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 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.

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].

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 (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.

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.