NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2021.

Cover of GeneReviews®

GeneReviews® [Internet].

Show details

ASXL3-Related Disorder

Synonym: Bainbridge-Ropers Syndrome (BRPS)

, MBBS, DCH, FRCPCH, MD and , MBChB, MSc, MRCP.

Author Information

Initial Posting: .

Estimated reading time: 23 minutes

Summary

Clinical characteristics.

ASXL3-related disorder is characterized by developmental delay or intellectual disability, typically in the moderate to severe range, with speech and language delay and/or absent speech. Affected individuals may also display autistic features. There may be issues with feeding. While dysmorphic facial features have been described, they are typically nonspecific. Affected individuals may also have hypotonia that can transition to spasticity resulting in unusual posture with flexion contractions of the elbows, wrists, and fingers. Other findings may include poor postnatal growth, strabismus, seizures, sleep disturbance, and dental anomalies.

Diagnosis/testing.

The diagnosis of ASXL3-related disorder is established in a proband by identification of a heterozygous pathogenic variant in ASXL3 by molecular genetic testing.

Management.

Treatment of manifestations: Feeding therapy; gastrostomy tube placement for those with persistent feeding issues; anti-reflux medication and/or fundoplication for those with gastroesophageal disease; standard treatment for epilepsy, joint contractures, sleep apnea, dental anomalies, strabismus and/or refractive error, and developmental delay / intellectual disability.

Surveillance: At each visit: Measurement of growth parameters and nutritional status; assessment of developmental progress, behavioral issues, new neurologic manifestations (change in tone, seizure onset and/or frequency), mobility and self-help skills, as well as signs and symptoms of sleep disturbance. Dental evaluation every six months after age three years or as clinically indicated. At least annual ophthalmology evaluation.

Genetic counseling.

ASXL3-related disorder is an autosomal dominant disorder typically caused by a de novo pathogenic variant. Rarely, individuals diagnosed with ASXL3-related disorder have the disorder as the result of a pathogenic variant inherited from a parent. If the ASXL3 pathogenic variant identified in the proband is not identified in either parent, the risk to sibs is presumed to be low but greater than that of the general population because of the possibility of parental germline mosaicism. Once the ASXL3 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

Diagnosis

Formal clinical diagnostic criteria for ASXL3-related disorder have not been established.

Suggestive Findings

ASXL-related disorder should be considered in individuals with the following clinical findings:

  • Developmental delay (DD) or intellectual disability, typically in the moderate to severe range; AND
  • Any of the following features presenting in infancy or childhood:
    • Speech and language delay and/or absent speech
    • Autism spectrum disorder or autistic traits
    • Dysmorphic facial features including prominent forehead; highly arched eyebrows; synophrys, widely spaced eyes; downslanted palpebral fissures; long, tubular nose with prominent nasal bridge; wide mouth with full, everted vermilion of the lower lip; and crowded teeth
    • Feeding difficulties
    • Hypotonia
    • Poor postnatal growth
    • Epilepsy including generalized tonic-clonic seizures and absence seizures
    • Vision impairment including strabismus
    • Skeletal findings such as Marfanoid habitus, pectus excavatum, scoliosis, arachnodactyly, and joint flexion with contractures

Establishing the Diagnosis

The diagnosis of ASXL3-related disorder is established in a proband by identification of a heterozygous pathogenic variant in ASXL3 by molecular genetic testing (see Table 1). Note: Identification of a heterozygous ASXL3 variant of uncertain significance does not establish or rule out a diagnosis of ASXL3-related disorder.

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 ASXL3, followed by gene-targeted deletion/duplication analysis) is rarely useful due to the nonspecific nature of clinical presentation and typically NOT recommended.

Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including ASXL3) that cannot be detected by sequence analysis.

An intellectual disability multigene panel that includes ASXL3 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. (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.

Comprehensive genomic testing does not require the clinician to determine which gene(s) are likely involved. Exome sequencing is most commonly used, but genome sequencing may be performed, and yields results similar to an ID multigene panel with the additional advantage that exome and genome sequencing includes genes recently identified as causing ID, whereas some multigene panels may not.

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 ASXL3-Related Disorder

Gene 1MethodProportion of Probands with a Pathogenic Variant 2 Detectable by Method
ASXL3 Sequence analysis 398%-99% 4, 5
Gene-targeted deletion/duplication analysis 61%-2% 7
CMA 8Rare 7
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. 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.

From Balasubramanian et al [2017], Kuechler et al [2017], and data derived from the subscription-based professional view of Human Gene Mutation Database [Stenson et al 2017]

5.

Most individuals so far reported with ASXL3-related disorder have truncating or splice site variants in ASXL3.

