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Coffin-Siris Syndrome

Synonyms: Fifth Digit Syndrome. Includes: ARID1A-Related Coffin-Siris Syndrome, ARID1B-Related Coffin-Siris Syndrome, SMARCA4-Related Coffin-Siris Syndrome, SMARCB1-Related Coffin-Siris Syndrome, SMARCE1-Related Coffin-Siris Syndrome

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

Author Information
, MD
Division of Medical Genetics and Metabolism
Children’s Hospital of the King’s Daughters
Norfolk, Virginia
, MD, PhD
Center for Human and Clinical Genetics
Leiden University Medical Center
Leiden, The Netherlands
, MD
Institut für Humangenetik
Universität Duisburg-Essen
Universitätsklinikum Essen
Essen, Germany
, MD
Institute of Human Genetics and Center for Molecular Medicine Cologne
University Medical Faculty
University of Cologne
Cologne, Germany
, MD, PhD
Department of Human Genetics
Yokohama City University Graduate School of Medicine
Yokohama, Japan
, MD, PhD
Division of Genetics
The Children's Hospital of Philadelphia
Philadelphia, Pennsylvania

Initial Posting: ; Last Revision: July 11, 2013.


Disease characteristics. Coffin-Siris syndrome (CSS) is characterized by aplasia or hypoplasia of the distal phalanx or nail of the fifth digit, distinctive facial features, and moderate to severe developmental/cognitive delay. Expressive language is more severely affected than receptive language. On average, children with CSS learn to sit at 12 months, walk at 30 months, and speak their first words at 24 months. Other findings commonly include failure to thrive, feeding difficulties, short stature, ophthalmologic abnormalities, microcephaly, brain malformations, and hearing loss.

Diagnosis/testing. Before the molecular basis was known, the diagnosis of CSS was based strictly on clinical findings. With the recent detection of heterozygous mutations in ARID1A, ARID1B, SMARCA4, SMARCB1, or SMARCE1 in some (but not all) individuals with CSS, it is likely that diagnostic criteria will evolve.

Management. Treatment of manifestations: Occupational, physical, and/or speech therapies to optimize developmental outcomes. Nutritional supplementation and/or gastrostomy tube placement as needed to meet nutritional needs. Routine management of ophthalmologic abnormalities and hearing loss.

Surveillance: Yearly evaluation by a developmental pediatrician to assess developmental progress and therapeutic and educational interventions; follow up with a gastroenterologist and feeding specialists as needed to monitor feeding and weight gain. Routine follow-up of ophthalmologic and/or audiologic abnormalities. Although mutations in a subset of the genes causing CSS have been implicated in tumorigenesis, the rarity of tumors in CSS has precluded determination of the utility of tumor surveillance.

Genetic counseling. CSS caused by a heterozygous mutation in one of five genes (ARID1A, ARID1B, SMARCA4, SMARCB1, and SMARCE1) is inherited in an autosomal dominant manner, but most commonly results from a de novo mutation. (Of note, autosomal recessive inheritance cannot be excluded in the rare instance of reports of recurrence in sibs with molecularly unconfirmed CSS.) If the disease-causing mutation has been identified in a family member, prenatal testing for pregnancies at increased risk is possible either through laboratories offering either testing for the gene of interest or custom testing. Note: With the exception of one older report of parental transmission of molecularly unconfirmed CSS, individuals with CSS typically do not reproduce.


Formal diagnostic criteria for Coffin-Siris syndrome (CSS) have not been established.

Most individuals with a clinical diagnosis of Coffin-Siris syndrome (CSS) have all three of the following major findings and one of each of the three following categories of minor findings [Fleck et al 2001, Schrier et al 2012]. However, as more individuals with mutations in genes associated with CSS are identified, the diagnostic criteria will likely evolve to include both clinical features and molecular findings.

Major findings: Presence of all three.

  • Fifth digit nail/distal phalanx hypoplasia/aplasia. To date, all individuals with a clinical diagnosis of CSS have had either aplasia or hypoplasia of the distal phalanx of the fifth digit or absence of the nail of the fifth digit (Figure 1C, D, E, F). Fingers, toes, or both can be affected.

