Alternative titles; symbols
HGNC Approved Gene Symbol: SMARCB1
Cytogenetic location: 22q11.23 Genomic coordinates (GRCh38): 22:23,786,966-23,838,009 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 22q11.23 | {Rhabdoid tumor predisposition syndrome 1} | 609322 | Autosomal dominant | 3 |
| {Schwannomatosis-1, susceptibility to} | 162091 | Autosomal dominant | 3 | |
| Coffin-Siris syndrome 3 | 614608 | Autosomal dominant | 3 | |
| Rhabdoid tumors, somatic | 609322 | 3 |
The SMARCB1 gene encodes a subunit of the SWI/SNF ATP-dependent chromatin-remodeling complex.
Versteege et al. (1998) identified the SMARCB1 gene, which they called SNF5/INI1, within a region frequently deleted in malignant rhabdoid tumors (MRT). By RT-PCR, they cloned SNF5/INI1. The deduced 385-amino acid protein has a C-terminal domain similar to yeast Snf5, which includes a repeated peptide sequence and possible C-terminal coiled-coil structure. Use of a cryptic splice donor site in exon 2 results in a SNF5/INI1 protein lacking a short peptide sequence in its N-terminal region.
Turelli et al. (2001) showed that incoming retroviral preintegration complexes trigger the exportin (602559)-mediated cytoplasmic export of the SWI/SNF component INI1 and of the nuclear body constituent PML (102578). They further showed that the human immunodeficiency virus (HIV) genome associates with these proteins before nuclear migration. In the presence of arsenic, PML was sequestered in the nucleus, and the efficiency of HIV-mediated transduction was markedly increased. These results unveiled an unsuspected cellular response that interferes with the early steps of HIV replication.
Wu et al. (2002) noted that GADD34 (PPP1R15A; 611048) and SNF5 can coexist in a trimeric complex with chimeric leukemic HRX (MLL; 159555) fusion proteins, leading to inhibition of GADD34-mediated apoptosis. By mutation analysis, they showed that the GADD34 region homologous to the HSV-1 ICP34.5 protein was necessary for interaction with SNF5. SNF5 could bind independently with the protein phosphatase-1 (PP1) catalytic subunit (PPP1CA; 176875) and stimulate its activity in solution and in complex with GADD34. SNF5 and PP1 did not compete for GADD34 binding, but rather formed a stable trimeric complex with GADD34. Wu et al. (2002) proposed that GADD34 mediates growth suppression, at least in part, through its interaction with SNF5. They suggested that SNF5 may function as a regulatory subunit of PP1, either independently or together with GADD34.
Vries et al. (2005) found that loss of SNF5 function in malignant rhabdoid tumor-derived cells led to polyploidy and chromosomal instability. Reexpression of SNF5 restored the coupling between cell cycle progression and ploidy checkpoints. In contrast, cancer-associated SNF5 mutations exacerbated poly- and aneuploidization by abrogating chromosome segregation. Vries et al. (2005) found that loss of SNF5 function caused elevated levels of MAD2 (MAD2L1; 601467) due to unregulated E2F1 (189971) activity, which can be sufficient to cause defective spindle checkpoint. They concluded that SNF5 exerts ploidy control through a pathway that includes p16(INK4a) (CDKN2A; 600160), cyclin D (see 168461), CDK4 (123829), RB1 (614041), and E2F.
Using mass spectrometry, immunoprecipitation, and chromatin immunoprecipitation analysis, Jagani et al. (2010) found that mouse Snf5 interacted with Gli (165220) at Gli-responsive promoters, including the Gli promoter itself. Knockdown of Snf5 in mouse embryonic fibroblasts increased expression of Gli and Gli-responsive genes, notably those of the hedgehog pathway (see SHH; 600725). Conversely, expression of SNF5 in SNF5-deficient human cells reduced GLI expression. Microarray analysis revealed that primary human tumors with reduced SNF5 expression showed enriched expression of genes associated with hedgehog pathway activation and GLI overexpression. Knockdown studies also showed that GLI was required for proliferation of SNF5-deficient human cells. Jagani et al. (2010) concluded that SNF5 is a negative regulator of GLI-hedgehog signaling.