6.

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.

7.

At least two individuals in a cohort with typical ASXL3-related disorder have ASXL3 deletions identified on chromosomal microarray (CMA) [Authors, personal observation]. Both individuals had deletions that included only ASXL3 without deletion of adjacent genes.

8.

Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including ASXL3) 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 18q12.1 region. CMA designs in current clinical use target the 18q12.1 region.

Clinical Characteristics

Clinical Description

To date, 44 individuals from 40 families have been identified with a pathogenic variant in ASXL3 [Bainbridge et al 2013, Dinwiddie et al 2013, Hori et al 2016, Retterer et al 2016, Srivastava et al 2016, Balasubramanian et al 2017, Chinen et al 2017, Dad et al 2017, Kuechler et al 2017, Bacrot et al 2018, Contreras-Capetillo et al 2018, Koboldt et al 2018, Myers et al 2018a, Myers et al 2018b, Verhoeven et al 2018, Zhang et al 2018, Qiao et al 2019, Wayhelova et al 2019, Schirwani et al 2020]. The authors have collected clinical and molecular data on another 45 affected individuals in an additional cohort study that will be submitted for publication. The following description of the phenotypic features associated with this condition is based on these published reports and the additional cohort study (n=89 affected individuals).

Table 2.

Select Features of ASXL3-Related Disorder

Feature% of Persons
w/Feature
Comment
Speech delay100%Most are nonverbal or have very limited speech.
Intellectual disability99%Typically moderate to severe
Facial dysmorphism98%See Suggestive Findings.
Hypotonia86%Central hypotonia can be assoc w/↑ tone in upper & lower limbs.
Behavioral concerns78%Incl autistic traits or an ASD diagnosis
Feeding difficulties78%Most patients in the early stages are referred w/feeding difficulties & failure to thrive.
Skeletal findings74%
Eyes~50%Strabismus is the most common finding.
Seizures38%GTCS & absence seizures; most have normal brain MRI imaging.

ASD = autism spectrum disorder; GTCS = generalized tonic-clonic seizures

Speech delay. All individuals with ASXL3-related disorder have delayed speech and language development. First word was achieved in 32% of affected individuals, at an average age of 28.8 months [Authors, personal observation].

  • A majority of known individuals with ASXL3-related disorder are nonverbal.
    Use of communication devices with expert speech and language therapy input can often be helpful in these individuals to develop alternate modes of communication, as it appears that receptive language skills may be better than expressive language skills in persons with this disorder.
  • Less commonly, communication through gesture, sounds, words, and sentences has been described.

Intellectual disability (ID). A majority of the individuals with ASXL3-related disorder have developmental delay and intellectual disability that is generally moderate to severe. However, a spectrum of intellectual capabilities has been described.

  • Initial reports were of affected individuals with profound ID partly attributed to ascertainment bias; however, as more affected individuals have been identified, milder degrees of ID are being observed.
  • The authors are aware of a father and son with a paternally inherited truncating ASXL3 pathogenic variant, suggesting that a few individuals with ASXL3-related disorder may have normal cognition [Authors, personal observation].

Children with ASXL3-related disorder may be able to attend a mainstream school with dedicated support. However, so far, most individuals have required special educational provisions. The vast majority of adults described to date have required assisted living with some degree of independence.

Dysmorphic features. Individuals with ASXL3-related disorder have similar but typically nonspecific facial features (see Suggestive Findings) which are often recognized only after a diagnosis has been established.

Behavioral concerns. More than three-quarters of individuals with ASXL3-related disorder have significant behavioral, social, and communication difficulties with substantial impact on the affected individuals and their families.

  • About half of affected individuals meet the formal clinical diagnostic criteria of an autism spectrum disorder (ASD), whereas others have autistic-like features. However, others are described as having a very friendly, placid personality.
  • Other (more rarely) associated behaviors can include:
    • Hand flapping
    • Agitation
    • Motor and/or vocal tics (Tourette syndrome)
    • Hyperventilation episodes
    • Teeth grinding (bruxism)
    • Attention-deficit disorder (ADD)
    • Pica
    • Self-harm behaviors including self-biting, face scratching, and head banging
      Onset of self-injurious behavior can be as early as age two years; some individuals display this behavior later in life.

Growth. Most affected individuals display normal birth weight for gestational age but often experience poor postnatal growth due to feeding issues during infancy. During this time, growth may decline to 2 SD below the mean or more for age. Short stature is not a primary feature of ASXL3-related disorder and growth (both weight and length/height) typically stabilize or normalize after appropriate treatment of feeding issues (see following).

