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Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2019.

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ARID1B-Related Disorder

, MD, , MSc, and , MD, PhD.

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Estimated reading time: 23 minutes

Summary

Clinical characteristics.

ARID1B-related disorder (ARID1B-RD) constitutes a clinical continuum, from classic Coffin-Siris syndrome to intellectual disability with or without nonspecific dysmorphic features. Coffin-Siris syndrome is classically characterized by aplasia or hypoplasia of the distal phalanx or nail of the fifth and additional digits, developmental or cognitive delay of varying degree, distinctive facial features, hypotonia, hypertrichosis, and sparse scalp hair. Frequencies of other features, such as developmental delay (with speech often more affected than motor development), is consistent across the clinical spectrum, and may include malformations of the cardiac, gastrointestinal, genitourinary, and/or central nervous systems. Other findings seen in individuals with ARID1B-RD include feeding difficulties, slow growth, ophthalmologic abnormalities, hearing impairment, seizures, attention-deficit/hyperactivity disorder, and autistic features.

Diagnosis/testing.

The diagnosis of ARID1B-RD is established by identification of a heterozygous pathogenic variant in ARID1B by molecular genetic testing.

Management.

Treatment of manifestations: Standard treatment for strabismus, refractive error, hearing loss, congenital heart defects, obstructive sleep apnea, constipation, gastroesophageal reflux, cryptorchidism, scoliosis, and seizure disorders. For significant feeding issues, a nasogastric and/or gastrostomy tube may be required. Developmental therapies, including speech/language and feeding therapy, is recommended for those with developmental delay.

Surveillance: At least annual assessment of developmental progress and educational needs; annual ophthalmology evaluation and assessment for scoliosis (until growth is complete). Audiology evaluation, behavior assessment, and hormonal evaluation/bone age as needed based on symptoms. Those with seizures should be monitored as clinically indicated.

Genetic counseling.

ARID1B-related disorder is inherited in an autosomal dominant fashion. With the exception of two families in which a parent and child had features consistent with ARID1B-related disorder, all individuals diagnosed to date have the disorder as the result of a de novo pathogenic variant. Once the ARID1B pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible.

GeneReview Scope

ARID1B-Related Disorder: Included Phenotypes 1
  • ARID1B intellectual disability
  • ARID1B intellectual disability with nonspecific dysmorphic features
  • ARID1B Coffin-Siris syndrome 2
1.

For other genetic causes of these phenotypes see Differential Diagnosis.

2.

Diagnosis

Heterozygous pathogenic variants in ARID1B lead to a phenotypic spectrum, from Coffin-Siris syndrome (CSS) (with dysmorphic features and/or organ system involvement) to intellectual disability with or without nonspecific dysmorphic features. See Coffin-Siris Syndrome for more information.

Note: The information presented in the Coffin-Siris syndrome GeneReviews chapter includes information on individuals with CSS from a variety of genetic causes including ARID1B but is not specific to individuals with a pathogenic variant in ARID1B.

Suggestive Findings

ARID1B Coffin-Siris syndrome (ARID1B-CSS) should be suspected in individuals with the following findings [Fleck et al 2001, Schrier et al 2012, Kosho et al 2014, Santen et al 2014]:

  • Fifth-digit nail and/or distal phalanx hypoplasia (although other digits may be affected) OR aplasia of the hands or feet
  • Developmental or cognitive delay of variable degree
  • Typical facial features including a wide mouth with thick, everted vermilion of the upper and lower lips, broad nasal bridge with broad nasal tip, thick eyebrows, and long eyelashes
  • Central hypotonia
  • Hypertrichosis in atypical areas (e.g., the back) or excessive hair growth on the arms or face
  • Sparse scalp hair, especially in infancy, particularly in the temporal regions

Though admittedly a large group, ARID1B intellectual disability with or without nonspecific dysmorphic features (ARID1B-ID) should be considered in individuals presenting with the following clinical findings:

  • Mild-to-profound developmental delay (DD) and/or intellectual disability (ID)
    AND
  • Any of the following features presenting in infancy or childhood:
    • Generalized hypotonia of infancy
    • Infant feeding difficulties
    • Spasticity
    • Epilepsy (predominately tonic-clonic)
    • Behavior problems, such as attention-deficit/hyperactivity disorder (ADHD) and autistic features
    • Cryptorchidism
    • Laryngomalacia
    • Myopia
    • Delayed speech development
    • Suggestive dysmorphic features (see Clinical Description)

Establishing the Diagnosis

The diagnosis of an ARID1B-related disorder is established in a proband with suggestive clinical features by identification of a heterozygous pathogenic variant in ARID1B by molecular genetic testing (see Table 1).