    Note: Because molecular genetic testing has identified causative mutations in several individuals with intellectual disability and facial features that overlap with those of classic CSS but with little or no fifth digit involvement, evaluation of individuals with a broader phenotype is needed to determine the frequency of this finding in persons with molecularly confirmed CSS. For example: ARID1B mutations have been observed in persons with intellectual disability, some without fifth finger or distal digital hypoplasia [Halgren et al 2012, Hoyer et al 2012, Santen et al 2012].
  • Developmental or cognitive delay (100%). The degree of developmental delay in individuals with CSS ranges from mild to severe.
  • Facial features. It has been suggested that facial features can classify individuals with CSS as “classic/type A” or “variant/type B” [Schrier et al 2012]. Of note, molecular testing to date is more successful in identifying causative mutations in individuals with classic CSS facial features than in those with variant facial features. Classic facial features (Figure 1A, B):
    • Wide mouth with thick, everted upper and lower lips
    • Broad nasal bridge with broad nasal tip
    • Thick eyebrows and long eyelashes
    • Variant facial features (subtle and/or less coarse):
    • Thin vermillion border of the upper lip
    • Narrow nasal bridge with or without anteverted nares
    • Thin, arched, “penciled” eyebrows
Figure 1


Figure 1. Coffin-Siris syndrome classic features

Facial features (i.e., bushy eyebrows, coarse facies, and thick, everted lips) in (A) a clinically diagnosed boy age five years and (B) a clinically diagnosed man age 29 years

Fifth (more...)

Minor findings: At least one feature from each of the three following categories:

  • Ectodermal
    • Hirsutism/hypertrichosis (93%). Hair growth in atypical areas (e.g., the back) or excessive hair growth on the arms or face. Thick eyebrows and long eyelashes are reported, particularly in individuals with classic facial features. (Paradoxically, scalp hair is often sparse, particularly in the temporal regions.)
    • Sparse scalp hair, especially in infancy
    • Dental anomalies
  • Constitutional
    • Microcephaly
    • Intrauterine growth retardation (IUGR)
    • Short stature
    • Failure to thrive
    • Frequent infections
  • Organ related
    • Cardiac anomalies
    • Feeding difficulties
    • Gastrointestinal anomalies
    • Genitourinary/renal anomalies
    • Brain/cranial malformations or seizures
    • Vision changes (Note: Details have not been reported.)
    • Hearing loss

To confirm/establish the diagnosis of CSS in a proband it is necessary to perform molecular genetic testing to identify a heterozygous mutation or genomic rearrangement involving one of the five genes in which mutations are known to cause CSS (see Table 1).

Table 1. Summary of Molecular Genetic Testing Used in Coffin-Siris Syndrome

Gene 1, 2Proportion of CSS Attributed to Mutations in This Gene 3Test Method ( / 4)Mutations Detected 5
ARID1A13% (3/24)Sequence analysis (3/3)Sequence variants 6
Deletion / duplication analysis 7Exonic or whole-gene deletions
ARID1B33% (9/27)Sequence analysis (8/9)Sequence variants 6
Deletion/duplication analysis 7 (1/9)Exonic or whole-gene deletions and genomic rearrangements 8
SMARCA425% (6/24)Sequence analysis (6/6)Sequence variants 6
Deletion / duplication analysis 7Exonic or whole-gene deletions
SMARCB117% (4/24)Sequence analysis (4/4)Sequence variants 6
Deletion / duplication analysis 7Exonic or whole-gene deletions; none reported
SMARCE14% (1/24)Sequence analysis (1/1)Sequence variants 6
Deletion / duplication analysis 7Exonic or whole-gene deletions
UnknownSee footnote 9NANA

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. After heterozygous SMARCA2 mutations were identified in Nicolaides-Baraitser syndrome (NCBRS) [Van Houdt et al 2012], reevaluation of an individual initially thought to have CSS concluded that findings were more consistent with NCBRS [Tsurusaki et al 2012]. See Differential Diagnosis.

3. Based on patients clinically ascertained prior to the identification of a molecular etiology [Santen et al 2012; Tsurusaki et al 2012]

4. Number of individual with an identified mutation / number of individuals tested

5. See Molecular Genetics for information on allelic variants.

6. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

7. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment. Specific exon-targeted deletion/duplication analysis (e.g., MLPA and qPCR) has not yet been reported.

