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BCL11A-Related Intellectual Disability

Synonyms: Dias-Logan Syndrome, Intellectual Developmental Disorder with Persistence of Fetal Hemoglobin

, MD, , BA, MBBS, MA, , MD, PhD, and , MD, PhD.

Author Information

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Estimated reading time: 20 minutes

Summary

Clinical characteristics.

BCL11A-related intellectual disability (BCL11A-ID) is characterized by developmental delay / intellectual disability of variable degree, neonatal hypotonia, microcephaly, distinctive but variable facial characteristics, behavior problems, and asymptomatic persistence of fetal hemoglobin. Growth delay, seizures, and autism spectrum disorder have also been reported in some affected individuals.

Diagnosis/testing.

The diagnosis of BCL11A-ID is established in a proband with suggestive clinical and laboratory findings and a heterozygous pathogenic variant in BCL11A identified by molecular genetic testing.

Management.

Treatment of manifestations: Treatment is primarily supportive and dictated by symptoms. Standard antiepileptic medication for seizure disorder; standard treatment for abnormal vision and/or strabismus, sleep disturbance, scoliosis, joint laxity, gastroesophageal reflux disease (GERD), constipation, and developmental issues.

Surveillance: Assessment of growth parameters, feeding difficulties, GERD, constipation, scoliosis, developmental progress, and behavior at each visit. Monitor seizures as clinically indicated. Assessment of vision and eye alignment as needed.

Genetic counseling.

BCL11A-ID is inherited in an autosomal dominant manner; however, most affected individuals have the disorder as the result of a de novo BCL11A pathogenic variant. Once the BCL11A pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible.

Diagnosis

Formal clinical diagnostic criteria for BCL11A-related intellectual disability (BCL11A-ID) have not been established.

Suggestive Findings

BCL11A-ID should be considered in individuals presenting with the following clinical, laboratory, and neuroimaging findings.

Clinical findings

  • Mild-to-severe developmental delay or intellectual disability; AND
  • Any of the following features presenting in infancy or childhood:
    • Microcephaly
    • Craniofacial features including flat midface, small nares, thin vermilion of the upper lip and everted vermilion of the lower lip [Dias et al 2016] (see Figure 1)
    • External ear anomalies
    • Strabismus
    • Blue sclerae in infancy
    • Generalized hypotonia of infancy
    • Infant feeding difficulties
    • Language delay and/or dyspraxia
    • Joint laxity
    • Behavioral concerns (repetitive behavior, autism spectrum disorder)
    • Sleep disturbance
    • Seizures

Laboratory findings. Persistence of fetal hemoglobin detected by standardized laboratory methods, such as hemoglobin HPLC (high-performance liquid chromatography) or hemoglobin electrophoresis

Nonspecific brain MRI findings. Hypoplasia of the corpus callosum, hypoplasia of the cerebellar vermis, or white matter abnormalities

Establishing the Diagnosis

The diagnosis of BCL11A-ID is established in a proband with suggestive findings by identification of a heterozygous pathogenic variant in BCL11A on molecular genetic testing (see Table 1).

Molecular genetic testing in a child with developmental delay or an older individual with intellectual disability typically begins with chromosomal microarray analysis (CMA). If CMA is not diagnostic, the next step is typically either a multigene panel or exome sequencing.

Note: Single-gene testing (sequence analysis of BCL11A, followed by gene-targeted deletion/duplication analysis) may be considered in individuals with nonfamilial persistence of fetal hemoglobin identified by hematologic assays.

CMA uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including BCL11A) that cannot be detected by sequence analysis. See Genetically Related Disorders for discussion of individuals who have larger deletions or duplications of the 2p15-p16.1 region, which includes BCL11A and surrounding genes.

An intellectual disability (ID) multigene panel that includes BCL11A and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition in a person with a nondiagnostic CMA at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. Of note, given the rarity of BCL11A-ID, some panels for ID may not include this gene. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Exome sequencing, which does not require the clinician to determine which gene is likely involved, yields results similar to an ID multigene panel but has the advantage that all rare genes recently identified as causing ID are represented, while some newly identified ID genes may not be included on a multigene panel.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in BCL11A-Related Intellectual Disability

Gene 1MethodProportion of Probands with a Pathogenic
Variant 2 Detectable by Method
BCL11ASequence analysis 321/27 4
Gene-targeted deletion/duplication analysis 5Unknown 6
CMA 7, 86/27 9
1.
2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.
5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

6.

No data on detection rate of gene-targeted deletion/duplication analysis are available.

7.

Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including BCL11A) that cannot be detected by sequence analysis. The ability to determine the size of the deletion/duplication depends on the type of microarray used and the density of probes in the 2p15-p16.1 region. CMA designs in current clinical use target the 2p15-p16.2 region.

8.

