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Coffin-Siris Syndrome

Synonym: Fifth Digit Syndrome

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

Author Information and Affiliations

Initial Posting: ; Last Update: May 15, 2025.

Estimated reading time: 46 minutes

Summary

Clinical characteristics.

Classically, Coffin-Siris syndrome (CSS) was characterized by specific dysmorphic features (coarse facies, sparse scalp hair, thick eyebrows with long lashes, wide nasal bridge with broad nasal tip, anteverted nares with thick ala nasi, wide mouth with thick, everted vermilion of the upper and lower lips, and hypertrichosis), the absence or underdevelopment of the fifth digit finger/toe or nail, learning and developmental differences, and various organ system-related anomalies. As genetic technology has evolved, more individuals with subtle physical exam findings are being diagnosed with CSS. The vast majority of affected individuals have developmental delay / intellectual disability, typically in the moderate-to-severe range, although those with mild cognitive impairment or even normal intelligence have more rarely been described. Most affected individuals have feeding difficulties (with ~25%-50% requiring a feeding tube in childhood, some of whom then outgrow it), hypotonia, and frequent infections. About half of affected individuals have epilepsy. Other findings may include skeletal features (joint laxity, scoliosis), hearing impairment (both conductive and sensorineural), eye issues (ptosis, strabismus), congenital heart defects, genitourinary malformations, and behavioral issues (including hyperactivity and/or aggressiveness).

Diagnosis/testing.

The diagnosis of CSS is established in a proband with suggestive findings and a heterozygous pathogenic variant in one of the following 14 known genes identified by molecular genetic testing: ARID1A, ARID1B, ARID2, BICRA, DPF2, PHF6, SMARCA2, CMARCA4, SMARCB1, SMARCC2, SMARCD1, SMARCE1, SOX4, or SOX11.

Management.

Treatment of manifestations: Feeding therapy with consideration of placement of gastrostomy tube in those with persistent feeding issues. Standard treatment for developmental delay / intellectual disability, epilepsy, tics, sleep disturbance, scoliosis, joint laxity, knee subluxations, obesity, refractive error, strabismus, ptosis, hearing loss, congenital heart defects, undervirilization, inguinal hernia, frequent infections, and hepatoblastoma.

Surveillance: At each visit, measurement of growth parameters; evaluation of nutrition status and safety of oral intake; assessment for new neurologic manifestations, such as seizures or tics; monitoring of developmental progress and educational needs; behavioral assessment for anxiety, ADHD, ASD, aggression, & self-injury; monitoring for signs and symptoms of sleep disturbance; evaluation for mobility and self-help skills; and assessment for signs and symptoms of frequent infections. Annually or as clinically indicated, ophthalmology evaluation and vision assessment; audiology evaluation. At least every six months in those with teeth, dental evaluation. In those with ARID1A-related CSS: serum AFP level (with consideration of liver ultrasound) every three months until age four years.

Genetic counseling.

CSS is inherited in an autosomal dominant manner; however, most affected individuals have the disorder as the result of a de novo CSS-causing pathogenic variant. If the CSS-causing pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Diagnosis

No consensus clinical diagnostic criteria for Coffin-Siris syndrome (CCS) have been published.

Suggestive Findings

CSS should be suspected in individuals with the following clinical findings and family history:

Clinical findings

  • Facial features (see Figure 1A, 1B, 1C) including:
    • Coarse facies
    • Sparse scalp hair, particularly in the temporal regions, especially in infancy
    • Thick eyebrows
    • Long eyelashes
    • Wide nasal bridge with broad nasal tip
    • Anteverted nares with thick ala nasi
    • A wide mouth with thick, everted vermilion of the upper and lower lips suggestive of coarseness
  • Fifth digit nail / distal phalanx hypoplasia/aplasia (Figure 1D, 1E, 1F, 1G)
  • Hirsutism/hypertrichosis. Hair growth in atypical areas (e.g., the back) or excessive hair growth on the arms or face
  • Central hypotonia
  • Developmental delay (DD) or intellectual disability (ID) of variable degree, most typically in the moderate-to-severe range
Figure 1.

Figure 1.

Coffin-Siris syndrome classic features Facial features in a one-year-old girl (A), a young adult female (B), and a young adult male (C). Coarse facial features are evident in A but tend to become more apparent as individuals age; these may include thick (more...)

Family history. Because CSS is typically caused by a de novo pathogenic variant, most probands represent a simplex case (i.e., a single occurrence in a family). Rarely, the family history may be consistent with autosomal dominant inheritance (e.g., affected males and females in multiple generations).

Establishing the Diagnosis

The diagnosis of CSS is established in a proband with suggestive findings and a heterozygous pathogenic (or likely pathogenic) variant in one of the genes listed in Table 1 identified by molecular genetic testing.

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of a heterozygous variant of uncertain significance (VUS) in one of the genes listed in Table 1 does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see Option 1), whereas comprehensive genomic testing does not (see Option 2).

Option 1

When the phenotypic findings suggest the diagnosis of CSS, molecular genetic testing approaches can include use of a multigene panel.

A multigene panel that includes some or all of the genes listed in Table 1 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition while limiting identification of pathogenic variants and variants of uncertain significance 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.

Option 2

When the diagnosis of CCS has not been considered because an individual has atypical phenotypic features, comprehensive genomic testing may be considered.

Comprehensive genomic testing does not require the clinician to determine which gene is likely involved. Exome sequencing is most often used; genome sequencing is also possible.