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing or multigene panel) and comprehensive genomic testing (chromosomal microarray analysis and exome sequencing) depending on the phenotype.

Classic ARID1B Coffin-Siris Syndrome

When the phenotypic findings suggest the diagnosis of ARID1B-CSS, molecular genetic testing approaches can include single-gene testing or use of a multigene panel:

  • Single-gene testing. Sequence analysis of ARID1B detects small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. Perform sequence analysis first. If no pathogenic variant is found, perform gene-targeted deletion/duplication analysis to detect intragenic or whole-gene deletions or duplications.
  • A Coffin-Siris syndrome multigene panel that includes ARID1A, ARID1B, ARID2, DPF2, PHF6, SMARCA2, SMARCA4, SMARCB1, SMARCE1, SOX11, and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition 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.

ARID1B Intellectual Disability with or without Nonspecific Dysmorphic Features

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:

  • Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP (single-nucleotide polymorphism) arrays to detect genome-wide large deletions/duplications (including ARID1B) that may not be detected by sequence analysis.
  • An intellectual disability multigene panel that includes ARID1B and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition in a person with a non-diagnostic 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 this disorder an intellectual disability multigene panel that also includes deletion/duplication analysis is recommended (see Table 1).
    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 two advantages: (1) a multigene panel may not include all rare genes recently identified as causing ID; and (2) exome sequencing may be able to detect pathogenic variants in genes which – for technical reasons – do not sequence well.
    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 ARID1B-Related Disorder

Gene 1PhenotypeMethodProportion of Probands with a Pathogenic Variant 2 Detectable by Method
ARID1BCoffin-Siris syndromeSequence analysis 371/80 4
Gene-targeted deletion/duplication analysis 59/80 6
ARID1B intellectual disabilitySequence analysis 354/63 7, 8
CMA 99/63 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. 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.

Microdeletions of chromosome 6q25.3 that include ARID1B have been reported in: (a) children with CSS ascertained prior to the understanding of the molecular basis of CSS [Tsurusaki et al 2012]; (b) children ascertained with a microdeletion containing ARID1B and secondarily noted to have features similar to CSS [Santen et al 2012]; and (c) individuals with mildly or variably syndromic intellectual disability [Nagamani et al 2009, Halgren et al 2012, Hoyer et al 2012, Michelson et al 2012] for whom available clinical information is insufficient to determine the similarity to CSS. Of note, these individuals may have complex clinical findings due to the involvement of additional genes surrounding the ARID1B locus.

7.
8.

Although the Santen et al [2013] study included sequence analysis results of individuals with clinical features of Coffin-Siris syndrome, it is the only study where all affected individuals underwent both MLPA and sequencing analysis, and therefore likely reflects the mutational spectrum best.

9.

Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including ARID1B) 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 6q25.3 region. CMA designs in current clinical use target the 6q25.3 region.

Clinical Characteristics

Clinical Description

Most individuals with a heterozygous pathogenic variant in ARID1B have some features consistent with Coffin-Siris syndrome.

Note: (1) The Coffin-Siris syndrome GeneReviews chapter includes information on individuals with CSS from a variety of genetic causes including ARID1B but is not specific to individuals with a pathogenic variant in ARID1B. (2) Approximately 1/2 to 2/3 of individuals with molecularly confirmed CSS have a pathogenic variant in ARID1B [van der Sluijs et al 2019]. More data are needed to determine which CSS features are found more or less frequently in individuals with a pathogenic variant in ARID1B.

To date, approximately 100 individuals who do not have the classic Coffin-Siris syndrome phenotype have been identified with a heterozygous pathogenic variant in ARID1B [Santen et al 2013, Santen et al 2014, Ben-Salem et al 2016, Mannino et al 2018, van der Sluijs et al 2019].