Includes partial or whole-gene deletions of BCL11A without disrupting other protein-coding genes (excludes contiguous gene deletion syndromes, namely 2p15-16.1 microdeletion syndrome).

9.

Clinical Characteristics

Clinical Description

BCL11A-related intellectual disability (BCL11A-ID) is characterized by developmental delay / intellectual disability of variable degree (from mild to severe, but most frequently in the moderate range), neonatal hypotonia, microcephaly, distinctive but variable facial characteristics, behavior problems, and asymptomatic persistence of fetal hemoglobin (HbF). Growth delay, seizures, and autism spectrum disorder have also been reported in some affected individuals.

To date, 27 individuals have been reported with a pathogenic (or likely pathogenic) variant in BCL11A [Firth et al 2009, De Rubeis et al 2014, Iossifov et al 2014, Peter et al 2014, Balci et al 2015, Deciphering Developmental Disorders Study Group 2015, Dias et al 2016, Cai et al 2017, Landrum et al 2018, Peron et al 2018, Soblet et al 2018, Yoshida et al 2018]; the authors are aware of additional affected individuals. The following description of the phenotypic features associated with this condition is based on the reported cases and the authors' experience.

Developmental delay (DD) and intellectual disability (ID). All individuals with BCL11A-ID present with DD. Speech delay is always present, and gross and fine motor delays are usually seen as well. All affected individuals have ID, with variable levels ranging from mild to severe.

Other neurodevelopmental features:

  • Neonatal hypotonia is seen in the majority of affected individuals, and may result in delayed acquisition of motor milestones (average age at walking: ~30 months). Hypotonia may resolve in childhood, though in some it persists into adolescence.
  • Infant feeding difficulties are occasionally present and thought to be associated with central hypotonia as opposed to primary dysphagia.
  • Ataxia and/or broad-based gait has been reported in three affected individuals.

Epilepsy has been reported in 5/25 affected individuals [Cai et al 2017, Peron et al 2018, Yoshida et al 2018].

  • Various types of seizures have been described (including myoclonic, tonic, and atonic seizures; absence seizures; and spasms) without a common electroclinical pattern.
  • Age at seizure onset among individuals reported in the literature varied from two months to three years.
  • Seizures are usually controlled with single or combined (2) antiepileptic medication(s). Three reported individuals had seizures that were drug resistant [Peron et al 2018, Yoshida et al 2018] (see also Genetically Related Disorders).

Behavior problems. Most individuals reported have presented with behavior problems [Dias et al 2016].

  • Autism spectrum disorder has been described in a subset of affected individuals [De Rubeis et al 2014, Iossifov et al 2014, Dias et al 2016, Cai et al 2017].
  • Others exhibit autistic-like traits, such as repetitive behaviors.
  • Other behavior problems:
    • Attention deficit and self-injurious behaviors have been reported in one person each.
    • Sleep disturbances have been reported in three people.

Hematologic. A key manifestation of BCL11A-ID is the persistence of fetal hemoglobin (HbF) in affected individuals. In individuals from the general population, HbF is high in the second and third trimester of gestation and in the neonatal period, physiologically decreasing after birth and within the first 12 months of life (with a transition to adult hemoglobin). Therefore, age-specific reference values for hemoglobin variants should be used up to age 24 months.

Growth. Intrauterine growth restriction (IUGR) and postnatal growth delay are occasionally present [Dias et al 2016, Cai et al 2017, Yoshida et al 2018], but more than half of the affected individuals have normal growth parameters.

Microcephaly (-2 to -3.5 SD) is seen in approximately half of affected individuals [Dias et al 2016, Cai et al 2017, Soblet et al 2018, Yoshida et al 2018].

Eyes. Strabismus has been reported in 10/21 affected individuals [Dias et al 2016, Cai et al 2017, Peron et al 2018] but no other vision or hearing impairments have been documented. Some affected children with pathogenic loss-of-function variants exhibit blue sclerae in infancy (see Genotype-Phenotype Correlations) [Dias et al 2016].

Neuroimaging. Brain MRI is normal in only a minority of affected individuals; however, most abnormal brain MRI findings are mild and/or nonspecific.

  • Structural anomalies of the central nervous system can be present, including hypoplasia of the corpus callosum and/or cerebellar vermis [Dias et al 2016, Peron et al 2018].
  • White matter abnormalities, including reduced white matter volume, have been reported [Dias et al 2016].

Other associated features

  • Musculoskeletal features
    • Joint hypermobility is a common finding (>80%) in individuals with BCL11A-ID.
    • Scoliosis has occasionally been reported [Dias et al 2016, Cai et al 2017].
  • Gastrointestinal problems. Infantile feeding problems with poor weight gain, gastroesophageal reflux disease (GERD), and constipation have occasionally been reported [Dias et al 2016].
  • Craniofacial features. No specific dysmorphic features have been observed. If present, dysmorphic features are nonspecific.