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 Coffin-Siris Syndrome

Gene 1, 2Proportion of CSS Attributed to Pathogenic Variants in GeneProportion of Pathogenic Variants 3 Identified by Method
Sequence analysis 4Gene-targeted deletion/duplication analysis 5
ARID1A <5%100% 6Unknown 7
ARID1B ~37%~95%~5% 8
ARID2 Rare 9100%Unknown 7
BICRA Rare 10~97%Rare
DPF2 Rare 11100%Unknown 7
PHF6 12Rare 13100%Unknown 7
SMARCA2 14~2%>90%1 affected person
SMARCA4 ~7%100%Unknown 7, 15
SMARCB1 ~7%100%Unknown 7, 15
SMARCC2 Rare 16~75%Unknown 16
SMARCD1 Rare 17100%Unknown 17
SMARCE1 ~2%100%Unknown 7, 15
SOX4 Rare 18100%Unknown 7
SOX11 ~2% 19~40% 20>10 persons have been described 21
Unknown 22~40%NA

NA = not applicable

1.

Genes are listed in alphabetic order.

2.
3.

See Molecular Genetics for information on variants detected in this gene.

4.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.

6.

Mosaic pathogenic variants have been noted for ARID1A [Santen et al 2013, Wieczorek et al 2013].

7.

No data on detection rate of gene-targeted deletion/duplication analysis are available.

8.

Small deletions 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 small deletion 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.

9.

Only seven individuals with pathogenic variants in this gene have been reported [Gazdagh et al 2019].

10.
11.

Fewer than ten affected individuals have been identified with pathogenic variants in this gene [Milone et al 2020].

12.

Individuals initially ascertained with CSS when younger have been found to have pathogenic variants in PHF6. Most of these have acquired facial features more consistent with Borjeson-Forssman-Lehmann syndrome as they age [Wieczorek et al 2013] (see Differential Diagnosis).

13.

Only two affected individuals with a CCS phenotype have been reported to have pathogenic variants in this gene [Wieczorek et al 2013].

14.

Reevaluation of an individual initially thought to have CSS concluded that findings were more consistent with Nicolaides-Baraitser syndrome [Tsurusaki et al 2012, Van Houdt et al 2012]; however, since a number of individuals with SMARCA2 pathogenic variants were initially ascertained with CSS, the authors have included them (see Differential Diagnosis).

15.

Evidence indicates that pathogenic variants in SMARCA4, SMARCB1, and SMARCE1 act through a gain-of-function mechanism, suggesting that large pathogenic deletions or duplications are unlikely to occur; however, in-frame deletions or duplications of relevant domains may be pathogenic; one such deletion in SMARCA4 has been reported (see Molecular Genetics).

16.

Approximately 80 individuals have been identified to date, and SMARCC2 is now listed in OMIM as a CSS-related gene [Bosch et al 2023].

17.
18.

Only four individuals with a CSS phenotype have been reported to have pathogenic variants in this gene [Zawerton et al 2019].

19.
20.
21.
22.

Approximately 40% of individuals with CSS do not have a pathogenic variant in one of the known genes [Tsurusaki et al 2012, Santen et al 2013, Wieczorek et al 2013, Tsurusaki et al 2014b, Sekiguchi et al 2019].

Epigenetic signature analysis / methylation array. A distinctive epigenetic signature (disorder-specific genome-wide changes in DNA methylation profiles) in peripheral blood leukocytes has been identified in individuals with Coffin-Siris syndrome [Trajkova et al 2024]. Epigenetic signature analysis of a peripheral blood sample or DNA banked from a blood sample can therefore be considered to clarify the diagnosis in individuals with: (1) suggestive findings of Coffin-Siris syndrome but in whom no pathogenic variant in one of the genes in Table 1 has been identified via sequence analysis or genomic testing; or (2) suggestive findings of Coffin-Siris syndrome and a variant of uncertain clinical significance in one of the genes listed in Table 1 identified by molecular genetic testing. For an introduction to epigenetic signature analysis click here.

Clinical Characteristics

Clinical Description

The clinical manifestations of Coffin-Siris syndrome have expanded over the years as greater phenotypic variability has been recognized. Classically, the syndrome was first identified by the absence or underdevelopment of the fifth digit finger/toe or nail. Additional "classic" features have included sparse scalp hair, hypertrichosis, learning and developmental differences, and various organ system-related anomalies. As genetic technology has evolved, more individuals with subtle physical exam findings are being diagnosed with CSS.

To date, at least 550 individuals have been identified with a diagnosis of Coffin-Siris syndrome, including those enrolled in the Coffin-Siris syndrome / BAF complex registry [Wieczorek et al 2013; Kosho et al 2014; Santen et al 2014; Ciliberto et al 2023; Schmetz et al 2024; Schrier Vergano 2024; S Schrier Vergano, unpublished data]. ARID1B has been reported in around 1% of cohorts of individuals with neurodevelopmental disorder [Hoyer et al 2012]. The following description of the phenotypic features associated with this condition is based on these reports.

Table 2.

Select Features of Coffin-Siris Syndrome

Feature% of Persons w/FeatureComment
Developmental delay / intellectual disability98%Typically in the moderate-to-severe range
Feeding problems90%
Hypotonia75%
Hypoplasia of the fifth digits/nails 165%-80%Some individuals with a molecularly confirmed diagnosis of CSS have little or no fifth digit involvement.
Dysmorphic facial features65%~30% at birth. Because facial features typically coarsen over time, the characteristic facies may not be apparent until later in childhood.
Frequent infections60%
Other skeletal findings40%-60%Including joint laxity and scoliosis
Epilepsy50%
Hearing impairment45%Both sensorineural and conductive hearing loss has been reported.
Eye issues~40%Ptosis, strabismus, myopia
Congenital heart defects35%
Genitourinary malformations33%
Behavioral issues25%May include hyperactivity &/or aggressiveness
1.