8. Microdeletions of chromosome 6q25.3 that include ARID1B have been reported in: (a) children with CSS ascertained prior to the understanding of the molecular basis of CSS [Tsurusaki et al 2012]; (b) children ascertained with a microdeletion containing ARID1B and secondarily noted to have features similar to CSS [Santen et al 2012]; and (c) individuals with mildly or variably syndromic intellectual disability [Nagamani et al 2009, Halgren et al 2012, Hoyer et al 2012, Michelson et al 2012] in 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. In one study, three of 22 individuals with CSS did not have a mutation in one of the known genes [Tsurusaki et al 2012], suggesting the existence of additional loci.

Clinical Description

Natural History

The understanding of the full phenotypic spectrum of Coffin-Siris syndrome (CSS) and its natural history are rapidly evolving due to the recent discovery of the molecular basis of CSS. The current knowledge regarding natural history has been derived largely from patients with detailed clinical information for whom the diagnosis was made on clinical findings alone. For these reasons the discussion of natural history below is based largely on detailed clinical reports published prior to the identification of the genes involved [Coffin & Siris 1970, Haspeslagh et al 1984, Swillen et al 1995, Fleck et al 2001, Schrier et al 2012].

Children with Coffin-Siris syndrome (CSS) typically manifest hypoplasia of the fifth digits/nails and mildly dysmorphic features at birth. Because facial features typically coarsen over time, the characteristic facies may not be apparent at birth or in early childhood.

Other findings that appear in infancy (e.g., feeding difficulties, failure to thrive, microcephaly, and neurologic abnormalities) may be the first indication of the disorder.

The developmental/cognitive delay is typically apparent when delayed developmental milestones are noted and/or formal cognitive testing is performed. Reports published prior to the era of molecular diagnosis indicated that the degree of developmental delay is typically moderate to severe, with IQs ranging from 40 to 69; however, IQs as high as 97 have been reported [Swillen et al 1995]. Expressive language is more severely affected than receptive language. On average, children with CSS learn to sit at 12 months, walk at 30 months, and speak their first words at 24 months.

Although autistic features have been reported in individuals with CSS, these findings may be a component of the development delay and not an inherent feature of the syndrome.

Other features described in the studies mentioned above include:

  • Failure to thrive (seen in 38/45). Approximately 50% had intrauterine growth retardation (IUGR), with subsequent weight and height below the fifth percentile.
  • Feeding difficulties (49/59). Structural gastrointestinal anomalies that have been reported include diaphragmatic hernia [Delvaux et al 1998], intussusception [Coffin & Siris 1970], and gastric outlet obstruction from redundant gastric mucosa [Bodurtha et al 1986]. Children may also have oral aversion or difficulty feeding in the absence of any evident intestinal malformations.
  • Ophthalmologic abnormalities (19/27) that may include ptosis, strabismus, cataracts
  • Short stature (25/38), apparently not secondary to hormone deficiencies
  • Microcephaly (31/54), which can be seen prenatally and may indicate an underlying brain malformation
  • Cardiac anomalies (31/68) including ventricular septal defects, atrial septal defects, tetralogy of Fallot, and patent ductus arteriosus
  • Renal (8/28) and GU malformations (15/35) that have included horseshoe kidney, hypospadias, and other abnormalities
  • Brain malformations that can include Dandy-Walker variant (5/53), gyral simplification, and agenesis of the corpus callosum (7/30)
  • Seizures and tics (10/27)
  • Hearing loss (8/21), apparently sensorineural rather than conductive
  • Delayed bone age, frequency unknown. When delayed, bone age appears to lag about two to three years behind chronologic age.
  • Hepatoblastoma. Although mutations in a subset of the genes causing CSS have been implicated in tumorigenesis, data on tumor risk in CSS are lacking. However, hepatoblastoma was reported in one of three individuals with an ARID1A mutation [Tsurusaki et al 2012].

Long-term studies have not been performed and, therefore, information on life span in individuals with Coffin-Siris syndrome is not available. Children have been reported to die of complications, including aspiration pneumonia and/or seizures [Schrier et al 2012].

Genotype-Phenotype Correlations

To date, no genotype-phenotype correlations have been clearly defined.