Prognosis. BCL11A-ID is a congenital disorder without known regression of skills. Life span and typical cause of death are unknown due to the limited number of individuals reported to date and ascertainment bias toward diagnosis in childhood. However, the lack of life-limiting congenital anomalies in affected individuals suggests a favorable long-term prognosis with appropriate support. The authors are aware of two affected individuals who are alive and well at 19 and 23 years, respectively [Authors, personal observation], demonstrating that survival into adulthood is possible. Since many adults with disabilities have not undergone advanced genetic testing, it is likely that adults with this condition are underrecognized and underreported.

Genotype-Phenotype Correlations

With the limited number of affected individuals reported to date, no statistically significant genotype-phenotype correlations can be made. However, certain features described to date have been seen only in individuals with loss-of-function (nonsense and frameshift) variants [Dias et al 2016, Yoshida et al 2018]:

  • Blue sclerae in infancy
  • Epicanthal folds
  • Micrognathia or retrognathia
  • Short stature (mild)

Prevalence

The prevalence of BCL11A-ID is unknown. To date, 27 affected individuals have been reported in the literature.

Differential Diagnosis

Table 2 describes specific conditions that may have features that overlap with BCL11A-related intellectual disability (BCL11A-ID).

Note: The phenotypic features associated with BCL11A-ID are generally not sufficient to diagnose this condition. All disorders with intellectual disability (ID) without other distinctive findings should be considered in the differential diagnosis. To date more than 180 such disorders with ID have been identified. See OMIM Phenotypic Series: Autosomal dominant ID, Autosomal recessive ID, Nonsyndromic X-linked ID, and Syndromic X-linked ID.

Table 2.

Selected Disorders to Consider in the Differential Diagnosis of BCL11A-Related Intellectual Disability

DisorderGene(s)MOIKey Clinical Features of Differential Diagnosis Disorder
Overlapping w/BCL11A-IDDistinguishing from BCL11A-ID
KANSL1-related intellectual disability syndromeKANSL1ADID, infant hypotonia, joint hypermobility, everted lower lip, strabismus
  • Facial features incl blepharophimosis & bulbous or tubular nose
  • More frequent congenital anomalies (renal & urogenital anomalies, heart defects)
Alpha-thalassemia X-linked intellectual disability syndrome (ATRX)ATRXXL
  • ID, hypotonia, small head circumference, everted lower lip, short nose, short stature
  • Facial gestalt in a subset of individuals w/BCL11A-ID resembles that of ATRX. 1
  • Craniofacial features (telecanthus, tented vermilion of upper lip, progressive coarsening of facial features), genital abnormalities, & skeletal abnormalities
  • ID is typically severe to profound in boys (heterozygous females w/craniofacial features, ID, & growth restriction have been described). 2
  • Alpha-thalassemia (in ~85% of individuals)

AD = autosomal dominant; ID = intellectual disability; MOI = mode of inheritance; XL = X-linked

1.
2.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with BCL11A-ID, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to diagnosis) are recommended.

Table 3.

Recommended Evaluations Following Initial Diagnosis in Individuals with BCL11A-Related Intellectual Disability

System/ConcernEvaluationComment
NeurologicAssessment for hypotonia & signs/symptoms of seizures
  • EEG if seizures suspected
  • Consider brain MRI to detect brain abnormalities.
Psychiatric/
Behavioral
Neuropsychiatric evaluationFor individuals age >18 mos: screen for behavior problems incl sleep disturbances, ADHD, anxiety, &/or traits suggestive of ASD.
ConstitutionalWeight, length/height, & head circumferenceAssess for evidence of short stature, failure to thrive, microcephaly.
EyesOphthalmologic evaluationAssess for strabismus, visual acuity.
MusculoskeletalClinical evaluation for scoliosisConsider radiographic scoliosis survey based on clinical suspicion & referral to orthopedic surgeon as appropriate.
Clinical evaluation for joint laxityConsider referral to rehabilitation specialist & occupational therapist.
Gastrointestinal/
Feeding
Assessment of feeding problems in infancy & for GERD at any ageReferral to feeding therapist if feeding problems identified
HematologicHemoglobin HPLC or hemoglobin electrophoresisExpect elevated HbF.
Miscellaneous/
Other
Developmental assessment
  • Incl evaluation of motor, speech/language, general cognitive, & vocational skills
  • Refer to speech & rehabilitation therapy, PT, & OT as appropriate.
Consultation w/clinical geneticist &/or genetic counselor

ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; GERD = gastroesophageal reflux disorder; HbF = fetal hemoglobin; HPLC = high-performance liquid chromatography; OT = occupational therapy; PT = physical therapy

Treatment of Manifestations

Table 4.