Typically, individuals with a clinical diagnosis of CSS have either aplasia or hypoplasia of the distal phalanx or absence of the nail, classically involving the fifth finger, but other digits may also be affected. Toes can also be affected, where the finding tends to involve multiple digits.

Dysmorphic facial features typically prompt consideration of this diagnosis (see Suggestive Findings and Figures 1A, 1B, 1C).

Developmental delay (DD) and intellectual disability (ID). Intellectual disability is present in most and is typically moderate to severe (IQ range: 40 to 69); however, IQ as high as 97 has been reported [Santen et al 2012]. Ranges of IQ/DQ (developmental quotient) may depend on the gene involved and the degree of other medical challenges (see Phenotype Correlations by Gene).

While formal studies of IQ have not yet been conducted, those who have been tested range from mild to severe depending on the gene (i.e., individuals with ARID2-related CSS tend to range from mild to moderate) [Schrier Vergano 2024].

  • On average, children with CSS learn to sit at 12 months, walk at 30 months, and speak their first words at 24 months.
  • Expressive language is more severely affected than receptive language, with no speech in about 12% of individuals (median age: 10 years). A review of language acquisition in registry-enrolled individuals reported by Vasko & Schrier Vergano [2022] identified that:
    • 26% of individuals had normal speech development (words by 18 months)
    • <1% had mild development delay (speech by 19-21 months)
    • 13% had moderate speech delay (speech by 22-25 months)
    • 60% had severe speech delay (speech after 25 months)
  • In a study of 35 adult individuals with CSS, only one presented with absence of ID [Schmetz et al 2024].

Other neurodevelopmental features

  • Hypotonia is usually noted in infancy and is typically persistent, although some affected individuals experience improvement with age and therapies.
  • Infant feeding difficulties may be due to an oral aversion or difficulty feeding in the absence of any evident intestinal malformations. Approximately 25%-50% of reported individuals used a feeding tube, some of whom grew out of it [Mannino et al 2018] (see Management).

Epilepsy/tics. Both seizures and tics have been described in affected individuals. Seizure frequency may be as high as 38% but has varied depending on the age of the cohort [Ciliberto et al 2023]. A variety of seizure types have been reported. There is no typical age of onset for seizures or tics. Seizures can begin even in the teenage years, and some affected individuals may begin experiencing seizures after puberty. The majority of affected individuals who develop seizures appear to respond to traditional anti-seizure medication [Ciliberto et al 2023] (see Management).

Neurobehavioral/psychiatric manifestations. Autism has been reported in as high as 44% of individuals, although as with many features, the true prevalence may be underestimated depending on the age of the individual and available testing/evaluations [Vasko & Schrier Vergano 2022]. Behavioral abnormalities include hyperactivity (~10%), aggressiveness (~10%), and attention-deficit/hyperactivity disorder (25%).

Sleep disturbances are not uncommon but the prevalence of certain conditions like narcolepsy and restless leg syndrome are unknown. Many families report disrupted sleep, particularly in individuals with a concomitant diagnosis of autism.

Skeletal findings. The most striking clinical feature of CCS is the finding of small nails on the fifth finger or toe, affecting about 40% of individuals. Individuals with a diagnosis of CSS have either aplasia or hypoplasia of the distal phalanx or absence of the nail, typically involving the fifth finger, but other digits may also be affected. Toes can also be affected, where the finding tends to involve multiple digits. As the phenotype expands, more individuals with pathogenic variants in the BAF complex do not have the classic digit findings (see Molecular Pathogenesis).

Other skeletal findings can include the following:

  • Joint laxity (66%). Some individuals may have an increased prevalence of knee subluxations [van der Sluijs et al 2024].
  • Scoliosis (30%-40%). This appears to be primarily neuromuscular in origin. If present, it should continue to be monitored by primary providers with a referral to an orthopedist if it is rapidly progressive or impacting respiratory efforts (see Management).
  • Delayed bone age (40%)
  • Fifth digit clinodactyly of the hands

Skin and hair findings

  • Hypertrichosis (95%) may appear in areas unexpected for an individual's ancestry (i.e., back, shoulders).
  • A low anterior hairline is common (75%).
  • Sparse scalp hair (60%), particularly involving the temporal region. Hair may appear at an appropriate age but may be very thin.
  • Hernias (10%)

Growth issues/dental. Weight and height is below the 50th centile for most, and below the 5th centile for 20%-35% of affected individuals. Nineteen of 35 adult individuals with CSS were reported to have obesity [Schmetz et al 2024].

  • Bone age typically lags about two to three years behind chronologic age.
  • Primary and secondary dentition is delayed in about 40% of affected individuals.

Hearing impairment (15%-45%) is often associated with recurrent upper respiratory tract infections. Both sensorineural and conductive hearing loss has been reported, although conductive hearing loss occurs more often due to frequent infections or small ear canals. A minority of individuals with hearing loss need hearing aids (see Management).

Ophthalmologic abnormalities can include ptosis (50%), strabismus (50%), and/or myopia (20%). In a cohort of 35 adults, 29 had ophthalmic issues [Schmetz et al 2024].

Frequent infections. These are poorly characterized but are often consistent with upper respiratory viral infections. While some individuals with CSS have undergone immunology testing, there do not appear to be consistent defects in cellular immunity. Much of the frequency of illnesses may be attributed to overall hypotonia and difficult with clearing of secretions.

Other associated features

  • Cardiac anomalies have been reported in about one third of affected individuals and have included ventricular septal defects, atrial septal defects, tetralogy of Fallot, and patent ductus arteriosus.
  • Renal and genitourinary malformations can include cryptorchidism (in males) most commonly, but also horseshoe kidney, hypospadias, and other abnormalities.
  • Neuroimaging. Central nervous system malformations can include Dandy-Walker variant, gyral simplification, and agenesis of the corpus callosum.

