Alternative titles; symbols
HGNC Approved Gene Symbol: RAD21
Cytogenetic location: 8q24.11 Genomic coordinates (GRCh38) : 8:116,845,934-116,874,776 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 8q24.11 | ?Mungan syndrome | 611376 | Autosomal recessive | 3 |
| Cornelia de Lange syndrome 4 | 614701 | Autosomal dominant | 3 |
Eukaryotic sister chromatids remain connected from the time of synthesis until they are separated in anaphase. This cohesion depends on a complex of proteins known as cohesins. In vertebrates, unlike in yeast, the cohesins dissociate from chromosome arms earlier in M phase, during prophase. Small amounts of cohesin remain near the centromere until metaphase, with complete removal at the beginning of anaphase. Cohesin complexes contain SCC1 (RAD21), SMC1 (300040), SMC3 (606062), and either SA1 (STAG1; 604358) or SA2 (STAG2; 300826). The complexes, in turn, interact with PDS5 (see 613200), a protein implicated in chromosome cohesion, condensation, and recombination in yeast (summary by Sumara et al., 2000).
By sequencing cDNAs randomly selected from a cDNA library derived from a human immature myeloid cell line, Nomura et al. (1994) identified a cDNA encoding a homolog of S. pombe Rad21 that they termed KIAA0078. The deduced KIAA0078 protein has 631 amino acids. Northern blot analysis detected equivalent expression of KIAA0078 in all tissues tested.
By searching EST databases for sequences similar to yeast Rad21 and subsequently searching with the worm and fly sequences these searches identified, McKay et al. (1996) isolated a cDNA encoding a mouse homolog of Rad21. By probing a testis cDNA library with the mouse sequence, they obtained a cDNA encoding human RAD21, which they termed HR21. Sequence analysis predicted that the 631-amino acid phosphoprotein is 96% and 25% identical to the mouse and yeast proteins, respectively, and that they are most conserved at the N and C termini. These proteins all have 2 nuclear localization signals and an acidic stretch consistent with a chromatin-binding role. Northern blot analysis revealed ubiquitous expression of a 3.1-kb transcript in mouse tissues, with highest expression in testis and thymus. Testis also expressed a 2.2-kb transcript in postmeiotic cells. Northern blot analysis determined that expression increases during S phase and peaks in G2 phase in HeLa cells. There was no increase in expression after ionizing radiation.
By immunoscreening a placenta cDNA expression library, Sadano et al. (2000) cloned RAD21, which they designated NXP1. Western blot analysis and immunofluorescence microscopy showed nuclear expression of a 110-kD protein, which was higher than the predicted 70 kD most likely due to phosphorylation. Mutation and immunoprecipitation analyses with truncated proteins indicated that the N terminus of RAD21 is responsible for the nuclear localization and binding to a 28-kD nuclear matrix protein.
By immunoblot analysis, Hoque and Ishikawa (2001) showed that the approximately 120-kD RAD21 protein is expressed in the nucleus at the same level throughout the cell cycle and that it becomes hyperphosphorylated during M phase. Immunofluorescence microscopy demonstrated that RAD21 begins to dissociate from arm region chromatin during prophase and from centromere regions during metaphase and anaphase and is associated with spindles. In telophase and cytokinesis, RAD21 is associated with microtubules and then resumes association with chromatin during cytokinesis.
Hauf et al. (2001) identified separase (see 604143) cleavage sites in SCC1/RAD21 after arg172 and after arg450. Immunofluorescence microscopy demonstrated that cleavage-site mutant RAD21 dissociated from chromosomes by prophase, like wildtype, but was associated with multiple mitotic abnormalities. Flow cytometric and video microscopic analyses showed that cells with noncleavable RAD21 tend to express aneuploidy in interphase and that they initiate cytokinesis without segregating chromosomes. Analysis of metaphase cells suggested that these cells reenter interphase with sister chromatids still connected and form diplochromosomes in the subsequent mitosis. Hauf et al. (2001) proposed that anaphase defects may be caused by RAD21 cleavage defects as well as by securin (PTTG1; 604147) overexpression or deletion.
Hakimi et al. (2002) reported the isolation of a human SNF2 (600014)-containing chromatin remodeling complex that encompasses components of the cohesin and NURD (see 603526) complexes. They showed that the RAD21 subunit of the cohesin complex directly interacts with the ATPase subunit SNF2. Mapping of RAD21, SNF2, and Mi2 (see 603277) binding sites by chromatin immunoprecipitation experiments revealed the specific association of these 3 proteins with human DNA elements containing alu sequences. Hakimi et al. (2002) found a correlation between modification of histone tails and association of the SNF2/cohesin complex with chromatin. In addition, they showed that the association of the cohesin complex with chromatin can be regulated by the state of DNA methylation. Finally, they presented evidence pointing to a role for the ATPase activity of SNF2 in the loading of RAD21 on chromatin.
Hoque and Ishikawa (2002) found that expression of N-terminally truncated SCC1 had a dominant-negative effect on SCC1 function in several human cell lines. Cells expressing the N-terminally truncated protein showed impaired cell growth. Within mitotic cells, chromatids condensed normally, but the 2 pairs of sister chromatids were disjoined, separated prematurely, and became positioned randomly within nuclei. Spindle assembly checkpoint was activated.
