Coffin-Siris syndrome has been described as mental retardation associated with coarse facial features, hypertrichosis, and hypoplastic or absent fifth fingernails or toenails (summary by Santen et al., 2012). Other features including ptosis, choanal atresia, cardiac defects, and genital ... Coffin-Siris syndrome has been described as mental retardation associated with coarse facial features, hypertrichosis, and hypoplastic or absent fifth fingernails or toenails (summary by Santen et al., 2012). Other features including ptosis, choanal atresia, cardiac defects, and genital anomalies have been reported (Jones, 2006). In patients with a diagnosis of Coffin-Siris syndrome, Tsurusaki et al. (2012) identified mutations in 6 of 15 genes encoding subunits of the SWI/SNF complex. The genes with mutations identified by Tsurusaki et al. (2012) included SMARCB1 (601607), SMARCA4 (603254), SMARCA2 (600014) (mutation in which resulted in a phenotype more aptly described as Nicolaides-Baraitser syndrome, 601358), ARID1A (603024), and ARID1B (614556). Santen et al. (2012) classified the phenotypes of the 6 patients they identified with mutations in ARID1B as Coffin-Siris syndrome; however, the facial gestalt of these patients was quite variable.
Coffin and Siris (1970) described 3 unrelated girls with mental retardation and absent nail and terminal phalanx of the fifth finger. The nails and distal phalanges of the lateral toes were either absent or hypoplastic. No similar cases ... Coffin and Siris (1970) described 3 unrelated girls with mental retardation and absent nail and terminal phalanx of the fifth finger. The nails and distal phalanges of the lateral toes were either absent or hypoplastic. No similar cases were found in any of the 3 families. Mattei et al. (1981) reported 2 affected sisters of North African origin. One sister had massive unilateral hydronephrosis. Consanguinity was suspected, but not proven, and autosomal recessive inheritance was suggested. As noted by Gorlin (1981), the sibs reported by Mattei et al. (1981) had Coffin-Siris syndrome, not Coffin-Lowry syndrome (303600) as originally reported. Haspeslagh et al. (1984) analyzed 23 published cases of Coffin-Siris syndrome. The female:male ratio was about 4:1. Qazi et al. (1990) described a white female infant with the typical features of Coffin-Siris syndrome including thick eyebrows, flat nasal bridge, anteverted and wide nasal tip, generalized hypertrichosis, scalp hypotrichosis, absence of the fifth fingernails and toenails, absence of the distal phalanges of the fifth fingers and of the second to fifth toes, small patellas, inguinal hernia, and sucking and feeding difficulties. There was decreased fetal activity and intrauterine growth retardation. Rabe et al. (1991) described 2 sisters, 3 and 6 years of age, with a disorder resembling Coffin-Siris syndrome. Both sibs had developmental retardation, facial and skeletal anomalies, and hyperphosphatasia. A major diagnostic clue was hypoplasia/aplasia of the terminal phalanx of the fifth finger, recognized radiologically. Swillen et al. (1995) presented data on cognitive development, language, behavior, and social skills of 9 girls and 3 boys, aged 2.5 to 19 years, with Coffin-Siris syndrome. Mental retardation was mild in 3 patients and moderate in 9 others. Speech development was severely retarded with little interest in language. In the 7 patients aged 7 to 19 years, language comprehension was appropriate to the mental level. Gross motor functioning and autonomy, with the lowest score on 'task orientation,' were equal to the mental development. Most frequently, aggressive disturbed behavior was observed, especially in the youngest children, while mixed disturbed behavior was observed in the oldest patients. Five of 12 patients presented symptoms of pervasive developmental disorder, with 2 of the 11 scoring in the pathologic range. Obsessive interests, strong dependence on patterns and rituals, and unusual fears were characteristic behavioral problems also when the children got older. Bonioli et al. (1995) described a family in which 3 sisters with first-cousin parents had a phenotype resembling Coffin-Siris syndrome. Hypoplasia of the distal phalanges and mental retardation were features. Two of the sisters died at 10 days and 1 day of age of cardiac abnormalities. At the age of 16 months, the surviving sister showed hypertrichosis, synophrys, umbilical hernia, rectal prolapse, bilateral clinodactyly of the fifth finger with hypoplastic nails, and lesser hypoplasia of the other nails and distal phalanges. Fleck et al. (2001) reviewed Coffin-Siris syndrome and reported 18 new cases. The most frequent findings included some degree of mental retardation or developmental delay, coarse facial appearance, feeding difficulties, frequent infections, and hypoplastic to absent fifth fingernails and fifth distal phalanges.
Formal diagnostic criteria for Coffin-Siris syndrome (CSS) have not been established. ...