Tumor risk. Although pathogenic variants in a subset of the genes causing CSS have been implicated in tumorigenesis, data on tumor risk in CSS are lacking. Tumors have been reported in individuals with CSS, but not all cases are connected to the constitutional CSS genetic change. In a cohort of 35 adults with CSS, no one had a malignancy [Schmetz et al 2024]. Apart from hepatoblastoma screening, routine cancer surveillance is not recommended.

  • Pathogenic variants in ARID1A have been associated with a number of cases of hepatoblastoma, and the frequency is estimated to be about 3.6% [Tsurusaki et al 2012, Kosho et al 2014, Cárcamo et al 2022, Borja et al 2023, van der Sluijs et al 2023]. As this frequency appears to exceed the recommended 1% screening threshold for hepatoblastoma in the United States, consideration of alpha-fetoprotein levels (AFPs) every three months may be warranted (see Management).
  • An individual with a 4.2-Mb deletion that included (among 14 genes) ARID1B developed papillary thyroid cancer [Vengoechea et al 2014]. However, given the large number of individuals reported with ARID1B pathogenic variants with no subsequent reports of thyroid cancer, the authors feel that it is unlikely that there is a strong relationship between the two.
  • Multiple studies have reported the same single individual who has CSS, schwannomatosis, and a pathogenic variant in SMARCB1 [Carter et al 2012, Schrier et al 2012, Gossai et al 2015]. Formal screening recommendations have not been developed at this time, but clinicians should be aware of the possibility of schwannomas in individuals with a pathogenic variant in SMARCB1.

Prognosis. In the absence of long-term studies, information on life span in individuals with CSS is not available. Children have been reported to succumb to aspiration pneumonia and/or seizures, although this is not common [Schrier et al 2012]. As with any rare conditions, individuals with tracheostomies or needing respiratory support may have higher mortality at younger ages.

It is unknown whether life span in CSS is abnormal. One reported individual is alive at age 69 years [Määttänen et al 2018], demonstrating that survival into adulthood is possible. Schmetz et al [2024] reported 35 individuals aged 18 to 37 years, and van der Sluijs et al [2024] reported a large cohort of adults with CSS aged 18-69 years. Since many adults with disabilities have not undergone advanced genetic testing, it is likely that adults with this condition are underrecognized and underreported.

Phenotype Correlations by Gene

Phenotype correlations by gene have been seen in individuals with pathogenic variants in ARID1A, ARID1B, ARID2, BICRA, DPF2, SMARCA4, SMARCB1, SMARCE1, SOX4, and SOX11 [Wieczorek et al 2013, Kosho et al 2014, Santen et al 2014, Tsurusaki et al 2014a, Hempel et al 2016, Vasileiou et al 2018, Gazdagh et al 2019, Machol et al 2019, Zawerton et al 2019, Bosch et al 2023, Schmetz et al 2024].

ARID1A. Heterozygous pathogenic variants in ARID1A have been associated with a number of cases of hepatoblastoma; the risk is estimated to be about 3.6% (see Clinical Description, Tumor risk).

ARID1B. Individuals with a pathogenic variant in ARID1B are typically at the milder end of the spectrum of CSS and often have normal growth. Moderately severe feeding problems are noted in two thirds, seizures in one third, and hypoplasia of the corpus callosum in one third of affected individuals. Facial gestalt is consistent with CSS, albeit at times milder.

ARID2. Affected individuals typically do not have significant birth defects but may have short stature, mild-to-moderate learning and developmental differences, and hypotonia. Hip dysplasia appears more common in individuals with ARID2-related CCS than in those with CSS due to other genes [Schrier Vergano 2024].

BICRA. A small cohort of individuals with a pathogenic variant in BICRA have been reported; individuals appear to have moderate-to-severe developmental delay / intellectual disability with autism, seizures, and behavioral challenges. However, one affected individual with a heterozygous pathogenic variant in BICRA has been reported with normal intelligence. Classic CSS features, such as digital anomalies, have not been consistently reported.

DPF2. Individuals with a pathogenic variant in DPF2 tend to have mild-to-moderate learning and developmental differences, as well as some classic CSS features including digital anomalies and coarse facial features.

SMARCA4. Individuals with a pathogenic variant in SMARCA4 appear to have growth impairment that is mild prenatally and mild to moderate postnatally; sucking/feeding difficulty is almost always observed. While individuals can sometimes have severe developmental delays, significant behavioral challenges tend to be more characteristic. Facial features have demonstrated less coarseness, while hypoplastic fifth fingers or toes and hypoplastic fifth fingernails or toenails are a near-constant finding (with hypoplasia of other fingernails or toenails being an occasional finding). Prominence of interphalangeal joints and distal phalanges is also noted in some affected individuals.

SMARCB1. Individuals with a pathogenic variant in SMARCB1 typically are more severely affected; all have growth impairment (usually noted as mild prenatally and moderate to severe postnatally) with sucking/feeding difficulties. Structural central nervous system abnormalities with hypotonia and seizures are typical findings, accompanied by severe developmental delay / intellectual disability. Affected individuals are usually nonverbal. Typical skeletal findings include hypoplastic fifth fingers or toes, hypoplastic other fingernails or toenails, prominent distal phalanges, and scoliosis. Some individuals may walk independently. Gastrointestinal complications and hernia as well as cardiovascular and genitourinary complications are common.

SMARCE1. Individuals with pathogenic SMARCE1 variants tend to have severe intellectual disability, typical facial gestalt, and hypoplastic or absent fifth finger- and toenails associated with hypoplasia of other nails. The hands are characterized by long and slender fingers. Individuals are typically small for gestational age and have postnatal short stature and severe microcephaly, complex congenital heart defects, feeding difficulties, and seizures.