Mutations in ARIDB1 have been noted in individuals with mild syndromic and/or apparently isolated intellectual disability [Hoyer et al 2012]. Although these individuals have many of the features of CSS (developmental delay, hearing loss, seizures, dysmorphic facial features), only a subset have fifth digit anomalies.


Penetrance for Coffin-Siris syndrome appears to be complete.

More females than males with CSS were reported in the literature prior to 2001 [Fleck et al 2001]; however, no evidence exists for X-linked dominant, sex-limited, or mitochondrial inheritance. Of note, at least one recent report of persons with molecularly confirmed CSS confirms the previously observed female bias [Tsurusaki et al 2012]. It may be possible that this is an ascertainment bias, with hypertrichosis being more noticed in females.


Anticipation has not been reported in Coffin-Siris syndrome.


Currently fewer than 100 individuals with features suggestive of Coffin-Siris syndrome have been reported, indicating that this diagnosis is rare.

However, the identification of a mutation in one of the five genes known to be associated with CSS in some members of large cohorts with intellectual disability (who may or may not have been evaluated for features of CSS) suggests that the prevalence of mutations in these genes (and possibly subtle phenotypic features of CSS) may be higher than currently appreciated among those with intellectual disability.

Differential Diagnosis

A clinical diagnostic algorithm has been developed to assist in the differential diagnosis of Coffin-Siris syndrome (CSS) [Schrier et al 2012]. See Figure 2.

Figure 2


Figure 2. Coffin-Siris syndrome diagnostic algorithm

  • Nicolaides-Baraitser syndrome (NCBRS) (OMIM 601358) is characterized by severe intellectual disability, short stature, dysmorphic facial features, and sparse hair [Sousa et al 2009]. Heterozygous mutations in SMARCA2 have been identified in Nicolaides-Baraitser syndrome (NCBRS) [Van Houdt et al 2012]. Of note, after heterozygous SMARCA2 mutations were identified in Nicolaides-Baraitser syndrome (NCBRS) [Van Houdt et al 2012], reevaluation of an individual initially thought to have CSS concluded that findings were more consistent with NCBRS [Tsurusaki et al 2012].
  • 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. This latter characteristic is most likely to distinguish individuals with BOD syndrome from CSS, as the cognitive disability in CSS is nearly always moderate to severe. Inheritance appears to be autosomal dominant.
  • Deafness, onychodystrophy, osteodystrophy, and “mental retardation” (DOOR) syndrome (OMIM 220500). Features in common with CSS include hypoplastic terminal phalanges and/or nail anomalies, deafness, and neurologic abnormalities. Elevated levels of urinary 2-oxyglutarate have been reported in individuals with DOOR syndrome [Patton et al 1987, Rajab et al 2000]. Inheritance is autosomal recessive.
  • Fetal alcohol spectrum (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.
  • Mabry syndrome/ hyperphosphatasia with mental retardation syndrome 1 (OMIM 239300). Mabry syndrome is characterized by delayed development, coarse facial features, and hypoplastic fifth digits. Elevated serum concentrations of alkaline phosphatase are reported [Gomes & Hunter 1970, Kruse et al 1988, Thompson et al 2010]. Biallelic mutations in PIGV are causative [Krawitz et al 2010]. Inheritance is autosomal recessive.
  • Cornelia de Lange syndrome (CdLS). Classic CdLS is characterized by distinctive craniofacial features (arched eyebrows, synophrys, upturned nose, small teeth, microcephaly); growth retardation; and limb anomalies, which can at times include the fifth finger hypoplasia seen in CSS. Other findings may include cardiac defects, gastrointestinal anomalies, and genitourinary malformations. Mutations in NIPBL, SMC1A, SMC3, HDAC8, or RAD21 are causative. CdLS is inherited in an autosomal dominant (NIPBL, SMC3 and RAD21) or X-linked (SMC1A and HDAC8) manner.
  • 4q deletion syndrome. This chromosomal deletion syndrome results in a characteristic curved, volar, fifth digit nail, which may resemble a hypoplastic distal phalanx.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).


Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of an individual diagnosed with Coffin-Siris syndrome (CSS), the following evaluations are recommended:

  • Medical genetics consultation to establish the diagnosis, evaluate the molecular etiology, and provide recurrence risk assessment
  • Neurologic and/or developmental examination to record developmental milestones and identify neurologic symptoms or deficits
  • Evaluation for occupational, speech, or physical therapy as needed
  • Gastrointestinal evaluation for feeding difficulties or failure to thrive
  • Dietary evaluation by a nutritionist as needed
  • Echocardiogram to evaluate for structural cardiac defects
  • Renal ultrasonography to evaluate for structural kidney or genitourinary (GU) anomalies
  • Ophthalmologic examination, including a dilated fundus examination and visual acuity
  • Audiology evaluation with auditory brain stem response testing and otoacoustic emission testing to assess for hearing loss

Treatment of Manifestations

The following are appropriate:

  • Occupational, physical and/or speech therapies to optimize developmental outcomes
  • Nutritional supplementation and/or gastrostomy tube placement as needed to meet nutritional needs
  • Spectacles as needed to correct refractive errors and surgery as needed for strabismus and/or ptosis
  • Hearing aids, as needed


Surveillance includes the following:

  • Yearly evaluation by a developmental pediatrician to assess developmental progress and therapeutic and educational interventions
  • Annual follow up with a gastroenterologist and feeding specialists as needed to monitor feeding and weight gain
  • Regular follow up of ophthalmologic and/or audiologic abnormalities

Because of the rarity of tumors in CSS, the utility for tumor surveillance has not been determined.

Evaluation of Relatives at Risk

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

Pregnancy Management

As no females with CSS have been reported to reproduce, potential complications of pregnancy are unknown.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

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

Mode of Inheritance

Coffin-Siris syndrome (CSS), caused by a heterozygous mutation in one of five genes (ARID1A, ARID1B, SMARCA4, SMARCB1, and SMARCE1), most commonly results from a de novo mutation. When transmitted in a family, it is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • A proband with CSS usually has the disorder as the result of a new mutation. The proportion of cases caused by de novo mutations is unknown, but likely approaches 100%, given the paucity of reports of affected parents in the literature.
  • Two sibs diagnosed with CSS have been reported to have an affected parent [Haspeslagh et al 1984].
  • If the disease-causing mutation found in the proband cannot be detected in leukocyte DNA of either parent, two possible explanations are germline mosaicism in a parent or a de novo mutation in the proband. Although no instances of germline mosaicism have been reported, it remains a possibility.
  • Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include testing of the parents for the mutation identified in the proband. 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 fully confirmed until appropriate evaluations have been performed.

Sibs of a proband

Offspring of a proband. With the exception of one report of parental transmission, typically individuals with CSS do not reproduce.

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

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has clinical evidence of the disorder it is likely that the proband has a de novo mutation. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to couples who have had an affected child.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the disease-causing mutation has been identified in an affected family member, prenatal diagnosis is possible for pregnancies at increased risk by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation). Such testing may be available through laboratories offering gene-specific testing or custom testing.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutations have been identified.


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.

  • Genetic and Rare Diseases Information Center (GARD)
    P.O. Box 8126
    Gaithersburg MD 20898-8126
    Phone: 888-205-2311; 888-205-3223 (TTY); 301-251-4925
    Fax: 301-251-4911
    Email: GARDinfo@nih.gov
  • American Association on Intellectual and Developmental Disabilities (AAIDD)
    501 3rd Street Northwest
    Suite 200
    Washington DC 20001
    Phone: 800-424-3688 (toll-free); 202-387-1968
    Fax: 202-387-2193
    Email: anam@aaidd.org
  • Medline Plus
  • National Center on Birth Defects and Developmental Disabilities
    1600 Clifton Road
    MS E-87
    Atlanta GA 30333
    Phone: 800-232-4636 (toll-free); 888-232-6348 (TTY)
    Email: cdcinfo@cdc.gov

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)


Molecular Genetic Pathogenesis

Each of the proteins identified in CSS to date encode human homologs of proteins first identified in yeast in the SWI/SNF (switch/sucrose nonfermentable) nucleosome remodeling complex. This complex contains a DNA-stimulated ATPase activity capable of destabilizing histone-DNA interactions in an ATP-dependent manner.


Normal allelic variants. ARID1A (NM_006015.4) comprises 20 exons and makes an 8585-bp transcript.

Pathologic allelic variants. Frameshift and nonsense mutations have been noted, suggesting haploinsufficiency as the pathogenic mechanism.