DiagnosisFormal 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 lipsBroad nasal bridge with broad nasal tipThick eyebrows and long eyelashes Variant facial features (subtle and/or less coarse): Thin vermillion border of the upper lipNarrow nasal bridge with or without anteverted nares Thin, arched, “penciled” eyebrowsFigureFigure 1. CSS 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 digit (more...)Minor findings: At least one feature from each of the three following categories: EctodermalHirsutism/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 infancyDental anomaliesConstitutionalMicrocephalyIntrauterine growth retardation (IUGR) Short statureFailure to thriveFrequent infectionsOrgan relatedCardiac anomaliesFeeding difficultiesGastrointestinal anomaliesGenitourinary/renal anomaliesBrain/cranial malformations or seizuresVision changes (Note: Details have not been reported.)Hearing lossTo 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).For those individuals in whom the diagnosis of CSS is likely, sequence analysis for ARID1B should be performed first, followed by deletion/duplication testing. If no ARID1B mutation is identified, sequence analysis followed by deletion/duplication testing should be performed on the other genes (in order of the likelihood of identifying a mutation: SMARCA4, SMARCB1, ARID1A, SMARCE1).Table 1. Summary of Molecular Genetic Testing Used in Coffin-Siris SyndromeView in own windowGene Symbol 1, 2Proportion of CSS Attributed to Mutations in This Gene 3Test Method ( / 4)Mutations Detected 5Test AvailabilityARID1A13% (3/24)Sequence analysis (3/3)Sequence variants 6ResearchDeletion / duplication analysis 7Exonic or whole-gene deletionsARID1B33% (9/27)Sequence analysis (8/9)Sequence variants 6ClinicalDeletion/duplication analysis 7 (1/9)Exonic or whole-gene deletions and genomic rearrangements 8ResearchSMARCA425% (6/24)Sequence analysis (6/6)Sequence variants 6ResearchDeletion / duplication analysis 7Exonic or whole-gene deletionsSMARCB117% (4/24)Sequence analysis (4/4)Sequence variants 6ClinicalDeletion / duplication analysis 7Exonic or whole-gene deletions; none reportedSMARCE14% (1/24)Sequence analysis (1/1)Sequence variants 6ResearchDeletion / duplication analysis 7Exonic or whole-gene deletionsUnknownSee footnote 9NANANA1. 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 tested5. 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. Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this GeneReview have been associated with mutations in ARID1A and SMARCE1.Phenotypes in addition to classic Coffin-Siris syndrome have been associated with mutations in ARID1B, SMARCA4, and SMARCB1.ARID1B. Both mutations in and microdeletions containing ARID1B have been reported in several individuals with isolated intellectual disability [Nagamani et al 2009, Hoyer et al 2012, Michelson et al 2012]. SMARCA4. Heterozygous germline mutations in SMARCA4 have been reported to cause the rhabdoid tumor predisposition syndrome; likewise, somatic mutations in SMARCA4 have been found in atypical teratoid and rhabdoid tumors [Schneppenheim et al 2010, Hasselblatt et al 2011]. SMARCB1. Heterozygous germline mutations in SMARCB1 have been reported to cause the rhabdoid tumor predisposition syndrome and correspondingly, somatic mutations in the SMARCB1 have been found in atypical teratoid and rhabdoid tumors [Roberts & Biegel 2009].
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]....
Natural HistoryThe 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 arteriosusRenal (8/28) and GU malformations (15/35) that have included horseshoe kidney, hypospadias, and other abnormalitiesBrain 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 conductiveDelayed 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].
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. ...
Differential DiagnosisA clinical diagnostic algorithm has been developed to assist in the differential diagnosis of Coffin-Siris syndrome (CSS) [Schrier et al 2012]. See Figure 2. FigureFigure 2. CSS 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 , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
To establish the extent of disease and needs of an individual diagnosed with Coffin-Siris syndrome (CSS), the following evaluations are recommended:...
ManagementEvaluations 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 assessmentNeurologic and/or developmental examination to record developmental milestones and identify neurologic symptoms or deficitsEvaluation for occupational, speech, or physical therapy as neededGastrointestinal evaluation for feeding difficulties or failure to thriveDietary evaluation by a nutritionist as neededEchocardiogram to evaluate for structural cardiac defectsRenal ultrasonography to evaluate for structural kidney or genitourinary (GU) anomaliesOphthalmologic examination, including a dilated fundus examination and visual acuityAudiology evaluation with auditory brain stem response testing and otoacoustic emission testing to assess for hearing lossTreatment of ManifestationsThe following are appropriate:Occupational, physical and/or speech therapies to optimize developmental outcomesNutritional supplementation and/or gastrostomy tube placement as needed to meet nutritional needsSpectacles as needed to correct refractive errors and surgery as needed for strabismus and/or ptosisHearing aids, as neededSurveillanceSurveillance 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 gainRegular follow up of ophthalmologic and/or audiologic abnormalitiesBecause of the rarity of tumors in CSS, the utility for tumor surveillance has not been determined. Evaluation of Relatives at RiskSee 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 InvestigationSearch 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.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Coffin-Siris Syndrome: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDSMARCB122q11.23SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1SMARCB1 homepage - Mendelian genesSMARCB1SMARCA419p13.2Transcription activator BRG1SMARCA4 homepage - Mendelian genesSMARCA4SMARCE117q21.2SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily E member 1SMARCE1 @ LOVDSMARCE1ARID1A1p36.11AT-rich interactive domain-containing protein 1AARID1A @ LOVDARID1AARID1B6q25.3AT-rich interactive domain-containing protein 1BARID1B @ LOVDARID1BData are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Coffin-Siris Syndrome (View All in OMIM) View in own window 135900COFFIN-SIRIS SYNDROME; CSS 601607SWI/SNF-RELATED, MATRIX-ASSOCIATED, ACTIN-DEPENDENT REGULATOR OF CHROMATIN, SUBFAMILY B, MEMBER 1; SMARCB1 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 614556AT-RICH INTERACTION DOMAIN-CONTAINING PROTEIN 1B; ARID1BMolecular 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. ARID1ANormal 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. ARID1BNormal 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. SMARCA4Normal 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. SMARCB1Normal 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. SMARCE1Normal 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.