SOX4. Severely affected individuals may show neurologic complications including hypotonia, spastic quadriparesis, and epilepsy.

SOX11. Neurodevelopmental abnormalities tend to be more prevalent than organ system or physical complications, but cohort studies have identified idiopathic hypogonadotropic hypogonadism and physical features including microcephaly and short stature, with some researchers suggesting that it may represent a separate neurodevelopmental condition [Al-Jawahiri et al 2022].

Genotype-Phenotype Correlations

No clinically relevant genotype-phenotype correlations have been identified for ARID1A, ARID2, BICRA, DPF2, PHF6, SMARCA2, SMARCA4, SMARCB1, SMARCC2, SMARCD1, SMARCE1, SOX4, or SOX11.

ARID1B. Affected individuals with a pathogenic variant in exon 1 of ARID1B may have a milder phenotype. Although some individuals with this type of pathogenic variant have features that are indistinguishable from those with pathogenic variants in the other exons of ARID1B, other individuals with pathogenic variants in exon 1 have very mild clinical features. Inheritance from apparently unaffected parents has been occasionally described in individuals who have a pathogenic variant in exon 1, although usually parents who have undergone more thorough phenotyping may be found to also be mildly affected. This has not been described up to now for pathogenic variants in the other exons (see ARID1B-Related Disorder).

Prevalence

More than 530 individuals with molecularly confirmed CSS have been reported (per the CSS registry). Rough estimates suggest a possible frequency of one in 100,000 births based on known cases, indicating that the diagnosis is still rare. True prevalence is likely higher.

In addition, the identification of a pathogenic variant in ARID1B in some members of a large cohort with intellectual disability [Hoyer et al 2012] suggests that the prevalence of pathogenic variants in genes associated with CSS (and possibly of subtle phenotypic features of CSS) may be higher than currently appreciated among those with apparently nonsyndromic intellectual disability.

Differential Diagnosis

Genes of interest in the differential diagnosis of Coffin-Siris syndrome (CSS) are listed in Table 4.

Table 4.

Genes of Interest in the Differential Diagnosis of Coffin-Siris Syndrome

Gene(s)DisorderMOIClinical CharacteristicsComment
BRD4
HDAC8
NIPBL
RAD21
SMC1A
SMC3
Cornelia de Lange syndrome (CdLS)AD
XL 1
Severe (classic) CdLS is characterized by distinctive facial features, growth restriction, hypertrichosis, & upper limb reduction defects that range from subtle phalangeal abnormalities to oligodactyly (missing digits).CdLS-related limb anomalies may incl 5th finger hypoplasia similar to CSS.
PHF6 Borjeson-Forssman-Lehmann syndrome (OMIM 301900)XLSee Genetically Related Disorders.See Genetically Related Disorders.
PIGV Mabry syndrome (OMIM 239300)ARDD, seizures, coarse facial features, hypoplastic 5th digits, & ↑ serum concentrations of ALP
SMARCA2 Nicolaides-Baraitser syndrome (NCBRS)ADSee Genetically Related Disorders.See Genetically Related Disorders.
TBC1D24 DOORS syndrome (See TBC1D24-Related Disorders.)ARDeafness, onychodystrophy, osteodystrophy, ID, & seizuresFeatures in common w/CSS incl hypoplastic terminal phalanges &/or nail anomalies, deafness, & neurologic abnormalities.

AD = autosomal dominant; ALP = alkaline phosphatase; AR = autosomal recessive; CSS = Coffin-Siris syndrome; DD = developmental delay; ID = intellectual disability; MOI = mode of inheritance; XL = X-linked

1.

NIPBL-, RAD21-, SMC3-, and BRD4-related CdLS are inherited in an autosomal dominant manner; HDAC8- and SMC1A-related CdLS are inherited in an X-linked manner.

2.
3.

Other conditions with limb/nail abnormalities in the differential diagnosis of CSS:

  • 4q deletion syndrome. This chromosome deletion syndrome results in a characteristic curved, volar fifth digit nail, which may resemble a hypoplastic distal phalanx [Vogt et al 2006].
  • Brachymorphism-onychodysplasia-dysphalangism (BOD) syndrome (OMIM 113477), a disorder of unknown genetic cause, is characterized by short stature, tiny dysplastic nails, short fifth fingers, a wide mouth with broad nose, and mild intellectual deficits. 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.
  • Fetal alcohol spectrum disorder (FASD). Small nails, prenatal and postnatal growth restriction, dysmorphic facial features, and cognitive disabilities may be seen in FASD.
  • Fetal hydantoin/phenytoin embryopathy. Small nails with hypoplasia of distal phalanges, dysmorphic facial features, digitalized thumbs, low hairline, short or webbed neck, growth restriction, and cognitive disabilities have been described in this syndrome, caused by prenatal exposure to phenytoin.

Management

Several publications have recommended various medical surveillance guidelines for individuals with Coffin-Siris syndrome (CSS) [Mannino et al 2018, Schrier Vergano 2024, van der Sluijs et al 2024]. However, as clinical variability between individuals is high, clinicians are encouraged to use their own clinical judgment when evaluating and managing these individuals.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with CSS, the evaluations summarized in Table 5 (if not performed as part of the evaluation that led to diagnosis) are recommended.

