: A refinement ofthe phenotype to BCL11A.2015] [Bcl11a (Ctip1) Controls Migration of Cortical Projection Neurons through Regulation of Sema3c.2015] [Low load for disruptive mutations in autism genes and their biased transmission.2015] [BCL11A Haploinsufficiency Causes an Intellectual Disability Syndrome and Dysregulates Transcription.2016] [Identifying candidate genes for 2p15p16.1 microdeletion syndrome using clinical, genomic, and functional analysis.2016] [The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies.2016] [A clinical utility study of exome sequencing versus conventional genetic testing in pediatric neurology.2017]
10/1/2016
2S
icon
2S

Decreased from 2S to 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

Reports Added
[Identifying candidate genes for 2p15p16.1 microdeletion syndrome using clinical, genomic, and functional analysis.2016] [The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies.2016]
7/1/2016
2
icon
2S

Decreased from 2 to 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.

Reports Added
[BCL11A Haploinsufficiency Causes an Intellectual Disability Syndrome and Dysregulates Transcription.2016]
1/1/2016
2
icon
2

Decreased from 2 to 2

Description

A de novo LoF variant in the BCL11A gene was identified in an ASD proband from the Simons Simplex Collection (PMID 22542183), while a second de novo LoF variant in this gene was identified in one ASD proband from 2,270 trios screened by the Autism Sequencing Consortium (PMID 25363760). 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

Reports Added
[De novo gene disruptions in children on the autistic spectrum.2012] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [De novo microdeletion of BCL11A is associated with severe speech sound disorder.2014] [BCL11A deletions result in fetal hemoglobin persistence and neurodevelopmental alterations.2015] [Brain malformations in a patient with deletion 2p16.1: A refinement ofthe phenotype to BCL11A.2015] [Bcl11a (Ctip1) Controls Migration of Cortical Projection Neurons through Regulation of Sema3c.2015] [Low load for disruptive mutations in autism genes and their biased transmission.2015]
7/1/2015
2
icon
2

Decreased from 2 to 2

Description

A de novo LoF variant in the BCL11A gene was identified in an ASD proband from the Simons Simplex Collection (PMID 22542183), while a second de novo LoF variant in this gene was identified in one ASD proband from 2,270 trios screened by the Autism Sequencing Consortium (PMID 25363760). 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

Reports Added
[De novo gene disruptions in children on the autistic spectrum.2012] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [De novo microdeletion of BCL11A is associated with severe speech sound disorder.2014] [BCL11A deletions result in fetal hemoglobin persistence and neurodevelopmental alterations.2015] [Brain malformations in a patient with deletion 2p16.1: A refinement ofthe phenotype to BCL11A.2015] [Bcl11a (Ctip1) Controls Migration of Cortical Projection Neurons through Regulation of Sema3c.2015]
4/1/2015
2
icon
2

Decreased from 2 to 2

Description

A de novo LoF variant in the BCL11A gene was identified in an ASD proband from the Simons Simplex Collection (PMID 22542183), while a second de novo LoF variant in this gene was identified in one ASD proband from 2,270 trios screened by the Autism Sequencing Consortium (PMID 25363760). 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

Reports Added
[BCL11A deletions result in fetal hemoglobin persistence and neurodevelopmental alterations.2015] [Brain malformations in a patient with deletion 2p16.1: A refinement ofthe phenotype to BCL11A.2015]
10/1/2014
icon
2

Increased from to 2

Description

A de novo LoF variant in the BCL11A gene was identified in an ASD proband from the Simons Simplex Collection (PMID 22542183), while a second de novo LoF variant in this gene was identified in one ASD proband from 2,270 trios screened by the Autism Sequencing Consortium (PMID 25363760). 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

Krishnan Probability Score

Score 0.64514098570556

Ranking 44/25841 scored genes


[Show Scoring Methodology]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning approach on a human brain-specific gene network. The method was first presented in Nat Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed in column G of supplementary table 3 (see: http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at asd.princeton.edu.
Original Source
ExAC Score

Score 0.82899968474484

Ranking 3759/18225 scored genes


[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of- function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of- function mutations in autism in such a gene would be more likely to confer risk. For a full list of pLI scores see: ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle aned_exac_nonTCGA_z_pli_rec_null_data.txt
Original Source
Iossifov Probability Score

Score 0.992

Ranking 22/239 scored genes


[Show Scoring Methodology]
Supplementary dataset S2 in the paper by Iossifov et al. (PNAS 112, E5600-E5607 (2015)) lists 239 genes with a probability of at least 0.8 of being associated with autism risk (column I). This probability metric combines the evidence from de novo likely-gene- disrupting and missense mutations and assesses it against the background mutation rate in unaffected individuals from the University of Washington’s Exome Variant Sequence database (evs.gs.washington.edu/EVS/). The list of probability scores can be found here: www.pnas.org/lookup/suppl/doi:10.1073/pnas.1516376112/- /DCSupplemental/pnas.1516376112.sd02.xlsx
Original Source
Sanders TADA Score

Score 0.037244493272064

Ranking 41/18665 scored genes


[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013), and is a statistic that integrates evidence from both de novo and transmitted mutations. It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233 (2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper (the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
Original Source
Larsen Cumulative Evidence Score

Score 22

Ranking 91/461 scored genes


[Show Scoring Methodology]
Larsen and colleagues generated gene scores based on the sum of evidence for all available ASD-associated variants in a gene, with assessments based on mode of inheritance, effect size, and variant frequency in the general population. The approach was first presented in Mol Autism 7:44 (2016), and scores for 461 genes can be found in column I in supplementary table 4 from that paper.
Original Source
Zhang D Score

Score 0.38850158224497

Ranking 1582/20870 scored genes


[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures), or D score, was developed to combine evidence from de novo loss-of- function mutation with evidence from cell-type- specific gene expression in the mouse brain (specifically translational profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with positive D scores are more likely to be associated with autism risk, with higher-confidence genes having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204- 215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in supplementary table 2 from that paper.
Original Source
Interactome
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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