By reexpression of SMARCB1 in brain and kidney rhabdoid cell lines and in Smarcb1-null mouse embryonic fibroblasts, Wang et al. (2017) found that SMARCB1 increased the number of SWI-SNF complexes and increased protein levels of numerous SWI/SNF subunits, particularly ARID1A (603024) and ARID1B (614556). Chromatin immunoprecipitation analysis showed that reexpression of SMARCB1 also increased chromatin occupancy by SMARCA4 (603254) and SMARCC1 (601732). With or without SMARCB1, SWI/SNF complexes predominantly targeted enhancers distal to transcriptional start sites, with the number of sites markedly increased in the presence of SMARCB1. Wang et al. (2017) concluded that SMARCB1 stabilizes SWI/SNF complexes at enhancers.
Versteege et al. (1998) found that the SMARCB1 gene contains 9 exons and spans approximately 50 kb.
Cryoelectron Microscopy
He et al. (2020) reported the 3.7-angstrom resolution cryoelectron microscopy structure of human BRG1 (SMARCA4; 603254)/BRM-associated factor complex bound to the nucleosome. The structure revealed that the nucleosome is sandwiched by the base and the ATPase modules, which are bridged by the actin-related protein (ARP) module, composed of an ACTL6A (604958)-ACTB (102630) heterodimer and the long alpha helix of the helicase-SANT-associated region (HSA) of SMARCA4. The ATPase motor is positioned proximal to nucleosomal DNA and, upon ATP hydrolysis, engages with and pumps DNA along the nucleosome. The C-terminal alpha helix of SMARCB1, enriched in positively charged residues frequently mutated in cancers, mediates interactions with an acidic patch of the nucleosome. ARID1A (603024) and the SWI/SNF complex subunit SMARCC (601732) serve as a structural core and scaffold in the base module organization, respectively.
The SMARCB1 gene maps to chromosome 22q11.2 (Versteege et al., 1998).
Somatic Mutations in the SMARCB1 Gene
Versteege et al. (1998) mapped the most frequently deleted part of chromosome 22q11.2 from a panel of 13 cell lines from malignant rhabdoid tumors (MRT, see 609322) and observed 6 homozygous deletions that delineated the smallest region of overlap, which fell in the region of the SNF5/INI1 gene. Analysis of 12 of these lines showed somatic frameshift or nonsense mutations in the SMARCB1 gene (see, e.g., 601607.0001; 601607.0002). All were associated with loss of heterozygosity (LOH) at the other allele, consistent with the 2-hit recessive model of oncogenesis and consistent with the hypothesis that SNF5/INI1 is the MRT tumor suppressor gene. Versteege et al. (1998) noted that the SWI/SNF complexes, which have been identified in organisms from yeast to humans, are thought to be important in the remodeling of chromatin structure, and the authors concluded that altered chromatin organization at specific DNA sites may be crucial in the process of oncogenesis.
Sevenet et al. (1999) sought SNF5/INI1 mutations in 229 tumors of various origins using a screening method based on denaturing high-performance liquid chromatography. A total of 31 homozygous deletions and 36 point alterations were identified. Point mutations were scattered along the coding sequence and included nonsense (15), frameshift (15), splice site (3), missense (2), and editing (1) mutations. Mutations were retrieved in most rhabdoid tumors, whatever their sites of origin, indicating the common pathogenetic origin of these tumors. Recurrent SNF5/INI1 alterations were also observed in choroid plexus carcinomas and in a subset of central primitive neuroectodermal tumors and medulloblastomas. In contrast, SNF5/INI1 point mutations were not detected in breast cancers, Wilms tumors, gliomas, ependymomas, sarcomas, and other tumor types, even though most analyzed cases harbored loss of heterozygosity at 22q11.2 loci. Thus, SNF5/INI1 mutations define a genetically homogeneous family of highly aggressive cancers occurring mainly in young children and frequently, but not always, exhibiting a rhabdoid phenotype.
Schmitz et al. (2001) found the same somatic mutation in exon 9 of the SMARCB1 gene (arg377-to-his; R377H) in 4 of 126 meningiomas (607174). The data indicated that SMARCB1 is a candidate tumor suppressor gene on chromosome 22 that may be important for the genesis of meningiomas.