A comparison between individuals with a heterozygous pathogenic variant in ARID1B with an a priori clinical diagnosis of CSS and a group without the a priori clinical diagnosis suggests that apart from CSS-specific features (hypo/aplasia of the fifth digits or nails of the hands/feet, sparse scalp hair, coarse facial features, hypertrichosis) there are no major differences between the two groups [van der Sluijs et al 2019]. Therefore, the Authors treat them as a single entity, ARID1B-related disorder (ARID1B-RD).

Developmental delay (DD) and intellectual disability (ID). Intellectual disability ranges from profound to very mild, and intelligence quotients (IQs) in the normal range have been identified in some individuals with ARID1B-RD. Most affected individuals have developmental delay, with speech often more affected than motor development. An estimated 25% of affected individuals do not develop verbal language skills [van der Sluijs et al 2019].

Neurologic/epilepsy

  • Hypotonia is a frequent finding (40%-80% of affected individuals).
  • Epilepsy. Approximately one third of individuals with ARID1B-RD have experienced seizures, predominately of the tonic-clonic type. Additional individuals may have abnormal EEGs without apparent clinical seizure activity. Those with overt seizures appear to respond well to standard antiepileptic drugs. The age of onset of seizures ranges from birth to mid-teenage years [van der Sluijs et al 2019].

Behavior problems. Individuals with ARID1B-RD appear to be at increased risk for a diagnosis of ADHD or autism, but the overall prevalence is not known, as many individuals now receiving the diagnosis at a younger age may not yet be old enough to evaluate for certain neurodevelopmental abnormalities. There does not appear to be an increased prevalence of self-harm, aggression, or sleep disturbances. Some behavior abnormalities may be exacerbated by an individual's degree of speech delay and difficulty with communication.

Growth. There are limited data regarding prenatal growth in individuals with ARID1B-RD. Postnatal growth data show the following:

  • Weight may be normal or below average but appears to be in proportion to other growth parameters.
  • The majority of affected individuals appear to have a length/height 0 to 2 SD below the mean; data are not sufficient to predict final adult height.
    Bone age appears to be delayed in approximately 50% of individuals who have been evaluated.
  • Head circumference is normal in a majority of individuals with ARID1B-RD.

Gastrointestinal problems. Feeding difficulties are common and appear to approximate those seen in individuals with a diagnosis of CSS from a variety of genetic causes.

  • Individuals with feeding difficulties commencing around the time of birth appear to have more severe issues and tend to require a feeding tube of some type (nasogastric or gastrostomy tube).
  • In older children, milder feeding difficulties may occur, including oral aversion, particularly in those who required tube feeding as an infant or younger child.
  • Constipation and gastroesophageal reflux disease are also common and may approximate that seen in individuals with CSS or other genetic syndromes with varying degrees of neurologic impairment [Mannino et al 2018].

Sensory impairment

  • Approximately 25%-30% of affected individuals have some vision abnormality, although this frequency may not be significantly different from that of individuals with CSS from a variety of genetic causes [Mannino et al 2018]. The most frequently reported abnormalities include myopia, strabismus, and astigmatism.
  • Similarly, 25%-40% of affected individuals have some degree of hearing loss, the most common being congenital sensorineural hearing loss, although conductive hearing loss has also been reported [Mannino et al 2018, van der Sluijs et al 2019]. The range of severity of sensorineural hearing loss is not precisely known.

Neuroimaging. Of those individuals who have undergone brain imaging, approximately 30%-40% demonstrate brain anomalies. The most common abnormality is hypo- or aplasia of the corpus callosum [van der Sluijs et al 2019]. Delayed myelination or other white matter changes, colpocephaly, mega cisterna magna, and enlarged Virchow-Robin spaces are also seen. Additional brain abnormalities may be detected as more individuals undergo imaging.