Treatment of Manifestations in Individuals with BCL11A-Related Intellectual Disability

Manifestation/ConcernTreatmentConsiderations/Other
SeizuresStandardized treatment w/AEDs by experienced neurologist 1Many different AEDs may be effective, & no one AED has been demonstrated effective specifically for this disorder.
Sleep disturbancesStandard management.Consider melatonin.
Abnormal vision &/or strabismusStandard treatment(s) as recommended by ophthalmologist.
ScoliosisStandard management as recommended by orthopedist
Joint laxityPT &/or OT
GERD &/or constipationReferral to (pediatric) gastroenterologistSymptomatic management to enhance nutritional intake & hydration

AED = antiepileptic drug; GERD = gastroesophageal reflux disorder; OT = occupational therapy; PT = physical therapy

1.

Education of parents regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for parents or caregivers of children diagnosed with epilepsy, see Epilepsy & My Child Toolkit.

Developmental Delay / Intellectual Disability Management Issues

The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.

Ages 0-3 years. Referral to an early intervention program is recommended for access to occupational, physical, speech, and feeding therapy. In the US, early intervention is a federally funded program available in all states.

Ages 3-5 years. In the US, developmental preschool through the local public school district is recommended. Before placement, an evaluation is made to determine needed services and therapies and an individualized education plan (IEP) is developed.

Ages 5-21 years

  • In the US, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21.
  • Discussion about transition plans including financial, vocation/employment, guardianship, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood.

All ages. Consultation with a developmental pediatrician is recommended to ensure the involvement of appropriate community, state, and educational agencies and to support parents in maximizing quality of life.

Consideration of private supportive therapies based on the affected individual's needs is recommended. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.

In the US:

  • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
  • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.

Motor Dysfunction

Gross motor dysfunction

  • Physical therapy is recommended to maximize mobility.
  • Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).

Fine motor dysfunction. Occupational therapy is recommended for difficulty with fine motor skills that affect adaptive function such as feeding, grooming, dressing, and writing.

Oral motor dysfunction. Assuming that the individual is safe to eat by mouth, feeding therapy, typically from an occupational or speech therapist, is recommended for affected individuals who have difficulty feeding due to poor oral motor control.

Communication issues. Consider evaluation for alternative means of communication (e.g., Augmentative and Alternative Communication [AAC]) for individuals who have expressive language difficulties.

Social/Behavioral Concerns

Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and is typically performed one-on-one with a board-certified behavior analyst.

Consultation with a developmental pediatrician and/or a psychiatrist may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder (ADHD), when necessary.

Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.

Surveillance

Table 5.

Recommended Surveillance for Individuals with BCL11A-Related Intellectual Disability

System/ConcernEvaluationFrequency
NeurologicMonitor those w/seizures as clinically indicated.As clinically indicated
PsychiatricBehavioral assessment for anxiety, attention, & aggressive or self-injurious behaviorMonitor clinically at each visit; refer for evaluation as indicated.
ConstitutionalWeight, length/height, & head circumference measurements plotted on standard growth chartAt each visit
EyesOphthalmologic evaluationAs clinically indicated
MusculoskeletalMonitor for scoliosis. Orthopedic evaluation as indicated.Monitor clinically at each visit.
GastrointestinalAssessment of feeding difficulties, GERD, constipationAt each visit (particularly in infancy)
Miscellaneous/
Other
Monitor developmental progress & educational needs.At each visit

GERD = gastroesophageal reflux disorder

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

BCL11A-related intellectual disability (BCL11A-ID) is inherited in an autosomal dominant manner and is typically caused by a de novo pathogenic variant.

Risk to Family Members

Parents of a proband

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents:

Offspring of a proband. Each child of an individual with a BCL11A-ID has a 50% chance of inheriting the BCL11A pathogenic variant. It is not possible to reliably predict clinical severity in offspring who inherit the pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the BCL11A pathogenic variant, his or her family members may be at risk. However, given that almost all probands with BCL11A-ID reported to date have the disorder as a result of a de novo BCL11A pathogenic variant, the risk to other family members is presumed to be low.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the BCL11A pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • American Association on Intellectual and Developmental Disabilities (AAIDD)
    501 3rd Street Northwest
    Suite 200
    Washington DC 20001
    Phone: 202-387-1968
    Fax: 202-387-2193
    Email: sis@aaidd.org
  • Medline Plus
  • Rare Disease Foundation (RDF)
    4500 Oak Street
    Room C234
    Vancouver British Columbia V6H 3N1
    Canada
    Phone: 866-348-6677
    Email: families@rarediseasefoundation.org
  • Unique: The Rare Chromosome Disorder Support Group
    G1 The Stables
    Station Road West
    Oxted Surrey RH8 9EE
    United Kingdom
    Phone: +44 (0) 1883 723356
    Email: info@rarechromo.org; rarechromo@aol.com
  • VOR: Speaking out for people with intellectual and developmental disabilities
    836 South Arlington Heights Road, #351
    Elk Grove Village IL 60007
    Phone: 877-399-4867
    Fax: 847-253-0675
    Email: info@vor.net
  • Human Disease Gene Website Series - Registry