Feeding issues. Most individuals with ASXL3-related disorder, especially in the younger age groups, come to medical attention due to poor postnatal growth (see above) and ongoing feeding difficulties. They may display poor suck and swallow, recurrent vomiting, and gastroesophageal reflux disease.

  • Swallow studies have shown impairment of oral stage of swallowing and oral sensorimotor feeding delay characterized by oral motor weakness, reduced mastication skills for age, and suspected oral hypersensitivity. This may result in delay in weaning and food refusal behavior. Affected individuals may also have a high arched palate.
  • The severity of feeding difficulties varies considerably, with some affected children requiring long-term gastrostomy tube insertion while in others, feeding may be improved with the use of slow-flow nipples (see Treatment of Manifestations).
  • Although initial feeding issues may resolve with age, there may be ongoing difficulties with feeding due to food aversion, sensitivity to different food textures, and behavioral issues that may affect eating.

Neurologic

  • Hypotonia is a common feature in individuals with ASXL3-related disorder, especially during the neonatal period and in early infancy. Later in life, some children develop an unusual posture and contractures with elbow, wrist, and fingers held in the flexion position. This is likely due to spasticity that becomes apparent with age.
  • Seizures occur in about one third of affected individuals and can range from generalized tonic-clonic seizures to absence seizures. Seizures typically respond to standard antiepileptic medications.
  • Imaging. Most individuals with ASXL3-related disorder have normal brain imaging and do not have any characteristic brain findings.

Skeletal features. More than two thirds of individuals with ASXL3-related disorder have a skeletal abnormality. Findings may include:

  • Marfanoid habitus
  • Pectus excavatum
  • Joint hypermobility
  • Pes planus
  • Digital abnormalities including arachnodactyly, syndactyly, clinodactyly, contractures, and tapering fingers
  • Postural scoliosis (possibly due to hypotonia)
  • Delayed bone age

Sleep. Sleep disturbance is a common finding, with some affected individuals reported to have sleep apnea, for which a sleep study and further evaluation to establish a cause is warranted. Some affected individuals have abnormal breathing patterns including apnea, breath-holding episodes, and irregular breathing patterns (particularly at night) that coincide with sleep disturbances.

Eyes. Strabismus has been described in more than half of affected individuals. It can be persistent or intermittent. Some affected individuals have myopia, hyperopia, and ptosis. Visual difficulties (including astigmatism) needing correction may also be seen.

Dental. Dental abnormalities, ranging from dental overcrowding, malocclusion, and large teeth to severe hypodontia, are present in nearly 50% of individuals.

Other

  • Some affected individuals have problems with temperature regulation and are insensitive to cold/heat.
  • Altered pain perception has been described in association with this condition but is not a consistent finding.

Genotype-Phenotype Correlations

No genotype-phenotype correlations for ASXL3 have been identified.

Nomenclature

ASXL3-related disorder was first described by Bainbridge et al [2013] in four unrelated individuals with truncating variants in ASXL3; it is sometimes referred to as Bainbridge-Ropers syndrome.

Prevalence

The prevalence of ASXL3-related disorder is not known. However, to date ASXL3 is one of the top ten genes in which pathogenic variants have been found in large-scale exome sequencing studies of individuals with ID [Fitzgerald et al 2015, Wright et al 2015].

Affected individuals have been reported from all ethnicities and most have been identified in countries that undertake genomic testing in individuals with ID.

Differential Diagnosis

Because the clinical presentation of ASXL3-related disorder is typically nonspecific global developmental delay, all disorders associated 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.

Note: Heterozygous pathogenic variants ASXL1 and ASXL2, the other two genes in the ASXL gene family (see Molecular Pathogenesis), are associated with Bohring-Opitz syndrome (BOS) and Shashi-Pena syndrome, respectively. Both disorders are characterized by developmental delay but can be distinguished from ASXL3-related disorder by the characteristic facial dysmorphism associated with BOS, and by macrocephaly and abnormal brain imaging in Shashi-Pena syndrome.

Management

Consensus clinical management guidelines for ASXL3-related disorder have not been published.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with ASXL3-related disorder, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 3.