Table 5:

Coffin-Siris Syndrome: Recommended Evaluations Following Initial Diagnosis

System/ConcernEvaluationComment
Constitutional Measurement of growth parametersTo assess for growth restriction or poor growth in younger persons & obesity in adults
Neurologic Neurologic eval to incl assessment for signs & symptoms of seizures/tics
  • To incl brain MRI if clinically indicated
  • Consider EEG if seizures are a concern.
Development Developmental assessment
  • To incl motor, adaptive, cognitive, & speech-language eval
  • Eval for early intervention / special education
Neurobehavioral/
Psychiatric
Neuropsychiatric evalFor persons age >12 mos: screening for concerns incl ADHD, aggression, &/or findings suggestive of ASD
Respiratory Assessment for signs & symptoms of sleep disturbanceConsider referral to sleep medicine clinic &/or sleep study.
Musculoskeletal Orthopedics / physical medicine & rehab / PT & OT evalTo incl assessment of:
  • Gross motor & fine motor skills
  • Mobility, ADL, & need for adaptive devices
  • Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
  • Assessment for signs & symptoms of knee subluxation, joint laxity, & scoliosis
Gastrointestinal/
Feeding
Gastroenterology / nutrition / feeding team eval
  • To incl eval of aspiration risk, oral aversion, & nutritional status
  • Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk.
Eyes Ophthalmologic evalTo assess for ptosis, strabismus, & refractive errors
Hearing Audiologic evalTo assess for hearing loss
ENT/Mouth Dental evalIn those who have teeth
Cardiovascular EchocardiogramTo assess for congenital heart defects
Genitourinary Renal ultrasoundTo assess for structural renal anomalies
Assessment for undervirilization in males & inguinal herniaConsider referral to urologist or general surgeon, respectively.
Immunologic Assessment for signs & symptoms of recurrent infectionsConsider referral to immunologist w/frequent or unusual infections (recurrent pneumonia, skin infections, etc.).
Oncology Consider baseline ultrasound of liver & serum AFP levelTo evaluate for hepatoblastoma in those who have a heterozygous pathogenic variant in ARID1A
Genetic counseling By genetics professionals 1To obtain a pedigree & inform affected persons & their families re nature, MOI, & implications of CSS to facilitate medical & personal decision making
Family support
& resources
By clinicians, wider care team, & family support organizationsAssessment of family & social structure to determine need for:

ADHD = attention-deficit/hyperactivity disorder; AFP = alpha-fetoprotein; ADL = activities of daily living; ASD = autism spectrum disorder; CSS = Coffin-Siris syndrome; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy

1.

Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)

Treatment of Manifestations

There is no cure for CSS. Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 6).

Table 6.

Coffin-Siris Syndrome: Treatment of Manifestations

Manifestation/ConcernTreatmentConsiderations/Other
Developmental delay /
Intellectual disability /
Neurobehavioral issues
See Developmental Delay / Intellectual Disability Management Issues.
Epilepsy Standardized treatment w/ASM by experienced neurologist
  • Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
  • Education of parents/caregivers 1
Tics Standard treatment per neurologist
Sleep disturbance Standard treatment per sleep medicine specialist
Scoliosis, joint laxity, knee subluxation Orthopedist / physical medicine & rehab / PT & OTConsider need for positioning & mobility devices, disability parking placard.
Poor weight gain / Oral aversion
  • Feeding therapy
  • Gastrostomy tube placement may be required for persistent feeding issues.
Low threshold for clinical feeding eval &/or radiographic swallowing study when showing clinical signs or symptoms of dysphagia
Obesity Standard treatment per nutritionistMay develop in adults
Refractive errors, strabismus, ptosis Standard treatment per ophthalmologist
Hearing loss Standard treatment per otolaryngologist & audiologist
Hearing aids may be helpful.Community hearing services through early intervention or school district
Congenital heart defects Standard treatment per cardiologist
Undervirilization & inguinal hernia Standard treatment per urologist or general surgeon, respectively
Frequent infections Standard treatment per primary care physicianConsider referral to immunologist w/frequent or unusual infections (recurrent pneumonia, skin infections, etc.).
Hepatoblastoma Standard treatment per oncologistThis is a rare complication & is assoc specifically w/a pathogenic variant in ARID1A.
Family/Community
  • Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
  • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
  • Ongoing assessment of need for palliative care involvement &/or home nursing
  • Consider involvement in adaptive sports or Special Olympics.

ASM = anti-seizure medication; OT = occupational therapy; PT = physical therapy

1.

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

Developmental Delay / Intellectual Disability Management Issues

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

Ages 0-3 years. Referral to an early intervention program is recommended for access to occupational, physical, speech, and feeding therapy as well as infant mental health services, special educators, and sensory impairment specialists. In the US, early intervention is a federally funded program available in all states that provides in-home services to target individual therapy needs.

Ages 3-5 years. In the US, developmental preschool through the local public school district is recommended. Before placement, an evaluation is made to determine needed services and therapies and an individualized education plan (IEP) is developed for those who qualify based on established motor, language, social, or cognitive delay. The early intervention program typically assists with this transition. Developmental preschool is center based; for children too medically unstable to attend, home-based services are provided.

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

  • IEP services:
    • An IEP provides specially designed instruction and related services to children who qualify.
    • IEP services will be reviewed annually to determine whether any changes are needed.
    • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
    • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
    • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
    • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
  • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
  • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
  • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.

Motor Dysfunction

Gross motor dysfunction

  • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
  • Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, 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 should be assessed at each visit and clinical feeding evaluations and/or radiographic swallowing studies should be obtained for choking/gagging during feeds, poor weight gain, frequent respiratory illnesses, or feeding refusal that is not otherwise explained. Assuming that the child is safe to eat by mouth, feeding therapy (typically from an occupational or speech therapist) is recommended to help improve coordination or sensory-related feeding issues. Feeds can be thickened or chilled for safety. When feeding dysfunction is severe, an NG-tube or G-tube may be necessary.

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

Neurobehavioral/Psychiatric Concerns

Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.

Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.

Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 7 are recommended.

Table 7.