Other associated features

  • Respiratory abnormalities. Laryngomalacia has been documented, although it does not appear to occur more frequently than in individuals with CSS due to a variety of genetic causes [Mannino et al 2018, van der Sluijs et al 2019]. Asthma and obstructive sleep apnea have also been reported but may approximate the frequency of the general population.
  • Genitourinary (GU) abnormalities. The most commonly reported GU abnormality appears to be cryptorchidism in males; structural renal abnormalities have been seen but the frequency of specific malformations is not known.
  • Musculoskeletal. Scoliosis is seen with greater frequency than in the general population and may be acquired as affected individuals age. Shortened fifth digits or hypoplastic nails in the hands or feet may also be seen, as these are classically associated with CSS.
  • Dysmorphic features. Affected individuals may have some features also seen in individuals with CSS from a variety of genetic causes, including sparse scalp hair, long eyelashes, hypertrichosis, and coarse facial features; more specifically, individuals may have thick alae nasi, a long philtrum, and a thick vermilion of the lower lip.

Prognosis. It is unknown if life span in individuals with ARID1B-RD is abnormal. One reported individual is alive at age 51 years [Santen, personal observation], and a woman age 60 years has also been reported [Määttänen et al 2018], 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

To date, only loss-of-function variants (e.g., nonsense, splice site, frameshift, whole-gene deletions) cause ARID1B-RD. Missense variants do not appear to be pathogenic in general; however, a single missense variant in a proband (who had agenesis of the corpus callosum [ACC]) and the proband's mother (who did not have ACC but had mild ID) was described as de novo in the mother [Mignot et al 2016].

There do not appear to be specific genotype-phenotype correlations among individuals with ARID1B-related disorder to distinguish individuals with ARID1B intellectual disability with or without nonspecific dysmorphic features (ARID1B-ID) from those with ARID1B Coffin-Siris syndrome (ARID1B-CSS).

Prevalence

This condition is estimated to occur in approximately 1:10,000 to 1:100,000 individuals [Hoyer et al 2012].

Differential Diagnosis

ARID1B Coffin Siris Syndrome (ARID1B-CSS)

Table 2.

Other Disorders to Consider in the Differential Diagnosis of ARID1B Coffin-Siris Syndrome (CSS)

Differential Diagnosis DisorderGene(s) /
Genetic Mechanism
MOIClinical Features of Differential Diagnosis Disorder
Overlapping w/ARID1B-CSSDistinguishing from ARID1B-CSS
Coffin-Siris syndrome caused by genes other than ARID1BARID1A
DPF2
SMARCC2
SMARCA4
SMARCB1
SMARCE1
SOX11
ADFrequently clinically indistinguishable from ARID1B-CSSMicrocephaly seen more frequently in individuals w/a heterozygous pathogenic variant in SMARCB1 or SMARCE1
Nicolaides-Baraitser syndromeSMARCA2AD
  • Characteristic coarse facial features
  • Sparse scalp hair
  • ID
  • Prominence of interphalangeal joints & distal phalanges due to ↓ subcutaneous fat
  • Absence of 5th-digit nail / distal phalanx hypo/aplasia
Borjeson-Forssman-Lehmann syndrome
(OMIM 301900)
PHF6XLAffected females demonstrate some phenotypic overlap w/CSS, incl hypoplastic nails & fingers, sparse hair, & intellectual disability. 1, 2
  • Other digital anomalies incl tapering of digits, hammer toes, syndactyly of toes
  • Distinct facial gestalt incl prominent supraorbital ridges, deeply set eyes, prominent nasal bridge, short nose w/bulbous nasal tip
ARID2-ID
(OMIM 617808)
ARID2AD
  • Hypotonia
  • Behavior anomalies
  • Very mild hypoplasia of 5th fingernails & hypoplasia of 5th toenails in some individuals
  • Facies: coarse features, flat nasal bridge, slightly broad nose, prominent philtrum, & large mouth w/thick lower vermilion 3
  • ID
Birth defects not common
DOORS (deafness, onychodystrophy, osteodystrophy, mental retardation, & seizures) syndrome
(see TBC1D24-Related Disorders)
TBC1D24AR
  • Hypoplastic terminal phalanges &/or nail anomalies
  • Deafness
  • Neurologic abnormalities
  • ID
  • Osteodystrophy
  • Profound hearing loss (can occasionally occur in ARID1B-CSS)
Mabry syndrome
(OMIM 239300)
PIGVAR
  • Delayed development & ID
  • Seizures
  • Coarse facial features
  • Hypoplastic 5th digits
↑ serum concentrations of alkaline phosphatase
Cornelia de Lange syndromeHDAC8
NIPBL
RAD21
SMC1A
SMC3
AD,
XL
  • Limb anomalies may incl 5th-finger hypoplasia.
  • ID
  • Other findings may incl cardiac defects, gastrointestinal anomalies, & genitourinary malformations.
Distinctive craniofacial features (arched eyebrows, synophrys, upturned nose, small teeth, & microcephaly)
4q21 deletion syndrome
(OMIM 613509)
Contiguous-gene deletionAD 1
  • Curved, volar, 5th-digit nail that may resemble a hypoplastic distal phalanx
  • ID
  • Facial gestalt may include broad forehead, widely spaced eyes, & frontal bossing.
  • Postnatal growth restriction may be severe.