Recommended Evaluations Following Initial Diagnosis in Individuals with ASXL3-Related Disorder

System/ConcernEvaluationComment
Development Developmental assessmentTo incl motor, adaptive, cognitive, & speech/language eval
Eval for early intervention / special education
Psychiatric/
Behavioral
Neuropsychiatric evalFor persons age >12 mos: screen for behavior concerns incl sleep disturbances, ADD, &/or traits suggestive of ASD.
Constitutional Measurement of growth parametersTo evaluate for growth deficiency
Gastrointestinal/
Feeding
Gastroenterology / nutrition / feeding team evalTo incl eval of aspiration risk, GERD, & nutritional status
Consider eval for gastric tube placement in those w/dysphagia &/or aspiration risk.
Neurologic Neurologic eval
  • To incl brain MRI
  • Consider EEG if seizures are a concern.
Musculoskeletal Orthopedics / physical medicine & rehab / PT / OT evalTo incl assessment of:
  • Gross motor & fine motor skills
  • Contractures, pes planus, scoliosis & joint hypermobility
  • Mobility, activities of daily living, & need for adaptive devices
  • Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
Respiratory Assessment for sleep disturbance &/or evidence of sleep apnea
Dental Age-appropriate dental evalTo assess for malocclusion & hypodontia
Eyes Ophthalmologic evalTo assess for strabismus & ↓ vision
Miscellaneous/
Other
Consultation w/clinical geneticist &/or genetic counselorTo incl genetic counseling
Family support/resourcesAssess:

ADD = attention-deficit disorder; ASD = autism spectrum disorder; GERD = gastroesophageal reflux disease; OT = occupational therapy; PT = physical therapy

Treatment of Manifestations

Table 4.

Treatment of Manifestations in Individuals with ASXL3-Related Disorder

Manifestation/
Concern
TreatmentConsiderations/Other
DD/ID See Developmental Delay / Intellectual Disability Management Issues.
Poor weight gain /
Failure to thrive
Feeding therapy; gastrostomy tube placement may be required for persistent feeding issues.Low threshold for clinical feeding eval &/or radiographic swallowing study if clinical signs or symptoms of dysphagia
GERD Anti-reflux medication; fundoplication or percutaneous endoscopic gastrostomy in severe situationsConsider consultation w/gastroenterology specialist in those w/severe disease.
Epilepsy Standardized treatment w/AEDs by experienced neurologist
  • Many AEDs may be effective; none is demonstrated effective specifically for this disorder.
  • Education of parents/caregivers 1
Pes planus, joint
contractures,
scoliosis
Standard treatment per orthopedist
Sleep apnea Standard treatment per ENT / sleep specialist
Malocclusion
&/or hypodontia
Standard treatment per dentist/orthodontist
Strabismus &/or
refractive error
Standard treatment per ophthalmologist
Family/
Community
  • Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
  • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
  • Ongoing assessment of need for palliative care involvement &/or home nursing
  • Consider involvement in adaptive sports or Special Olympics.

AED = antiepileptic drug; DD = developmental delay; GERD = gastroesophageal reflux disease; ID = intellectual disability; OT = occupational therapy; PT = physical therapy

1.

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

Developmental Disability / 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 as well as infant mental health services, special educators, and sensory impairment specialists. In the US, early intervention is a federally funded program available in all states that provides in-home services to target individual therapy needs.

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 for those who qualify based on established motor, language, social, or cognitive delay. The early intervention program typically assists with this transition. Developmental preschool is center based; for children too medically unstable to attend, home-based services are provided.

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

  • Individualized education plan (IEP) services:
    • An IEP provides specially designed instruction and related services to children who qualify.
    • IEP services will be reviewed annually to determine whether any changes are needed.
    • As required by special education law, children should be in the least restrictive environment feasible at school and included in general education as much as possible and when appropriate.
    • Vision consultants should be a part of the child's IEP team to support access to academic material.
    • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
    • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
  • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
  • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US 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 and to reduce the risk for later-onset orthopedic complications (e.g, contractures, scoliosis, and hip dislocation).
  • Consider use of durable medical equipment and positioning devices as needed (e.g, wheelchairs, walkers, bath chairs, orthotics, and adaptive strollers).
  • For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox®, anti-parkinsonian medications, or orthopedic procedures.

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 should be assessed at each visit and clinical feeding evaluations and/or radiographic swallowing studies should be obtained for choking/gagging during feeds, poor weight gain, frequent respiratory illnesses, or feeding refusal that is not otherwise explained. Assuming that the child is safe to eat by mouth, feeding therapy (typically from an occupational or speech therapist) is recommended to help improve coordination or sensory-related feeding issues. Feeds can be thickened or chilled for safety. When feeding dysfunction is severe, an NG-tube or G-tube may be necessary.

Communication issues. Consider evaluation for alternative means of communication (e.g, Augmentative and Alternative Communication [AAC]) for individuals who have expressive language difficulties. An AAC evaluation can be completed by a speech-language pathologist who has expertise in the area. The evaluation will consider cognitive abilities and sensory impairments to determine the most appropriate form of communication. AAC devices can range from low-tech, such as picture exchange communication, to high-tech, such as voice-generating devices. Contrary to popular belief, AAC devices do not hinder verbal development of speech, and in many cases can improve it.