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

BCL11A-Related Intellectual Disability: Genes and Databases

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
BCL11A2p16​.1B-cell lymphoma/leukemia 11ABCL11A @ LOVDBCL11ABCL11A

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for BCL11A-Related Intellectual Disability (View All in OMIM)

606557BAF CHROMATIN REMODELING COMPLEX SUBUNIT BCL11A; BCL11A
617101INTELLECTUAL DEVELOPMENTAL DISORDER WITH PERSISTENCE OF FETAL HEMOGLOBIN

Molecular Pathogenesis

BCL11A is a COUP-TF-interacting transcription factor that associates with the BRG1- and BRM-associated factor (BAF) swi/snf chromatin remodeling complex [Kadoch et al 2013]. Pathogenic variants in genes encoding the BAF complex are a recurrent cause of intellectual disability [Kosho et al 2014]. BCL11A is highly expressed in developing mouse brain and in postnatal cortex, hippocampus and caudate nucleus, and in B-lymphocytes. BCL11A is expressed in fetal brain [Nowakowski et al 2017], and in adult brain is restricted to neurons [Uhlén et al 2015]. In addition, BCL11A is a transcriptional repressor of fetal hemoglobin (HbF), playing an important role in globin switching [Bauer & Orkin 2011, Liu et al 2018]. In humans, BCL11A is highly expressed in hematopoietic cells, particularly in B lymphoid and erythroid lineages.

Multiple alternatively spliced transcript variants encoding different isoforms have been identified for BCL11A. BCL11A isoforms share a conserved N terminus and at least one Krüppel C2H2-type zinc finger. The three major BCL11A isoforms, -XL, -L, and -S, encode 835, 773, and 243 amino acid peptides, respectively.

Mechanism of disease causation. BCL11A causes disease through a loss-of-function (LOF) mechanism [Dias et al 2016]. Nonsense and frameshift variants as well as partial or whole-gene deletions have been reported. All LOF variants are predicted to undergo nonsense-mediated decay with loss of isoforms X and XL.

Pathogenic missense variants cluster in the N-terminal region of BCL11A. This region is required for localization to the nucleus, via two C2H2 zinc finger domains. N-terminal missense variants affecting BCL11A localization, dimerization, and transcriptional activity, with putative hypomorphic function, also result in a loss-of-function phenotype.

Heterozygous knockout mice have decreased brain size and aberrant brain transcriptional profiles; they present impaired social memory and decreased social interaction [Dias et al 2016]. BCL11A is associated with neocortical development, specifically the neuronal switch from multipolar to bipolar morphology. BCL11A-deficient neurons have been demonstrated to show impaired radial migration and overexpression of Semac3c [Wiegreffe et al 2015].

BCL11A interacts with calcium/calmodulin-dependent serine kinase (CASK), a gene implicated in X-linked intellectual disability (see CASK-Related Disorders). In a cultured model of hippocampal neurons, CASK enhanced the ability of BCL11A to restrict axon outgrowth and branching [Kuo et al 2010]. CASK interacts with the TBR1 transcription factor, which is also highly expressed in deep layers of cortex and is co-located with BCL11A. Heterozygous variants cause intellectual developmental disorder with autism and speech delay (OMIM 604616). BCL11A regulates the expression of TBR1 in the cortex with residues 629-773 appearing crucial in the interaction between TBR1 and BCL11A [Cánovas et al 2015].

BCL11A-specific laboratory considerations. Individuals with BCL11A-related intellectual disability demonstrate persistence of HbF, with significantly higher levels of HbF than age-matched controls. HbF measurement may be performed to assist in the interpretation of variants of unknown significance.

