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.

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 (or likely pathogenic) variant in ASXL3 by molecular genetic testing (see Table 1).

Note: (1) Per ACMG variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) 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 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.

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).

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 as a result of 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 because of 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 as a result of 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 because of 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 anti-seizure 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.

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.

Treatment of Manifestations

Surveillance

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.

Mode of Inheritance

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

Parents of a proband

• To date, most individuals with ASXL3-related disorder whose parents have undergone molecular genetic testing have the disorder as a result of a de novo ASXL3 pathogenic variant.
• Rarely, individuals diagnosed with ASXL3-related disorder have the disorder as the result of a pathogenic variant inherited from a parent.
• Molecular genetic testing is recommended for the parents of a proband to confirm their genetic status and to allow reliable recurrence risk counseling.
• If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant. Note: A pathogenic variant is reported as "de novo" if: (1) the pathogenic variant found in the proband is not detected in parental DNA; and (2) parental identity testing has confirmed biological maternity and paternity. If parental identity testing is not performed, the variant is reported as "assumed de novo" [Richards et al 2015].
  • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Sib recurrence due to presumed parental germline mosaicism has been reported in three families [Koboldt et al 2018, Schirwani et al 2020]. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism.

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

• If a parent of the proband is heterozygous for the ASXL3 pathogenic variant, the risk to the sibs of inheriting the variant is 50%.
• If the ASXL3 pathogenic variant cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism [Koboldt et al 2018, Schirwani et al 2020].

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, the parent's 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.

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.

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].

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

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