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 typically performed one on one with a board-certified behavior analyst.

Consultation with a developmental pediatrician 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 ASXL3-Related Disorder

System/Concern Evaluation Frequency
Development Monitor developmental progress & educational needs.At each visit
Psychiatric/
Behavioral
Behavioral assessment for attention & aggressive or self-injurious behavior
Feeding
  • Measurement of growth parameters
  • Eval of nutritional status & signs/symptoms of GERD or feeding aversion
Neurologic
  • Monitor those w/seizures as clinically indicated.
  • Assess for new manifestations incl seizures & changes in tone.
Musculoskeletal Physical medicine, OT/PT assessment of mobility, self-help skills
Respiratory Assess for signs/symptoms of sleep disturbance & sleep apnea.
Miscellaneous/
Other
Assess family need for social work support (e.g, palliative/respite care, home nursing, & other local resources) & care coordination.
Dental Eval by dentistEvery 6 mos after age 3 yrs or as clinically indicated
Eyes Ophthalmology evalAnnually or as clinically indicated

GERD = gastroesophageal disease; OT = occupational therapy; PT = physical therapy

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, mode(s) of 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; it is not meant to address all personal, cultural, or ethical issues that may arise or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

ASXL3-related disorder is an autosomal dominant disorder typically caused by a de novo pathogenic variant.

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 ASXL3-related disorder has a 50% chance of inheriting the ASXL3 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 ASXL3 pathogenic variant, his or her family members may be at risk.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic 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 Testing

Once the ASXL3 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

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.

  • ASXL Rare Research Endowment
    P.O. Box 4662
    Portland ME 04112
    Email: info@arrefoundation.org
  • ASXL3 Mutations & Bainbridge-Ropers Syndrome
  • Unique: The Rare Chromosome Disorder Support Group
    United Kingdom
    Phone: 44(0)1883 723356
    Email: info@rarechromo.org
  • Simons Searchlight Registry
    Simons Searchlight is characterizing the medical, behavioral, and learning features of individuals with specific documented genetic changes associated with autism and other neurodevelopmental disorders with the goal of improving clinical care and treatment for these individuals.
    Phone: 855-329-5638
    Fax: 570-214-7327
    Email: coordinator@simonssearchlight.org

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.

ASXL3-Related Disorder: Genes and Databases

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 ASXL3-Related Disorder (View All in OMIM)

615115ASXL TRANSCRIPTIONAL REGULATOR 3; ASXL3
615485BAINBRIDGE-ROPERS SYNDROME; BRPS

Molecular Pathogenesis

ASXL1, ASXL2, and ASXL3 are human homologs of the Drosophila additional sex combs (asx) genes that encode putative polycomb proteins and are likely to act as histone methyltransferases in complexes with other proteins [Katoh 2015]. Polycomb group proteins are implicated in embryogenesis and carcinogenesis through transcriptional regulation of target genes; ASXL1 is thought to be one of the most frequently mutated genes in malignant myeloid diseases; ASXL is a scaffold protein interacting with methyltransferases and additional proteins of the epigenetic machinery [Fisher et al 2003, Duployez et al 2016].

Truncating pathogenic variants in ASXL1 have been reported in association with Bohring-Opitz syndrome (BOS), which has phenotypic overlap with ASXL3-related disorder [Hoischen et al 2011]. More recently, truncating variants in ASXL2 were reported in association with a newly recognizable clinical phenotype [Shashi et al 2016].

ASXL3 is expressed in similar tissues to ASXL1 including brain, spinal cord, kidney, liver, and bone marrow, but at a lower level [Sahtoe et al 2016]. The high correlation of expression patterns between ASXL1 and ASXL3 may account for some of the shared phenotypic features.

Mechanism of disease causation. Loss of function

Cancer and Benign Tumors

Somatic missense variants in ASXL3 have been identified in nonsyndromic parathyroid adenomas and may contribute to simplex (a single occurrence in a family) parathyroid tumorigenesis [Wei et al 2018]. Somatic truncating variants in ASXL3 have been reported in pancreatic and prostate cancers [Micol & Abdel-Wahab 2016].

Chapter Notes

Author Notes

Dr Balasubramanian's web page: mellanbycentre.org/meena-balasubramanian

In the area of pediatric dysmorphology / genomic medicine, the author has led several studies focused on genotype-phenotype correlation in newly identified genes from next-generation sequencing studies such as the Deciphering Developmental Disorders study and has several first/senior author papers published in this area in large cohorts of individuals with new syndromal diagnoses. The author has published the largest cohort of people so far with ASXL3-related disorder and continued to gather phenotypic data on more than 70 individuals with ASXL3-related disorder. She has also written the Unique patient support group information leaflet on the condition along with Anna Pelling from Unique (www.rarechromo.org).