References

Literature Cited

  • Badens C, Martini N, Courrier S, DesPortes V, Touraine R, Levy N, Edery P. ATRX syndrome in a girl with a heterozygous mutation in the ATRX Zn finger domain and a totally skewed X-inactivation pattern. Am J Med Genet A. 2006;140:2212–5. [PubMed: 16955409]
  • Bagheri H, Badduke C, Qiao Y, Colnaghi R, Abramowicz I, Alcantara D, Dunham C, Wen J, Wildin RS, Nowaczyk MJ, Eichmeyer J, Lehman A, Maranda B, Martell S, Shan X, Lewis SM, O'Driscoll M, Gregory-Evans CY, Rajcan-Separovic E. Identifying candidate genes for 2p15p16.1 microdeletion syndrome using clinical, genomic, and functional analysis. JCI insight. 2016;1:e85461. [PMC free article: PMC5033885] [PubMed: 27699255]
  • Balci TB, Sawyer SL, Davila J, Humphreys P, Dyment DA. Brain malformations in a patient with deletion 2p16.1: a refinement of the phenotype to BCL11A. Eur J Med Genet. 2015;58:351–4. [PubMed: 25979662]
  • Bauer DE, Orkin SH. Update on fetal hemoglobin gene regulation in hemoglobinopathies. Curr Opin Pediatr. 2011;23:1–8. [PMC free article: PMC3092400] [PubMed: 21157349]
  • Cai T, Chen X, Li J, Xiang B, Yang L, Liu Y, Chen Q, He Z, Sun K, Liu PP. Identification of novel mutations in the HbF repressor gene BCL11A in patients with autism and intelligence disabilities. Am J Hematol. 2017;92:E653–6. [PubMed: 28891213]
  • Cánovas J, Berndt FA, Sepúlveda H, Aguilar R, Veloso FA, Montecino M, Oliva C, Maass JC, Sierralta J, Kukuljan M. The specification of cortical subcerebral projection neurons depends on the direct repression of TBR1 by CTIP1/BCL11a. J Neurosci. 2015;35:7552–64. [PMC free article: PMC6705430] [PubMed: 25972180]
  • Deciphering Developmental Disorders Study Group. Large-scale discovery of novel genetic causes of developmental disorders. Nature. 2015;519:223–8. [PMC free article: PMC5955210] [PubMed: 25533962]
  • de Leeuw N, Pfundt R, Koolen DA, Neefs I, Scheltinga I, Mieloo H, Sistermans EA, Nillesen W, Smeets DF, de Vries BBA, Knoers NVAM. A newly recognised microdeletion syndrome involving 2p15p16.1: narrowing down the critical region by adding another patient detected by genome wide tiling path array comparative genomic hybridisation analysis. J Med Genet. 2008;45:122–4. [PubMed: 18245392]
  • De Rubeis S, He X, Goldberg AP, Poultney CS, Samocha K, Cicek AE, Kou Y, Liu L, Fromer M, Walker S, Singh T, Klei L, Kosmicki J, Shih-Chen F, Aleksic B, Biscaldi M, Bolton PF, Brownfeld JM, Cai J, Campbell NG, Carracedo A, Chahrour MH, Chiocchetti AG, Coon H, Crawford EL, Curran SR, Dawson G, Duketis E, Fernandez BA, Gallagher L, Geller E, Guter SJ, Hill RS, Ionita-Laza J, Jimenz Gonzalez P, Kilpinen H, Klauck SM, Kolevzon A, Lee I, Lei I, Lei J, Lehtimäki T, Lin CF, Ma'ayan A, Marshall CR, McInnes AL, Neale B, Owen MJ, Ozaki N, Parellada M, Parr JR, Purcell S, Puura K, Rajagopalan D, Rehnström K, Reichenberg A, Sabo A, Sachse M, Sanders SJ, Schafer C, Schulte-Rüther M, Skuse D, Stevens C, Szatmari P, Tammimies K, Valladares O, Voran A, Li-San W, Weiss LA, Willsey AJ, Yu TW, Yuen RK, Cook EH, Freitag CM, Gill M, Hultman CM, Lehner T, Palotie A, Schellenberg GD, Sklar P, State MW, Sutcliffe JS, Walsh CA, Scherer SW, Zwick ME, Barett JC, Cutler DJ, Roeder K, Devlin B, Daly MJ, Buxbaum JD, et al. Synaptic, transcriptional and chromatin genes disrupted in autism. Nature. 2014;515:209–15. [PMC free article: PMC4402723] [PubMed: 25363760]
  • Dias C, Estruch SB, Graham SA, McRae J, Sawiak SJ, Hurst JA, Joss SK, Holder SE, Morton JE, Turner C, Thevenon J, Mellul K, Sanchez-Andrade G, Ibarra-Soria X, Deriziotis P, Santos RF, Lee SC, Faivre L, Kleefstra T, Liu P, Hurles ME, Fisher SE, Logan DW. BCL11A haploinsufficiency causes an intellectual disability syndrome and dysregulates transcription. Am J Hum Genet. 2016;99:253–74. [PMC free article: PMC4974071] [PubMed: 27453576]