Rhabdoid Tumor Predisposition Syndrome 1
In affected members of 3 different families with the rhabdoid predisposition syndrome-1 (RTPS1; 609322), Sevenet et al. (1999) identified heterozygous germline loss-of-function mutations in the SMARCB1 gene (see, e.g., 601607.0003). Tumor tissue, when available, showed somatic loss of heterozygosity (LOH) at the SMARCB1 locus. In all tested cases, DNA from parents demonstrated normal SNF5/INI1 sequences, thereby indicating the de novo occurrence of the mutations, which were shown to involve the maternal allele in 1 case and the paternal allele in 2 other cases. The data indicated that constitutional mutation of this gene predisposes to renal or extrarenal MRT and also to a variety of tumors of the CNS, including choroid plexus carcinoma, medulloblastoma, and central primitive neuroectodermal tumor.
In a multigenerational family with RTPS1, Taylor et al. (2000) identified a G-to-A transition at position +1 of the donor splice site of exon 7 of the SMARCB1 gene (601607.0004). The mutation was predicted to cause a truncation of the protein. The mother of the proband had the mutation but was completely healthy; a maternal uncle had died at age 2 years from a posterior fossa choroid plexus carcinoma. A sib of the maternal grandfather had died in infancy from a disease process consistent with a pediatric brain tumor. The proband was aged 18 months when she presented with a cerebellar malignant rhabdoid tumor.
Schwannomatosis 1 and Meningiomas
Schwannomatosis-1 (SWN1; 162091) is characterized by the development of multiple spinal, peripheral, and cranial nerve schwannomas in the absence of vestibular schwannomas. The presence of vestibular schwannomas is diagnostic of neurofibromatosis type 2 (NF2; 101000). Molecular analyses identified somatically acquired mutations in the NF2 gene in schwannomas of patients with schwannomatosis. However, linkage studies performed in families affected with schwannomatosis excluded NF2 as the germline-transmissible schwannomatosis gene and suggested a location of the gene near marker D22S1174, which is in the region of chromosome 22 centromeric to NF2 (MacCollin et al., 2003). In a father and daughter who both had schwannomatosis, Hulsebos et al. (2007) reported an inactivating germline mutation in exon 1 of the tumor suppressor gene INI1/SMARCB1 (601607.0005). Inactivation of the wildtype INI1 allele, by a second mutation in exon 5 (601607.0006) or by clear loss, was found in 2 of 4 investigated schwannomas from these patients. All 4 schwannomas displayed complete loss of nuclear INI1 protein expression in part of the cells. Although the exact oncogenetic mechanism in these schwannomas remained to be elucidated, the findings suggested that INI1 is a predisposing gene in familial schwannomatosis.
Sestini et al. (2008) identified a de novo germline deletion/insertion in the SMARCB1 gene (601607.0007) in a patient with schwannomatosis. Three different tumors derived from this patient showed the deletion/insertion and a somatic NF2 mutation on the same allele, but no other SMARCB1 mutations. In addition, 2 of the tumors had somatic loss of heterozygosity encompassing the SMARCB1 and NF2 region. In tumor tissues from 2 other patients, Sestini et al. (2008) found a somatic SMARCB1 or NF2 mutation in association with loss of heterozygosity, but no germline mutations were identified. Sestini et al. (2008) postulated that a 4-hit mechanism involving 2 distinct but linked tumor suppressor genes, SMARCB1 and NF2, may underlie the development of tumors in a subset of patients with schwannomatosis. However, given the low frequency of SMARCB1 germline mutations, there may also be additional loci involved.
In 5 (33.3%) of 15 families with schwannomatosis and 2 (7.1%) of 28 individuals with sporadic schwannomatosis, Hadfield et al. (2008) identified germline mutations in the SMARCB1 gene (see, e.g., 601607.0008). In all of these individuals in whom tumor tissue was available, tumor tissue showed a second hit with loss of SMARCB1. In addition, all of these patients had biallelic somatic inactivation of the NF2 gene. Similar to the report of Sestini et al. (2008), the findings suggested that 4 hits of these 2 genes are usually necessary to develop schwannomas. Germline SMARCB1 mutations were associated with a higher number of spinal tumors in patients with a positive family history (p = 0.004).