Acknowledgments

We would like to thank all the families and their clinicians who have thus far contributed to ongoing ASXL3 research.

Revision History

  • 5 November 2020 (ma) Review posted live
  • 21 April 2020 (mb) Original submission

References

Literature Cited

  • Bacrot S, Mechler C, Talhi N, Martin-Coignard D, Roth P, Michot C, Ichkou A, Alibeu O, Nitschke P, Thomas S, Vekemans M, Razavi F, Boutaud L, Attie-Bitach T. Whole exome sequencing diagnoses the first fetal case of Bainbridge-Ropers syndrome presenting as pontocerebellar hypoplasia type 1. Birth Defects Res. 2018;110:538–542. [PubMed: 29316359]
  • Bainbridge MN, Hu H, Muzny DM, Musante L, Lupski JR, Graham BH, Chen W, Gripp KW, Jenny K, Wienker TF, Yang Y, Sutton VR, Gibbs RA, Ropers HH. De novo truncating mutations in ASXL3 are associated with a novel clinical phenotype with similarities to Bohring-Opitz syndrome. Genome Med. 2013;5:11. [PMC free article: PMC3707024] [PubMed: 23383720]
  • Balasubramanian M, Willoughby J, Fry AE, Weber A, Firth HV, Deshpande C, Berg JN, Chandler K, Metcalfe KA, Lam W, Pilz DT, Tomkins S. Delineating the phenotypic spectrum of Bainbridge-Ropers syndrome: 12 new patients with de novo, heterozygous loss-of-function mutations in ASXL3 and review of published literature. J Med Genet. 2017;54:537–43. [PubMed: 28100473]
  • Chinen Y, Nakamura S, Ganaha A, Hayashi S, Inazawa J, Yanagi K, Nakanishi K, Kaname T, Naritomi K. 2018. Mild prominence of the Sylvian fissure in a Bainbridge-Ropers syndrome patient with a novel frameshift variant in ASXL3. Clin Case Rep. 2017;6:330–6. [PMC free article: PMC5799615] [PubMed: 29445472]
  • Contreras-Capetillo SN, Vilchis-Zapata ZH, Ribbon-Conde J, Pinto-Escalante D. Global developmental delay and postnatal microcephaly: Bainbridge-Ropers syndrome with a new mutation in ASXL3. Neurologia. 2018;33:484–6. [PubMed: 28431838]
  • Dad R, Walker S, Scherer SW, Hassan MJ, Kang SY, Minassian BA. Hyperventilation-athetosis in ASXL3 deficiency (Bainbridge-Ropers) syndrome. Neurol Genet. 2017;3:e189. [PMC free article: PMC5610043] [PubMed: 28955728]
  • Dinwiddie DL, Soden SE, Saunders CJ, Miller NA, Farrow EG, Smith LD, Kingsmore SF. De novo frameshift mutation in ASXL3 in a patient with global developmental delay, microcephaly, and craniofacial anomalies. BMC Med Genomics. 2013;6:32. [PMC free article: PMC3851682] [PubMed: 24044690]
  • Duployez N, Micol JB, Boissel N, Petit A, Geffroy S, Bucci M, Lapillonne H, Renneville A, Leverger G, Ifrah N, Dombret H, Abdel-Wahab O, Jourdan E, Preudhomme C. Unlike ASXL1 and ASXL2 mutations, ASXL3 mutations are rare events in acute myeloid leukemia with t(8;21). Leuk Lymphoma. 2016;57:199–200. [PubMed: 25856206]
  • Fisher CL, Berger J, Randazzo F, Brock HW. A human homolog of Additional sex combs, ADDITIONAL SEX COMBS-LIKE 1, maps to chromosome 20q11. Gene. 2003;306:115–26. [PubMed: 12657473]
  • Fitzgerald TW, Gerety SS, Jones WD, van Kogelenberg M, King DA, McRae J, Morley KI, Parthiban V, Al-Turki S, Ambridge K, et al. Deciphering Developmental Disorders Study: Large-scale discovery of novel genetic causes of developmental disorders. Nature. 2015;519:223–8.
  • Fu F, Li R, Lei TY, Wang D, Yang X, Han J, Pan M, Zhen L, Li J, Li FT, Jing XY, Li DZ, Liao C. Compound heterozygous mutation of the ASXL3 gene causes autosomal recessive congenital heart disease. Hum Genet. 2020. Epub ahead of print. [PubMed: 32696347]
  • Hoischen A, Van Bon BW, Rodriguez-Santiago B, Gilissen C, Vissers LE, De Vries P, Janssen I, Van Lier B, Hastings R, Smithson SF, Newbury-Ecob R, Kjaergaard S, Goodship J, Mcgowan R, Bartholdi D, Rauch A, Peippo M, Cobben JM, Wieczorek D, Gillessen-Kaesbach G, Veltman JA, Brunner HG, De Vries BB. De novo nonsense mutations in ASXL1 cause Bohring-Opitz syndrome. Nat Genet. 2011;43:729–31. [PubMed: 21706002]
