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 and preimplantation genetic testing are possible.

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 (or likely pathogenic) variant in ARID1B by molecular genetic testing (see Table 1).

Note: 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.

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.

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 anti-seizure medications. 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].

ARID1B Coffin Siris Syndrome (ARID1B-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 without other distinctive findings should be considered in the differential diagnosis. See OMIM Autosomal Dominant, Autosomal Recessive, Nonsyndromic X-Linked, and Syndromic X-Linked Intellectual Developmental Disorder Phenotypic Series.

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.

Treatment of Manifestations

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.

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

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.

Mode of Inheritance

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

Risk to Family Members

Parents of a proband

• Most probands reported to date with ARID1B-RD whose parents have undergone molecular genetic testing have the disorder as a result of a de novo ARID1B pathogenic variant.
• Parental transmission of ARID1B pathogenic variants has been reported in two families in which the phenotype in the proband and the transmitting parent was consistent with ARID1B-RD; in both families, the transmitting parent was mildly affected [Mignot et al 2016, Smith et al 2016].
• Molecular genetic testing is recommended for the parents of a proband with an apparent de novo pathogenic variant.
• If the ARID1B pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the pathogenic variant most likely occurred de novo in the proband. Another possible explanation is that the proband inherited a pathogenic variant from a parent with germline mosaicism (parental germline mosaicism has been reported [Ben-Salem et al 2016]).
• The family history of some individuals diagnosed with ARID1B-RD may appear to be negative because of failure to recognize the disorder in family members; given the variability in the ARID1B-RD phenotype, a parent may be heterozygous for an ARID1B pathogenic variant while being only mildly affected [Santen, personal observation]. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has been performed on the parents of the proband.
• Theoretically, if the parent is the individual in whom the ARID1B pathogenic variant first occurred, the parent may have somatic mosaicism for the variant and may be mildly/minimally affected.

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 has the ARID1B pathogenic variant, the risk to the sibs of inheriting the variant is 50%.
• If the ARID1B pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is approximately 1%-2%, and therefore greater than that of the general population because of the possibility of parental germline mosaicism [Ben-Salem et al 2016].

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, 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 ARID1B pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing 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 use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

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.

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.

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 (humandiseasegenes.nl/arid1b) 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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