In 5 affected members of a family with schwannomatosis and multiple meningiomas, Christiaans et al. (2011) identified a heterozygous mutation in the SMARCB1 gene (P48L; 601607.0011). Meningiomas developed between ages 34 and 56 years, both in the cranium as extra-axial lesions and in the spinal cord as extramedullary lesions. In addition, 1 patient developed multiple chest wall and spinal schwannomas and another developed a vestibular schwannoma. Four meningiomas available for study all showed loss of the wildtype allele, consistent with the 2-hit hypothesis of tumorigenesis. Two different meningioma tumors from the same patient also carried 2 different heterozygous somatic mutations in the NF2 gene (607379) as well as loss of heterozygosity at the NF2 locus. Christiaans et al. (2011) concluded that the SMARCB1 P48L mutation predisposed the carriers to the development of meningiomas. The mutation may also have predisposed carriers to schwannomas, implying that meningiomas may be part of the schwannomatosis tumor spectrum, but the schwannomas may also be coincidental findings. The role of the NF2 mutations was uncertain, but may contribute to a 4-hit hypothesis involving 2 genes.
Coffin-Siris Syndrome 3
Tsurusaki et al. (2012) identified 2 mutations in the SMARCB1 gene in 4 patients with Coffin-Siris syndrome (CSS3; 614608). Three patients carried the same in-frame deletion (601607.0012) and 1 patient carried a missense mutation (601607.0013). That the mutations were nontruncating implied a gain-of-function or a dominant-negative effect.
Misawa et al. (2004) observed a translocation t(1;22) with concurrent deletion of 22q11.2 resulting in homozygous deletion of the SNF5 gene in a newly established cell line derived from an extrarenal rhabdoid tumor. The patient was a 5-month-old boy who was found to have a thoracic mass without metastases at the time of diagnosis. Cytogenetic analysis of peripheral lymphocytes demonstrated a normal male karyotype. Combined total resection, chemotherapy, and radiation therapy led to apparent cure by the age of 4 years.
Most samples and cell lines from malignant rhabdoid tumors show biallelic inactivating mutations of the SNF5 gene, suggesting that SNF5 may act as a tumor suppressor. Roberts et al. (2000) examined the role of Snf5 in development and cancer in a mouse model. They found that Snf5 is widely expressed during embryogenesis with focal areas of high-level expression in the mandibular portion of the first branchial arch and central nervous system. Homozygous knockout of Snf5 resulted in lethality by embryonic day 7, whereas heterozygous mice were born at the expected frequency and appeared normal. However, beginning as early as 5 weeks of age, heterozygous mice developed tumors consistent with malignant rhabdoid tumor. Most tumors arose in soft tissues derived from the first branchial arch.
Tsikitis et al. (2005) found that tumors developed from Ini1 +/- mice were rhabdoid, defective for Ini1 protein, and expressed cyclin D1 (CCND1; 168461). They crossed Ini1 +/- mice with Ccnd1 -/- mice and found that these mice did not develop spontaneous tumors, in contrast to parental Ini1 +/- mice. Tsikitis et al. (2005) concluded that CCND1 is a key mediator in the genesis of rhabdoid tumors.
In a cell line from a 21-year-old male with malignant rhabdoid tumor of the kidney (see 609322), Versteege et al. (1998) found a somatic 1-bp deletion of nucleotide 317 of the SNF5 gene in 1 allele and loss of heterozygosity at the other allele. The findings were consistent with a 2-hit recessive model of oncogenesis and supported the hypothesis that SMARCB1 acts as a tumor suppressor gene.
In a cell line from a 7-year-old female with malignant rhabdoid tumor of the abdomen (see 609322), Versteege et al. (1998) found a somatic 19-bp deletion beginning with nucleotide 37 in 1 allele of the SNF5 gene and loss of heterozygosity at the other allele. The findings were consistent with a 2-hit recessive model of oncogenesis and supported the hypothesis that SMARCB1 acts as a tumor suppressor gene.
In 3 sibs with the rhabdoid tumor predisposition syndrome-1 (RTPS1; 609322), Sevenet et al. (1999) identified a heterozygous germline 1-bp deletion (591delG) in the SMARCB1 gene, predicted to result in a frameshift and premature termination. One of the patients had a choroid plexus carcinoma at age 4 months, and 2 had atypical teratoid and rhabdoid tumor at ages 2 months and 12 months, respectively. Tumor tissue from 1 of the patients showed somatic loss of heterozygosity. In contrast, DNA from the healthy parents and from the 3 unaffected sibs demonstrated wildtype sequences. These studies demonstrated that the mutation was inherited from the mother and probably occurred during oogenesis, since both maternal fibroblast DNA and maternal blood DNA displayed normal sequences.