  • Hori I, Miya F, Ohashi K, Negishi Y, Hattori A, Ando N, Okamoto N, Kato M, Tsunoda T, Yamasaki M, Kanemura Y, Kosaki K, Saitoh S. Novel splicing mutation in the ASXL3 gene causing Bainbridge-Ropers syndrome. Am J Med Genet A. 2016;170:1863–7. [PubMed: 27075689]
  • Katoh M. Functional proteomics of the epigenetic regulators ASXL1, ASXL2 and ASXL3: a convergence of proteomics and epigenetics for translational medicine. Expert Rev Proteomics. 2015;12:317–28. [PubMed: 25835095]
  • Koboldt DC, Mihalic Mosher T, Kelly BJ, Sites E, Bartholomew D, Hickey SE, Mcbride K, Wilson RK, White P. A de novo nonsense mutation in ASXL3 shared by siblings with Bainbridge-Ropers syndrome. Cold Spring Harb Mol Case Stud. 2018;4:a002410. [PMC free article: PMC5983172] [PubMed: 29305346]
  • Kuechler A, Czeschik JC, Graf E, Grasshoff U, Huffmeier U, Busa T, Beck-Woedl S, Faivre L, Riviere JB, Bader I, Koch J, Reis A, Hehr U, Rittinger O, Sperl W, Haack TB, Wieland T, Engels H, Prokisch H, Strom TM, Ludecke HJ, Wieczorek D. Bainbridge-Ropers syndrome caused by loss-of-function variants in ASXL3: a recognizable condition. Eur J Hum Genet. 2017;25:183–191. [PMC free article: PMC5255962] [PubMed: 27901041]
  • Micol JB, Abdel-Wahab O. The role of additional sex combs-like proteins in cancer. Cold Spring Harb Perspect Med. 2016;6:a026526. [PMC free article: PMC5046687] [PubMed: 27527698]
  • Myers KA, White SM, Mohammed S, Metcalfe KA, Fry AE, Wraige E, Vasudevan PC, Balasubramanian M, Scheffer IE. Childhood-onset generalized epilepsy in Bainbridge-Ropers syndrome. Epilepsy Res. 2018a;140:166–70. [PubMed: 29367179]
  • Myers KA, White SM, Mohammed S, Metcalfe KA, Fry AE, Wraige E, Vasudevan PC, Balasubramanian M, Scheffer IE. Corrigendum to "Childhood-onset generalized epilepsy in Bainbridge-Ropers syndrome". Epilepsy Res. 2018b;147:121. [Epilepsy Res. 2018;140:166-70] [PubMed: 30104120]
  • Qiao L, Liu Y, Ge J, Li T. Novel Nonsense Mutation in ASXL3 causing Bainbridge-Ropers Syndrome. Indian Pediatr. 2019;56:792–4. [PubMed: 31638014]
  • Retterer K, Juusola J, Cho MT, Vitazka P, Millan F, Gibellini F, Vertino-Bell A, Smaoui N, Neidich J, Monaghan KG, Mcknight D, Bai R, Suchy S, Friedman B, Tahiliani J, Pineda-Alvarez D, Richard G, Brandt T, Haverfield E, Chung WK, Bale S. Clinical application of whole-exome sequencing across clinical indications. Genet Med. 2016;18:696–704. [PubMed: 26633542]
  • Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–24. [PMC free article: PMC4544753] [PubMed: 25741868]
  • Sahtoe DD, Van Dijk WJ, Ekkebus R, Ovaa H, Sixma TK. BAP1/ASXL1 recruitment and activation for H2A deubiquitination. Nat Commun. 2016;7:10292. [PMC free article: PMC4729829] [PubMed: 26739236]
  • Schirwani S, Hauser N, Platt A, Punj S, Prescott K, Canham N, Mansour S, Balasubramanian M, et al. Mosaicism in ASXL3-related syndrome: Description of five patients from three families. Eur J Med Genet. 2020;6:103925. [PubMed: 32240826]
  • Shashi V, Pena LD, Kim K, Burton B, Hempel M, Schoch K, Walkiewicz M, Mclaughlin HM, Cho M, Stong N, Hickey SE, Shuss CM, Undiagnosed Diseases N, Freemark MS, Bellet JS, Keels MA, Bonner MJ, El-Dairi M, Butler M, Kranz PG, Stumpel CT, Klinkenberg S, Oberndorff K, Alawi M, Santer R, Petrovski S, Kuismin O, Korpi-Heikkila S, Pietilainen O, Aarno P, Kurki MI, Hoischen A, Need AC, Goldstein DB, Kortum F. De Novo Truncating Variants in ASXL2 Are Associated with a Unique and Recognizable Clinical Phenotype. Am J Hum Genet. 2016;99:991–9. [PMC free article: PMC5065681] [PubMed: 27693232]