  • Firth HV, Richards SM, Bevan AP, Clayton S, Corpas M, Rajan D, Vooren SV, Moreau Y, Pettett RM, Carter NP. DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans Using Ensembl Resources. Am J Hum Genet. 2009;84:524–33. [PMC free article: PMC2667985] [PubMed: 19344873]
  • Florisson JMG, Mathijssen IMJ, Dumee B, Hoogeboom JAM, Poddighe PJ, Oostra BA, Frijns JP, Koster L, de Klein A, Eussen B, de Vries BBA, Swagemakers S, van der Spek PJ, Verkerk AJMH. Complex craniosynostosis is associated with the 2p15p16.1 microdeletion syndrome. Am J Med Genet A. 2013;161A:244–53. [PubMed: 23303641]
  • Hucthagowder V, Liu T-C, Paciorkowski AR, Thio LL, Keller MS, Anderson CD, Herman T, Dehner LP, Grange DK, Kulkarni S. Chromosome 2p15p16.1 microdeletion syndrome: 2.5 Mb deletion in a patient with renal anomalies, intractable seizures and a choledochal cyst. Eur J Med Genet. 2012;55:485–9. [PubMed: 22579565]
  • Iossifov I, O'roak BJ, Sanders SJ, Ronemus M, Krumm N, Levy D, Stessman HA, Witherspoon KT, Vives L, Patterson KE, Smith JD, Paeper B, Nickerson DA, Dea J, Dong S, Gonzalez LE, Mandell JD, Mane SM, Murtha MT, Sullivan CA, Walker MF, Waqar Z, Wei L, Willsey AJ, Yamrom B, Lee YH, Grabowska E, Dalkic E, Wang Z, Marks S, Andrews P, Leotta A, Kendall J, Hakker I, Rosenbaum J, Ma B, Rodgers L, Troge J, Narzisi G, Yoon S, Schatz MC, Ye K, Mccombie WR, Shendure J, Eichler EE, State MW, Wigler M. The contribution of de novo coding mutations to autism spectrum disorder. Nature. 2014;515:216–21. [PMC free article: PMC4313871] [PubMed: 25363768]
  • Jorgez CJ, Rosenfeld JA, Wilken NR, Vangapandu HV, Sahin A, Pham D, Carvalho CMB, Bandholz A, Miller A, Weaver DD, Burton B, Babu D, Bamforth JS, Wilks T, Flynn DP, Roeder E, Patel A, Cheung SW, Lupski JR, Lamb DJ. Genitourinary defects associated with genomic deletions in 2p15 encompassing OTX1. PLoS One. 2014;9:e107028. [PMC free article: PMC4159299] [PubMed: 25203062]
  • Kadoch C, Hargreaves DC, Hodges C, Elias L, Ho L, Ranish J, Crabtree GR. Proteomic and bioinformatic analysis of mammalian SWI/SNF complexes identifies extensive roles in human malignancy. Nat Genet. 2013;45:592–601. [PMC free article: PMC3667980] [PubMed: 23644491]
  • Kosho T, Miyake N, Carey JC. Coffin-Siris syndrome and related disorders involving components of the BAF (mSWI/SNF) complex: historical review and recent advances using next generation sequencing. Am J Med Genet C Semin Med Genet. 2014;166C:241–51. [PubMed: 25169878]
  • Kuo TY, Hong CJ, Chien HL, Hsueh YP. X-linked mental retardation gene CASK interacts with Bcl11A/CTIP1 and regulates axon branching and outgrowth. J Neurosci Res. 2010;88:2364–73. [PubMed: 20623620]
  • Landrum MJ, Lee JM, Benson M, Brown GR, Chao C, Chitipiralla S, Gu B, Hart J, Hoffman D, Jang W, Karapetyan K, Katz K, Liu C, Maddipatla Z, Malheiro A, McDaniel K, Ovetsky M, Riley G, Zhou G, Holmes JB, Kattman BL, Maglott DR. ClinVar: improving access to variant interpretations and supporting evidence. Nucleic Acids Res. 2018;46:D1062–7. [PMC free article: PMC5753237] [PubMed: 29165669]
  • Lévy J, Coussement A, Dupont C, Guimiot F, Baumann C, Viot G, Passemard S, Capri Y, Drunat S, Verloes A, Pipiras E, Benzacken B, Dupont JM, Tabet AC. Molecular and clinical delineation of 2p15p16.1 microdeletion syndrome. Am J Med Genet A. 2017;173:2081–7. [PubMed: 28573701]
  • Liang JS, Shimojima K, Ohno K, Sugiura C, Une Y, Ohno K, Yamamoto T. A newly recognised microdeletion syndrome of 2p15-16.1 manifesting moderate developmental delay, autistic behaviour, short stature, microcephaly, and dysmorphic features: a new patient with 3.2 Mb deletion. J Med Genet. 2009;46:645–7. [PubMed: 19724011]
  • Liu N, Hargreaves VV, Zhu Q, Kurland JV, Hong J, Kim W, Sher F, Macias-Trevino C, Rogers JM, Kurita R, Nakamura Y, Yuan G-C, Bauer DE, Xu J, Bulyk ML, Orkin SH. Direct promoter repression by BCL11A controls the fetal to adult hemoglobin switch. Cell. 2018;173:430–42.e17. [PMC free article: PMC5889339] [PubMed: 29606353]