Taylor et al. (2000) identified a family afflicted over multiple generations with posterior fossa tumors of infancy, including central nervous system malignant rhabdoid tumor and choroid plexus carcinoma, consistent with the rhabdoid tumor predisposition syndrome-1 (RTPS1; 609322). Both affected and some unaffected family members had a germline splice site mutation of the SMARCB1 gene, leading to exclusion of exon 7 from the mature cDNA and a subsequent frameshift. Tumor tissue showed loss of the wildtype SMARCB1 allele, in keeping with a tumor suppressor gene. The findings suggested that germline mutations in SMARCB1 are associated with a novel autosomal dominant syndrome with incomplete penetrance that predisposes to malignant posterior fossa brain tumors of infancy.
In blood DNA from a proband with schwannomatosis-1 (SWN1; 162091) and in DNA from a seborrheic keratitis lesion of her deceased father, Hulsebos et al. (2007) identified a heterozygous C-to-T transition at mRNA position 34 in exon 1 of the SMARCB1 gene that resulted in conversion of a glutamine to a stop codon at residue 12 (Q12X). The mutation was also found in DNA of all 4 schwannomas available for further analysis (1 from the proband and 3 from her father), but not in blood DNA from the clinically unaffected mother. The proband, a 22-year-old woman, presented with pain in her back that had been increasing for 3 years. MRI scan of the lumbar spine showed intradural tumors at L1 and L2-L3. After laminectomy, 3 tumors arising from the lumbar spinal nerve roots were removed and diagnosed histopathologically as schwannomas. MRI scans of the cervical and thoracic spine showed multiple intradural, extramedullary lesions of variable size. The most cranial lesion was at C6-C7. No vestibular schwannomas were present. No mutation was found in the NF2 gene (607379). The father of the proband had a history of diabetes mellitus and had surgery at the age of approximately 35 years for Wolff-Parkinson-White syndrome (194200). When he was 49 years of age, subcutaneous tumors were removed from his right thumb, right index finger, and the first web space of his left hand and were diagnosed histopathologically as schwannomas. In subsequent years, additional schwannomas were removed from his right upper arm and right thumb. Dermatologic and ophthalmologic examinations revealed no signs of neurofibromatosis.
In DNA from a schwannoma from a man whose daughter also had schwannomatosis (SWN1; 162091), Hulsebos et al. (2007) identified heterozygosity for a 544C-T transition in exon 5 of the SMARCB1 gene, which resulted in premature termination of the protein (gln182 to ter, Q182X). This mutation was found in conjunction with the germline mutation Q12X (601607.0005). No mutation in the NF2 gene (607379) was found.
In 1 of 21 unrelated patients with schwannomatosis (SWN1; 162091), Sestini et al. (2008) identified a de novo germline insertion/deletion (203delinsTACC) in exon 2 of the SMARCB1 gene, resulting in a frameshift. Three different tumors derived from this patient showed the same mutation, but no other SMARCB1 mutations; however, all 3 tumors showed a somatic NF2 (607379) mutation on the same allele. In addition, 2 of the tumors had loss of heterozygosity encompassing the SMARCB1 and NF2 region. Sestini et al. (2008) postulated that a 4-hit mechanism involving 2 distinct but linked tumor suppressor genes, SMARCB1 and NF2, may underlie the development of tumors in a subset of patients with schwannomatosis.
In affected members of a family with schwannomatosis (SWN1; 162091), Hadfield et al. (2008) identified a heterozygous 7-bp deletion at the start of exon 3 of the SMARCB1 gene, predicted to result in a splicing defect. Tumor tissue from these patients showed loss of heterozygosity for SMARCB1 as well as biallelic loss of NF2 (607379). The findings suggested that 4 hits of these 2 genes may be necessary to develop schwannomas.
In affected members of a family with hereditary schwannomatosis (SWN1; 162091) spanning 4 generations, Swensen et al. (2009) identified a heterozygous germline 2,631-bp duplication in chromosome 22q11 that included exon 6 of the SMARCB1 gene. The mutation was predicted to result in premature protein termination. Two patients with mutations had malignant rhabdoid tumors (RTPS1; 609322), and a third was believed to have had a rhabdoid tumor. Two rhabdoid tumors and several schwannomas showed somatic loss of the SMARCB1 gene.