Coffin-Siris Syndrome: Recommended Surveillance

System/ConcernEvaluationFrequency
Feeding
  • Measurement of growth parameters
  • Eval of nutritional status & safety of oral intake
At each visit
Neurologic
  • Monitoring of those w/seizures &/or tics as clinically indicated
  • Assessment for new manifestations such as seizures & tics
Development Monitoring of developmental progress & educational needs
Neurobehavioral/
Psychiatric
Behavioral assessment for anxiety, ADHD, ASD, aggression, & self-injury
Respiratory Monitoring for signs & symptoms of sleep disturbance
Musculoskeletal Physical medicine, OT/PT assessment of mobility, self-help skills
Immunologic Assessment for signs & symptoms of frequent infections
Family/
Community
Assessment of family need for social work support (e.g., palliative/respite care, home nursing, other local resources), care coordination, or follow-up genetic counseling if new questions arise (e.g., family planning)
Eyes Ophthalmology eval & vision assessmentAnnually or as clinically indicated
Hearing Audiology evaluation
Dental Dental evalAt least every 6 mos in those w/teeth
Oncology Consider serum AFP level & liver ultrasound in those who have a pathogenic variant in ARID1A1Every 3 mos until age 4 yrs

ADHD = attention-deficit/hyperactivity disorder; AFP = alpha-fetoprotein; ASD = autism spectrum disorder; OT = occupational therapy; PT = physical therapy

1.

Because of the rarity of tumors in CSS, the utility of tumor surveillance is unclear. There have been several reports of individuals with ARID1A variants who subsequently were diagnosed with hepatoblastoma [Cárcamo et al 2022, van der Sluijs et al 2023]; as the frequency appears to exceed the recommended threshold for cancer screening, consideration of serum AFP levels and liver ultrasound every three months until age four years may be appropriate for individuals with ARID1A-related CSS.

Evaluation of Relatives at Risk

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

Therapies Under Investigation

Van der Sluijs et al [2025] examined the utility of clonazepam in individuals with CSS based on preliminary data that identified decreased GABA-ergic inhibitory synapses in Arid1b+ mice, with some possible improvement in tone and attention to tasks and decreased anxiety [Jung et al 2017]. This study concluded that clonazepam did not provide any additional benefit to individuals with CCS due to pathogenic variants in ARID1B [van der Sluijs et al 2025].

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members; it is not meant to address all personal, cultural, or ethical issues that may arise or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Coffin-Siris syndrome (CSS) is an autosomal dominant disorder typically caused by a de novo pathogenic variant.

Risk to Family Members

Parents of a proband

  • Most individuals diagnosed with CSShave the disorder as the result of a de novo CSS-causing pathogenic variant.
  • Rarely, an individual diagnosed with CSS has an affected parent.
    • Transmission of a SOX11 pathogenic variant from a mother with mild learning differences to two daughters with intellectual disability has been reported [Hanker et al 2022]. All three individuals had hypoplastic nails and similar facial features. Additional individuals with maternally inherited SOX11 pathogenic variants and variable degrees of intellectual disability have been observed [S Schrier Vergano, unpublished data].
    • Several inherited ARID1B pathogenic variants in exon 1 have been described, often inherited from a mildly affected parent [van der Sluijs et al 2021].
  • If a molecular diagnosis has been established in the proband and the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment.
  • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of a milder phenotype. Therefore, an apparently negative family history cannot be confirmed without appropriate clinical evaluation of the parents and/or molecular genetic testing (if a molecular diagnosis has been established in the proband).

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

  • In the rare circumstance that a parent of the proband is affected and/or is known to have a CSS-causing pathogenic variant, the risk to the sibs is 50%.
  • If the proband has a known CSS-causing pathogenic variant that 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 gonadal mosaicism [Ben-Salem et al 2016; Cheng et al 2021; S Schrier Vergano, personal observation/registry].
  • If the parents are clinically unaffected but their genetic status is unknown, the risk to the sibs of a proband appears to be low but increased over that of the general population because of the possibility of parental gonadal mosaicism.

Offspring of a proband. Each child of an individual with CSS has a 50% chance of inheriting the CSS-related pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: in the rare event of an affected parent, other 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 couples who have had an affected child.

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Once the Coffin-Siris syndrome-causing 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 t and preimplantation genetic esting. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Coffin-Siris Syndrome Foundation
    Phone: 720-514-9904
    Email: Foundation@coffinsiris.org
  • Genetic and Rare Diseases Information Center (GARD)
    Phone: 888-205-2311
  • American Association on Intellectual and Developmental Disabilities (AAIDD)
    Phone: 202-387-1968
  • CDC - Child Development
    Phone: 800-232-4636
  • MedlinePlus
  • Clinical Registry of Individuals with Coffin-Siris Syndrome and Other BAF-Related Phenotypes
    Email: Samantha.vergano@seattlechildrens.org
  • CoRDS Registry
    Sanford Research
    Phone: 605-312-6300

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 B.

OMIM Entries for Coffin-Siris Syndrome (View All in OMIM)