AD = autosomal dominant; AR = autosomal recessive; CSS = Coffin-Siris syndrome; ID = intellectual disability; MOI = mode of inheritance; XL = X-linked

1.

To date, all reported probands have had the disorder as the result of a de novo deletion.

2.
3.

While some of these features demonstrate overlap with CSS, an assessment of a larger cohort of individuals with ARID2 pathogenic variants will be needed to determine whether it is clinically similar to or distinct from CSS.

The following genetic and teratogenic disorders may also be considered in the differential diagnosis of ARID1B-CSS:

  • Mosaic trisomy 9. An individual with mosaic trisomy 9 had features similar to those of CSS, including facial features (wide, bulbous nose), hirsutism, and hypoplasia of the fifth digits [Kushnick & Adessa 1976].
  • Brachymorphism-onychodysplasia-dysphalangism (BOD) syndrome (OMIM 113477) is characterized by short stature, tiny dysplastic nails, short fifth fingers, a wide mouth with broad nose, and mild intellectual deficits [Verloes et al 1993, Elliott & Teebi 2000]. This latter characteristic is most likely to distinguish individuals with BOD syndrome from those with CSS, as the cognitive disability in CSS is nearly always moderate to severe. Inheritance appears to be autosomal dominant.
  • Fetal alcohol syndrome (FAS). Small nails, prenatal and postnatal growth retardation, dysmorphic facial features, and cognitive disabilities may be seen in FAS.
  • Fetal hydantoin/phenytoin embryopathy. Small nails with hypoplasia of distal phalanges, dysmorphic facial features, digitalized thumbs, low hairline, short or webbed neck, growth retardation, and cognitive disabilities have been described in this syndrome, caused by prenatal exposure to phenytoin.

ARID1B Intellectual Disability with or without Nonspecific Dysmorphic Features

Because the phenotypic features associated with ARID1B-ID are not sufficiently distinctive 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.

Management

Evaluations Following Initial Diagnosis of ARID1B-Related Disorders

To establish the extent of disease and needs in an individual diagnosed with ARID1B-RD, the evaluations summarized in Table 2 (if not performed as part of the evaluation that led to diagnosis) are recommended. Note that some evaluations depend on whether the clinician thinks that the affected individual has ARID1B-CCS or ARID1B-ID.

Table 3.

Recommended Evaluations Following Initial Diagnosis in Individuals with ARID1B-RD

System/ConcernEvaluationComment
EyesOphthalmologic evaluationAssess for myopia, astigmatism, & strabismus.
ENTAudiologic evaluationAssess for hearing loss (even if newborn hearing screen is normal).
CardiovascularCardiology evaluation
  • ARID1B-CSS: Echocardiogram to evaluate for structural cardiac defects
  • ARID1B-ID: Consider an echocardiogram in infancy. 1, 2
RespiratoryAssess for signs & symptoms of obstructive sleep apnea.If present, consider ENT or sleep clinic evaluation &/or polysomnography.
Gastrointestinal/
Feeding
Assess growth parameters.Consider bone age studies or other hormonal assessments if individual has short stature ↓ predicted mid-parental height.
Assess feeding & nutritional status.Refer to gastroenterologist or feeding specialist, as needed, for persistent feeding issues.
GenitourinaryAssess males for cryptorchidism.Urologic evaluation if cryptorchidism present
Renal ultrasoundTo evaluate for occult renal malformations
MusculoskeletalClinical assessment for scoliosisConsider referral to orthopedist, if severe
NeurologicNeurologic evaluationIncl EEG & brain MRI, if indicated.
Psychiatric/
Behavioral
Neuropsychiatric evaluationScreen individuals age >12 mos for behavior concerns incl ADHD &/or traits suggestive of ASD.
Miscellaneous/
Other
Consultation w/clinical geneticist or genetic counselor
Developmental assessmentIncl evaluation of motor, speech/language, general cognitive, & vocational skills.

ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder

1.

An echocardiogram is recommended for those individuals with ARID1B-CSS. Although cardiac anomalies have not been described in individuals with ARID1B-ID, they can be a component of mild ARID1B-CSS and therefore a cardiology evaluation should be considered [Mannino et al 2018].

2.

Echocardiogram may not be warranted in older children without obvious cardiovascular signs or symptoms based on exam.

Treatment of Manifestations

Table 4.

Treatment of Manifestations in Individuals with ARID1B-RD

Manifestation/ConcernTreatmentConsiderations/Other
Abnormal vision &/or strabismusStandard treatment(s) as recommended by ophthalmologist
Hearing lossStandard therapy based on the type of hearing loss detectedSee Hereditary Hearing Loss and Deafness Overview
Congenital heart defectsStandard treatment
Obstructive sleep apneaStandard treatment
Feeding difficultiesNasogastric or gastrostomy tube may be required.Evaluation by a gastroenterologist &/or feeding specialist
Low threshold for clinical feeding evaluation &/or radiographic swallowing study when showing clinical signs or symptoms of dysphagia or feeding aversion
Constipation &/or GERDStandard therapy
Cryptorchidism / Renal anomaliesStandard treatment per urologist/nephrologist, as appropriate
ScoliosisBracing or casting as indicated by orthopedist
Seizures 1Standardized treatment w/AEDs by experienced neurologistMany different AEDs may be effective; no one AED has been demonstrated effective specifically for this disorder.

AEDs = antiepileptic drugs; GERD = gastroesophageal reflux disease

1.

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

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

Developmental Disability / Intellectual Disability Educational Issues

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. Before entering school, a neuropsychiatric evaluation may be of benefit to identify additional barriers to learning and other opportunities for assistance (i.e., identification of ADHD or autism spectrum traits).

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, 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. Some issues to consider:

  • 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.
  • 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/standers or gait trainers, 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. If 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. A swallow study may be necessary prior to initiation of oral feeds to evaluate for aspiration.

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 Difficulties

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 may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat 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 ARID1B-RD

System/ConcernEvaluationFrequency
ConstitutionalGrowth parametersAt each visit
EyesOphthalmologic evaluationAnnually
ENTAudiologic evaluationAs required
MusculoskeletalClinical assessment for scoliosisAnnually, until growth is complete
NeurologicMonitor those w/seizures as clinically indicated.As needed
PsychiatricBehavior assessment for anxiety, attention, & aggressive or self-injurious behaviorAs needed
EndocrineHormonal evaluation 1 &/or bone age studiesAs needed
Miscellaneous/OtherMonitor developmental progress & educational needs.Annually
1.

To assess for poor growth velocity and/or short stature; specific hormonal evaluations depend on the clinical scenario but could include thyroid function tests and evaluation of growth-specific factors (e.g., IGF1 and IGFBP3 levels).

Evaluation of Relatives at Risk

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

Therapies Under Investigation

Celen et al [2017] demonstrated potential response to growth hormone in ARID1B-haploinsufficient mice, although there have not been sufficient studies in humans with pathogenic ARID1B variants who are receiving growth hormone clinically to determine if this therapy is of benefit in increasing final adult height and improving muscle tone.

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

ARID1B-related disorder (ARID1B-RD) is inherited in an autosomal dominant manner.

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 ARID1B-RD has a 50% chance of inheriting the ARID1B 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 ARID1B 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 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 ARID1B 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.

No specific resources for ARID1B-Related Disorder have been identified by GeneReviews staff.

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.