Normal gene product. The ARID1A protein contains 2285 amino acids (NP_006006.3) and is part of the large ATP-dependent chromatin remodeling complex SNF/SWI, which is required for transcriptional activation of genes normally repressed by chromatin. It is thought that the protein encoded by this gene confers specificity to the SNF/SWI complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions.

Abnormal gene product. Mutations in ARID1A may result in aberrant chromatin remodeling, causing downstream dysregulation of further genes and resulting in the CSS phenotype.


Normal allelic variants. ARID1B comprises 20 exons and makes a transcript of 9648 bp (NM_020732.3). Alternatively spliced transcript variants encoding different isoforms have been described.

Pathologic allelic variants. Microdeletions, nonsense, frameshift, and missense ARID1B mutations have been seen in individuals with CSS [Santen et al 2012, Tsurusaki et al 2012]. Microdeletions and nonsense mutations were reported in nine patients with nonspecific intellectual disability [Hoyer et al 2012], suggesting that persons with haploinsufficiency for ARID1B may present with a phenotype that is distinct from CSS.

Normal gene product. The ARID1B protein contains 2249 amino acids (NP_065783.3) and is a component of the SWI/SNF chromatin remodeling complex, possibly playing a role in cell-cycle activation. The protein encoded by this locus is similar to ARID1A. These 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. Mutations in ARID1B may result in aberrant chromatin remodeling, causing downstream dysregulation of further genes and resulting in the CSS phenotype.


Normal allelic variants. SMARCA4 comprises 35 exons and makes a 5703-bp transcript (NM_003072.3). Multiple transcript variants encoding different isoforms have been found for this gene.

Pathologic allelic variants. Five missense mutations and an in-frame deletion have been identified in individuals diagnosed with CSS. All mutations to date are in exons 10-25, and encode residues in or near the BRK or helicase domains [Tsurusaki et al 2012].

Normal gene product. The SMARCA4 protein contains 1647 amino acids (NP_003063.2) and is part of the large ATP-dependent SNF/SWI chromatin remodeling complex, which is required for transcriptional activation of genes normally repressed by chromatin.

Abnormal gene product. SMARCA4 is involved in chromatin remodeling and transcriptional activation. Mutations may result in abnormal gene expression, although the exact role of SMARCA4 in the development of a CSS phenotype is not known at this time.


Normal allelic variants. SMARCB1 comprises nine exons and makes a 1717-bp transcript (NP_003064.2).

Pathologic allelic variants. Two different mutations have been reported in four individuals with CSS, three with the same in-frame deletion and one with a missense mutation. Both mutations retained the open reading frame and were located in the C-terminal portion of the protein near the end of the second SNF5 domain [Tsurusaki et al 2012].

Normal gene product. The SMARCB1 protein contains 385 amino acids (NP_003064.2) and is a core component of the BAF (hSWI/SNF) complex. This ATP-dependent chromatin-remodeling complex plays important roles in cell proliferation and differentiation, cellular antiviral activities, and inhibition of tumor formation.

Abnormal gene product. SMARCB1 is involved in chromatin remodeling and plays a role in tumor development in the rhabdoid tumor predisposition syndrome, in which most tumors are associated with biallelic loss of function mutations. The exact mechanism of SMARCB1in the development of a CSS phenotype is not known at this time.


Normal allelic variants. SMARCE1 comprises 11 exons and makes a 2425-bp transcript (NM_003079.4).

Pathologic allelic variants. A single missense mutation in SMARCE1 that converts a conserved tyrosine in the HMG domain to a cysteine has been reported [Tsurusaki et al 2012].

Normal gene product. The SMARCE1 protein contains 411 amino acids (NP_003070.3) and is part of the large ATP-dependent SNF/SWI chromatin remodeling complex, which is required for transcriptional activation of genes normally repressed by chromatin.

Abnormal gene product. The exact role of SMARCE1 in the development of the CSS phenotype is not known at this time.


Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page Image PubMed.jpg

Literature Cited

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Chapter Notes

Author Notes

All of the authors of this review study the clinical features and molecular basis of the Coffin-Siris syndrome.

Revision History

  • 11 July 2013 (aa) Revision: ARID1B deletion/duplication analysis available on a clinical basis
  • 4 April 2013 (me) Review posted live
  • 19 July 2012 (md) Original submission
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