In affected members of a family with multiple schwannomas (SWN1; 162091), Bacci et al. (2010) identified a heterozygous 92A-T transversion in exon 1 of the SMARCB1 gene, resulting in a glu31-to-val (E31V) substitution in a highly conserved residue. In silico analysis predicted that the E31V-mutant would disrupt a donor splice site, and RNA studies showed loss of the mutant transcript, suggesting altered splicing or nonsense-mediated decay. Three affected individuals with schwannomas also developed multiple meningiomas (607174), which Bacci et al. (2010) suggested should be considered a component of familial schwannomatosis.
In 5 affected members of a family with schwannomatosis (SWN1; 162091) and multiple meningiomas (607174), Christiaans et al. (2011) identified a heterozygous 143C-T transition in exon 2 of the SMARCB1 gene, resulting in a pro48-to-leu (P48L) substitution in a highly conserved residue. The mutation was not found in 100 controls. Meningiomas developed between ages 34 and 56 years, both in the cranium as extra-axial lesions and in the spinal cord as extramedullary lesions. In addition, 1 patient developed multiple chest wall and spinal schwannomas and another developed a vestibular schwannoma. Four meningiomas available for study all showed loss of the normal C allele in SMARCB1, which was transcribed into a stable mRNA. These findings were consistent with the 2-hit hypothesis of tumorigenesis. Two different meningioma tumors from the same patient also carried 2 different heterozygous somatic mutations in the NF2 gene (607379) as well as loss of heterozygosity at the NF2 locus. Christiaans et al. (2011) concluded that the SMARCB1 P48L mutation predisposed the carriers to the development of meningiomas. The mutation may also have predisposed carriers to schwannomas, implying that meningiomas may be part of the schwannomatosis tumor spectrum, but the schwannomas may also be coincidental findings. The role of the NF2 mutations was uncertain, but may contribute to a 4-hit hypothesis involving 2 genes.
Van den Munckhof et al. (2012) provided further studies of the family reported by Christiaans et al. (2011). Reexamination of tumor tissue from 4 meningiomas and 2 schwannomas showed that all tumors had LOH for both SMARCB1 and NF2, consistent with a deletion of a segment of chromosome 22 containing these 2 genes. Three meningiomas and 2 schwannomas were each found to carry somatic mutations in the NF2 gene. Thus, the genetic changes found in the 2 tumor types were the same and characteristic for SMARCB1-mutation positive tumors: retention of the exon 2 mutation, acquisition of an NF2 mutation, and LOH of the wildtype allele of both genes. In addition, van den Munckhof et al. (2012) identified 11 more carriers of the P48L mutation in this family. Eight of these 11 mutation carriers were found to carry 11 lesions suggestive of cranial meningioma and 6 spinal lesions consistent with meningiomas or schwannomas. Nine (82%) of the 11 cranial meningiomas were found in the falx cerebri. Van den Munckhof et al. (2012) concluded that meningiomas should be included in the schwannomatosis tumor spectrum.
In 3 patients (patients 4, 21, and 22) with Coffin-Siris syndrome (CSS3; 614608), Tsurusaki et al. (2012) identified a heterozygous 3-bp in-frame deletion in the SMARCB1 gene (1091_1093delAGA) that resulted in deletion of lysine-364 (lys364del). The mutation was de novo in 2 cases, and parental samples were unavailable in the third. This mutation was not seen in any of 502 Japanese control chromosomes.
In Patient 11 with Coffin-Siris syndrome (CSS3; 614608), Tsurusaki et al. (2012) detected a heterozygous de novo G-to-A transition at nucleotide 1130 of the SMARCB1 gene that resulted in an arg-to-his substitution at codon 377 (R377H). This mutation was not seen in any of 500 Japanese control chromosomes.
In a girl with Coffin-Siris syndrome (CSS3; 614608), Kleefstra et al. (2012) identified a de novo heterozygous G-to-A transition at nucleotide 110 of the SMARCB1 gene, resulting in an arg-to-his substitution at codon 37 (R37H). Kleefstra et al. (2012) described the phenotype as Kleefstra syndrome spectrum disorder (KSS). Neonatally, Down syndrome was suspected. Shunting was required at the age of 2.5 years for hydrocephalus, and the patient later required a plexectomy because of high cerebrospinal fluid production. In addition to intellectual disability and childhood hypotonia, the patient had brachycephaly, midface hypoplasia, coarse facies, hypertelorism, synophrys, short nose, anteverted nostrils, macroglossia, tented and cupid-bowed upper lip, and brachydactyly.
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