135900COFFIN-SIRIS SYNDROME 1; CSS1
184430SRY-BOX 4; SOX4
600898SRY-BOX 11; SOX11
601607SWI/SNF-RELATED, MATRIX-ASSOCIATED, ACTIN-DEPENDENT REGULATOR OF CHROMATIN, SUBFAMILY B, MEMBER 1; SMARCB1
601671D4, ZINC, AND DOUBLE PHD FINGERS FAMILY, MEMBER 2; DPF2
601734SWI/SNF-RELATED, MATRIX-ASSOCIATED, ACTIN-DEPENDENT REGULATOR OF CHROMATIN, SUBFAMILY C, MEMBER 2; SMARCC2
601735SWI/SNF-RELATED, MATRIX-ASSOCIATED, ACTIN-DEPENDENT REGULATOR OF CHROMATIN, SUBFAMILY D, MEMBER 1; SMARCD1
603024AT-RICH INTERACTION DOMAIN-CONTAINING PROTEIN 1A; ARID1A
603111SWI/SNF-RELATED, MATRIX-ASSOCIATED, ACTIN-DEPENDENT REGULATOR OF CHROMATIN, SUBFAMILY E, MEMBER 1; SMARCE1
603254SWI/SNF-RELATED, MATRIX-ASSOCIATED, ACTIN-DEPENDENT REGULATOR OF CHROMATIN, SUBFAMILY A, MEMBER 4; SMARCA4
605690BRD4-INTERACTING CHROMATIN REMODELING COMPLEX-ASSOCIATED PROTEIN; BICRA
609539AT-RICH INTERACTION DOMAIN-CONTAINING PROTEIN 2; ARID2
614556AT-RICH INTERACTION DOMAIN-CONTAINING PROTEIN 1B; ARID1B
617808COFFIN-SIRIS SYNDROME 6; CSS6
618027COFFIN-SIRIS SYNDROME 7; CSS7
618362COFFIN-SIRIS SYNDROME 8; CSS8
618506INTELLECTUAL DEVELOPMENTAL DISORDER WITH SPEECH DELAY AND DYSMORPHIC FACIES; IDDSDF
618779COFFIN-SIRIS SYNDROME 11; CSS11
619325COFFIN-SIRIS SYNDROME 12; CSS12

Molecular Pathogenesis

Many of the genes identified to be causative of the Coffin-Siris syndrome (CSS) phenotype to date encode human homologs of proteins first identified in yeast and Drosophila in the BRG1- and BRM-associated factor (BAF) complex, originally called the mammalian switch/sucrose non-fermentable (mSWI/SNF)-like nucleosome remodeling complex. This complex contains a DNA-stimulated ATPase activity capable of destabilizing histone-DNA interactions in an ATP-dependent manner [Ronan et al 2013]. Transcription factor SOX-11 (SOX11; encoded by SOX11) is predicted to act downstream of the BAF complex in neurogenesis and may be involved in the conversion of postnatal glia into neurons [Ninkovic et al 2013].

Table 8.

Coffin-Siris Syndrome: Mechanism of Disease Causation

Gene 1Mechanism
ARID1A Loss of function
ARID1B Loss of function
ARID2 Loss of function
BICRA Loss of function
DPF2 Loss of function
PHF6 Loss of function (assumed)
SMARCA2 Dominant-negative or gain of function
SMARCA4 Dominant-negative or gain of function
SMARCB1 Dominant-negative or gain of function
SMARCC2 Loss of function
SMARCD1 Loss of function (unclear)
SMARCE1 Dominant-negative or gain of function
SOX4 Loss of function
SOX11 Loss of function
1.

Genes from Table 1 in alphabetic order

Table 9.

Coffin-Siris Syndrome: Gene-Specific Laboratory Considerations

Gene 1Special Consideration
ARID1A Many pathogenic variants appear to be mosaic, a finding that should be taken into account when analyzing sequence data.
ARID1B Alternatively spliced transcript variants encoding different isoforms have been described.
SMARCA4 Multiple transcript variants encoding different isoforms have been found for this gene.
SOX11 Pathogenic variants in SOX11 include partial- or whole-gene deletions or de novo missense variants in the HMG-box DNA-binding domain2
1.

Genes from Table 1 in alphabetic order

2.

Table 10.

Coffin-Siris Syndrome: Pathogenic Variants Referenced in This GeneReview by Gene

Gene 1Reference SequencesDNA Nucleotide ChangePredicted Protein ChangeComment [Reference]
SMARCB1 NM_003073​.5
NP_003064​.2
c.1085AGA[2]p.Lys364delRecurrent de novo pathogenic variant; affected persons have strikingly similar clinical manifestations. 2
SMARCC2 NM_001330288​.2 c.1926+1G>T--Recurrent de novo splicing variant; affected persons have DD, minimal or absent speech, & hypotonia. 3

DD = developmental delay

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.

1.

Genes from Table 1 in alphabetic order

2.
3.

Chapter Notes

Author Notes

All of the authors of this chapter study the clinical features and molecular basis of Coffin-Siris syndrome (CSS).

Dr Samantha Schrier Vergano at Seattle Children's Hospital is actively involved in clinical research regarding individuals with CSS and runs the CSS clinical registry. She would be happy to communicate with persons who have any questions regarding the diagnosis of CSS or other considerations. Email gro.snerdlihcelttaes@yrtsigerssc for more information.

Dr Dagmar Wieczorek at the Institute of Human Genetics has long-standing experience in the identification of new genes and signaling pathways related to neurodevelopmental disorders (NDD), autism, and syndromal entities (especially craniofacial malformations). She has more than ten years' experience in the use of next-generation sequencing for the detection of causative genetic variations. She hosts large patient cohorts for the study of NDD. In 2025, she will start as one PI in a natural history study on ARID1B-related disorders (www.care4arid1b.org).

Acknowledgments

Dr Schrier Vergano would like to acknowledge Ashley Vasko, BS, and Catherine Nguyen, MS, who assisted with the 2021 revision of this chapter.

Author History

Matthew A Deardorff, MD, PhD; University of Southern California (2013-2025)
Naomichi Matsumoto, MD, PhD (2013-present)
Gijs Santen, MD, PhD (2013-present)
Samantha Schrier Vergano, MD (2013-present)
Dagmar Wieczorek, MD (2013-present)
Bernd Wollnik, MD; University of Cologne (2013-2025)

Revision History

  • 15 May 2025 (ma) Comprehensive update posted live
  • 12 May 2016 (ha) Comprehensive update posted live
  • 4 April 2013 (me) Review posted live
  • 19 July 2012 (md) Original submission

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