  • Srivastava A, Ritesh KC, Tsan YC, Liao R, Su F, Cao X, Hannibal MC, Keegan CE, Chinnaiyan AM, Martin DM, Bielas SL. De novo dominant ASXL3 mutations alter H2A deubiquitination and transcription in Bainbridge-Ropers syndrome. Hum Mol Genet. 2016;25:597–608. [PMC free article: PMC4731023] [PubMed: 26647312]
  • Stenson PD, Mort M, Ball EV, Evans K, Hayden M, Heywood S, Hussain M, Phillips AD, Cooper DN. The Human Gene Mutation Database: towards a comprehensive repository of inherited mutation data for medical research, genetic diagnosis and next-generation sequencing studies. Hum Genet. 2017;136:665–77. [PMC free article: PMC5429360] [PubMed: 28349240]
  • Verhoeven W, Egger J, Rakers E, Van Erkelens A, Pfundt R, Willemsen MH. Phenotypic characterization of an older adult male with late-onset epilepsy and a novel mutation in ASXL3 shows overlap with the associated Bainbridge-Ropers syndrome. Neuropsychiatr Dis Treat. 2018;14:867–70. [PMC free article: PMC5877499] [PubMed: 29628764]
  • Wayhelova M, Oppelt J, Smetana J, Hladilkova E, Filkova H, Makaturova E, Nikolova P, Beharka R, Gaillyova R, Kuglik P. Novel de novo frameshift variant in the ASXL3 gene in a child with microcephaly and global developmental delay. Mol Med Rep. 2019;20:505–12. [PMC free article: PMC6579994] [PubMed: 31180560]
  • Wei Z, Sun B, Wang ZP, et al. Whole-exome sequencing identifies novel recurrent somatic mutations in sporadic parathyroid adenomas. Endocrinology. 2018;159:3061–8. [PubMed: 29982334]
  • Wright CF, Fitzgerald TW, Jones WD, Clayton S, Mcrae JF, Van Kogelenberg M, King DA, Ambridge K, Barrett DM, Bayzetinova T, Bevan AP, Bragin E, Chatzimichali EA, Gribble S, Jones P, Krishnappa N, Mason LE, Miller R, Morley KI, Parthiban V, Prigmore E, Rajan D, Sifrim A, Swaminathan GJ, Tivey AR, Middleton A, Parker M, Carter NP, Barrett JC, Hurles ME, Fitzpatrick DR, Firth HV, et al. Genetic diagnosis of developmental disorders in the DDD study: a scalable analysis of genome-wide research data. Lancet. 2015;385:1305–14. [PMC free article: PMC4392068] [PubMed: 25529582]
  • Zhang R, He XH, Lin HY, Yang XH. Zhonghua Er Ke Za Zhi. 2018;56:138–141. [Bainbridge-Ropers syndrome with ASXL3 gene variation in a child and literature review] [PubMed: 29429203]
Copyright © 1993-2021, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.

GeneReviews® chapters are owned by the University of Washington. Permission is hereby granted to reproduce, distribute, and translate copies of content materials for noncommercial research purposes only, provided that (i) credit for source (http://www.genereviews.org/) and copyright (© 1993-2021 University of Washington) are included with each copy; (ii) a link to the original material is provided whenever the material is published elsewhere on the Web; and (iii) reproducers, distributors, and/or translators comply with the GeneReviews® Copyright Notice and Usage Disclaimer. No further modifications are allowed. For clarity, excerpts of GeneReviews chapters for use in lab reports and clinic notes are a permitted use.

For more information, see the GeneReviews® Copyright Notice and Usage Disclaimer.

For questions regarding permissions or whether a specified use is allowed, contact: ude.wu@tssamda.

Bookshelf ID: NBK563693PMID: 33151654

Views

Tests in GTR by Gene

Related information

  • OMIM
    Related OMIM records
  • PMC
    PubMed Central citations
  • PubMed
    Links to PubMed
  • Gene
    Locus Links

Similar articles in PubMed

See reviews...See all...

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...