  • Mimouni-Bloch A, Yeshaya J, Kahana S, Maya I, Basel-Vanagaite L. A de-novo interstitial microduplication involving 2p16.1-p15 and mirroring 2p16.1-p15 microdeletion syndrome: clinical and molecular analysis. Eur J Paediatr Neurol. 2015;19:711–5. [PubMed: 26278498]
  • Nowakowski TJ, Bhaduri A, Pollen AA, Alvarado B, Mostajo-Radji MA, Di Lullo E, Haeussler M, Sandoval-Espinosa C, Liu SJ, Velmeshev D, Ounadjela JR, Shuga J, Wang X, Lim DA, West JA, Leyrat AA, Kent WJ, Kriegstein AR. Spatiotemporal gene expression trajectories reveal developmental hierarchies of the human cortex. Science. 2017;358:1318. [PMC free article: PMC5991609] [PubMed: 29217575]
  • Pavone P, Falsaperla R, Rizzo R, Pratico AD, Ruggieri M. Chromosome 2p15-p16.1 microduplication in a boy with congenital anomalies: is it a distinctive syndrome? Eur J Med Genet. 2019;62:47–54. [PubMed: 29864511]
  • Peron A, Carlston C, Palumbos J, Tvrdik T, Ferreira P, Haffner D, Openshaw A, Lamb A, Paulraj P, Andersen E, Rong M, Carey JC, Viskochil D. Dias-Logan syndrome: delineating a newly recognised disorder of transcriptional regulation. J Investig Med. 2018;66:A203.
  • Peter B, Matsushita M, Oda K, Raskind W. De novo microdeletion of BCL11A is associated with severe speech sound disorder. Am J Med Genet A. 2014;164A:2091–6. [PubMed: 24810580]
  • Piccione M, Piro E, Serraino F, Cavani S, Ciccone R, Malacarne M, Pierluigi M, Vitaloni M, Zuffardi O, Corsello G. Interstitial deletion of chromosome 2p15-16.1: report of two patients and critical review of current genotype-phenotype correlation. Eur J Med Genet. 2012;55:238–44. [PubMed: 22406401]
  • Rahbari R, Wuster A, Lindsay SJ, Hardwick RJ, Alexandrov LB, Turki SA, Dominiczak A, Morris A, Porteous D, Smith B, Stratton MR, Hurles ME, et al. Timing, rates and spectra of human germline mutation. Nat Genet. 2016;48:126–33. [PMC free article: PMC4731925] [PubMed: 26656846]
  • Rajcan-Separovic E, Harvard C, Liu X, McGillivray B, Hall JG, Qiao Y, Hurlburt J, Hildebrand J, Mickelson ECR, Holden JJA, Lewis MES. Clinical and molecular cytogenetic characterisation of a newly recognised microdeletion syndrome involving 2p15-16.1. J Med Genet. 2007;44:269–76. [PMC free article: PMC2598046] [PubMed: 16963482]
  • Shimbo H, Yokoi T, Aida N, Mizuno S, Suzumura H, Nagai J, Ida K, Enomoto Y, Hatano C, Kurosawa K. Haploinsufficiency of BCL11A associated with cerebellar abnormalities in 2p15p16.1 deletion syndrome. Mol Genet Genomic Med. 2017;5:429–37. [PMC free article: PMC5511803] [PubMed: 28717667]
  • Soblet J, Dimov I, Graf von Kalckreuth C, Cano-Chervel J, Baijot S, Pelc K, Sottiaux M, Vilain C, Smits G, Deconinck N. BCL11A frameshift mutation associated with dyspraxia and hypotonia affecting the fine, gross, oral, and speech motor systems. Am J Med Genet A. 2018;176:201–8. [PMC free article: PMC5765401] [PubMed: 28960836]
  • Uhlén P, Fritz N, Smedler E, Malmersjö S, Kanatani S. Calcium signaling in neocortical development. Dev Neurobiol. 2015;75:360–8. [PubMed: 25652687]
  • Wiegreffe C, Simon R, Peschkes K, Kling C, Strehle M, Cheng J, Srivatsa S, Liu P, Jenkins NA, Copeland NG, Tarabykin V, Britsch S. Bcl11a (Ctip1) controls migration of cortical projection neurons through regulation of Sema3c. Neuron. 2015;87:311–25. [PubMed: 26182416]
  • Yoshida M, Nakashima M, Okanishi T, Kanai S, Fujimoto A, Itomi K, Morimoto M, Saitsu H, Kato M, Matsumoto N, Chiyonobu T. Identification of novel BCL11A variants in patients with epileptic encephalopathy: expanding the phenotypic spectrum. Clin Genet. 2018;93:368–73. [PubMed: 28589569]

Chapter Notes

Author Notes

The authors of this GeneReview clinically follow individuals with BCL11A-related intellectual disability and study the condition.

Acknowledgments

The authors would like to thank the patients and families. Cristina Dias's work is supported by the Wellcome Trust (209568/Z/17/Z).

Revision History

  • 26 September 2019 (ma) Review posted live
  • 11 February 2019 (ap, cd) Original submission
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