ARID1B-Related Disorder: Genes and Databases

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
ARID1B6q25​.3AT-rich interactive domain-containing protein 1BARID1B @ LOVDARID1BARID1B

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 ARID1B-Related Disorder (View All in OMIM)

135900COFFIN-SIRIS SYNDROME 1; CSS1
614556AT-RICH INTERACTION DOMAIN-CONTAINING PROTEIN 1B; ARID1B

Molecular Pathogenesis

The ARID1B protein serves the largest alternating subunit of the SWI/SNF complex, along with ARID1A. It functions as a primary chromatin remodeler, regulating gene transcription and protein-protein interactions, and acts as a tumor suppressor [Santen et al 2012, Bögershausen & Wollnik 2018]. Despite this fact, no increased incidence above the general population risk of tumor development has been found in individuals with ARID1B-related disorder and no tumor screening protocols are currently recommended (see Genetically Related Disorders and Cancer and Benign Tumors).

Gene structure. ARID1B encodes a 20-exon gene.

See Table A, Gene for a detailed summary of gene and protein information.

Benign variants. Exon 3 is a small (14-amino acid), in-frame exon that is present in transcript NM_020732.3 but not NM_017519.2. Loss-of-function variants have not been reported in this exon and may be benign; therefore, caution must be used in interpreting variants in this exon [Santen, personal communication].

Pathogenic variants. The vast majority of reported pathogenic variants are truncating (nonsense, frameshift, splice site, single-exon, multiexon, and whole-gene deletions).

A c.1259delA maternally inherited deletion has been reported in two probands – one de novo and one maternally inherited [Smith et al 2016].

Loss-of-function variants associated with CSS are rarely seen at the 5' end of ARID1B. The most 5' pathogenic variant described is a de novo nonsense variant, c.850C>T (p.Gln284Ter), in exon 1 [Santen, personal communication].

In addition, microdeletions and nonsense variants have been reported in several individuals with nonspecific intellectual disability. However, evaluation of several of these subjects revealed some mild overlap with CSS features suggesting a range of clinical features for individuals with haploinsufficiency of ARID1B [Hoyer et al 2012, Santen et al 2014]. Other than subjects with large microdeletions including additional genes having additional phenotypes, there is currently no clear genotype-phenotype correlation, suggesting the involvement of other phenotypic modifiers.

Table 6.

Pathogenic ARID1B Variants Discussed in This GeneReview

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.850C>Tp.Gln284TerNM_020732​.3
NP_065783​.3
c.1259delAp.Asn420IlefsTer10

Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. The ARID1B protein contains 2,249 amino acids (NP_065783.3) and is a component of the SWI/SNF chromatin remodeling complex, possibly playing a role in cell-cycle activation. ARID1B is similar to ARID1A, and the two proteins function as alternative, mutually exclusive ARID subunits of the SWI/SNF complex. The associated complexes play opposing roles in some contexts.

Abnormal gene product. Loss of ARID1B expression appears to result in aberrant chromatin remodeling, causing downstream dysregulation of further genes and resulting in the ARID1B-RD or CSS phenotype.

Cancer and Benign Tumors

Both somatic deletions and mutations of ARID1B have been reported in a small number of cases of childhood neuroblastoma in individuals without features of ARID1B-RD [Sausen et al 2013]. However, no individuals with germline pathogenic ARID1B variants are known to have neuroblastoma; therefore, there are currently no screening recommendations.

References

Literature Cited

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Chapter Notes

Author Notes

Dr Samantha Schrier Vergano is a clinical geneticist at the Children's Hospital of The King's Daughters in Norfolk, Virginia. Her primary research interest is Coffin-Siris syndrome. She runs an international IRB-approved registry for the condition. For more information, please visit www.coffinsiris.org or email her at gro.dkhc@onagreV.ahtnamaS.

Dr Gijs Santen is a clinical geneticist at the Leiden University Medical Center striving to improve clinical delineation of Coffin-Siris syndrome. He has a registry for individuals with pathogenic variants in ARID1B (www.arid1bgene.com) and runs a CSS clinic in The Netherlands.

Revision History

  • 23 May 2019 (ma) Review posted live
  • 26 July 2018 (sv, gs) Original submission
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