In yeast, the cohesin complex is essential for sister chromatid cohesion during mitosis. The Smc1 (300040) and Smc3 (606062) subunits are rod-shaped molecules with globular ABC-like ATPases at one end and dimerization domains at the other, connected by long coiled coils. Smc1 and Smc3 associate to form V-shaped heterodimers. Their ATPase heads are thought to be bridged by a third subunit, Scc1, creating a huge triangular ring that can trap sister DNA molecules. Gruber et al. (2003) studied whether cohesin forms such rings in vivo. Proteolytic cleavage of Scc1 by separase at the onset of anaphase triggers its dissociation from chromosomes. The authors showed that N- and C-terminal Scc1 cleavage fragments remain connected due to their association with different heads of a single Smc1/Smc3 heterodimer. Cleavage of the Smc3 coiled coil was sufficient to trigger cohesin release from chromosomes and loss of sister cohesion, consistent with a topologic association with chromatin.
Wendt et al. (2008) described cohesin-binding sites in the human genome and showed that most of these are associated with the CCCTC-binding factor (CTCF; 604167), a zinc finger protein required for transcriptional insulation. CTCF is dispensable for cohesin loading onto DNA, but is needed to enrich cohesin at specific binding sites. Cohesin enables CTCF to insulate promoters from distant enhancers and controls transcription at the H19 (103280)/IGF2 (147470) locus. This role of cohesin seems to be independent of its role in cohesion. Wendt et al. (2008) proposed that cohesin functions as a transcriptional insulator, and speculated that subtle deficiencies in this function contribute to 'cohesinopathies' such as Cornelia de Lange syndrome (see 122470).
Cohesin's Scc1, Smc1, and Smc3 subunits form a tripartite ring structure, and it had been proposed that cohesin holds sister DNA molecules together by trapping them inside its ring. To test this, Haering et al. (2008) used site-specific crosslinking to create chemical connections at the 3 interfaces between the 3 constituent polypeptides of the ring, thereby creating covalently closed cohesin rings. As predicted by the ring entrapment model, this procedure produced dimeric DNA-cohesin structures that are resistant to protein denaturation. Haering et al. (2008) concluded that cohesin rings concatenate individual sister minichromosome DNA molecules.
Seitan et al. (2011) deleted the cohesin locus Rad21 in mouse thymocytes at a time in development when these cells stop cycling and rearrange their T-cell receptor alpha locus (TCRA; see 186880). Rad21-deficient thymocytes had a normal life span and retained the ability to differentiate, albeit with reduced efficiency. Loss of Rad21 led to defective chromatin architecture at the Tcra locus, where cohesin-binding sites flank the TEA promoter and the E-alpha enhancer, and demarcate Tcra from interspersed Tcrd (see 186810) elements and neighboring housekeeping genes. Cohesin was required for long-range promoter-enhancer interactions, Tcra transcription, H3K4me3 histone modifications that recruit the recombination machinery, and Tcra rearrangement. Provision of prearranged TCR transgenes largely rescued thymocyte differentiation, demonstrating that among thousands of potential target genes across the genome, defective Tcra rearrangement was limiting for the differentiation of cohesin-deficient thymocytes. Seitan et al. (2011) concluded that their findings firmly established a cell division-independent role for cohesin in Tcra locus rearrangement and provided a comprehensive account of the mechanisms by which cohesin enables cellular differentiation in a well-characterized mammalian system.
Huis in 't Veld et al. (2014) found that cohesin's proposed DNA exit gate is formed by interactions between SCC1 and the coiled-coil region of SMC3. Mutation of this interface abolished cohesin's ability to stably associate with chromatin and to mediate cohesion. Electron microscopy revealed that weakening of the SMC3-SCC1 interface resulted in opening of cohesin rings, as did proteolytic cleavage of SCC1. Huis in 't Veld et al. (2014) suggested that these open forms may resemble intermediate states of cohesin normally generated by the release factor WAPL (610754) and the protease separase (ESPL1; 604143), respectively.
Liu et al. (2021) found that Wapl was required for maintaining the pluripotent transcriptional state of mouse embryonic stem cells (mESCs), as acute depletion of Wapl resulted in cohesin redistribution and mESC differentiation. RNA-sequencing analysis revealed differential expression of genes in Wapl-depleted mESCs, with 80% being associated with embryonic tissue development, embryonic morphogenesis, and cell differentiation. Cohesin was required for maintaining pluripotency-specific gene expression by binding to specific regions in mESCs in a Wapl-dependent manner, and redistribution of cohesin binding was a unique feature in differentiated cells. As a result, mESC differentiation upon Wapl depletion was accompanied by global redistribution of cohesin from mESC type-specific binding regions to regions specific to differentiated cells. This cohesin redistribution affected local chromatin interactions and gene expression in a reversible manner. Cohesin binding to pluripotency-specific sites was dependent on the pioneer transcription factors Oct4 (POU5F1; 164177) and Sox2 (184429), as these factors created an open chromatin platform for cohesin binding.
Xie et al. (2022) found that depletion of the cohesin complex component Rad21 triggered spatial mixing of accessible chromatin domains (ACDs) without affecting their compaction in mouse ESCs. Moreover, spatial mixing of ACDs was independent of transcription, but it involved the bromodomain and extraterminal (BET) protein family. Depletion analysis in mouse ESCs identified Brd2 (601540) as a BET protein involved in organizing accessible chromatin and showed that Brd2 maintained compaction of ACDs and promoted their interactions in the absence of cohesin. The interplay between Brd2 and cohesin regulated genome topology in the nucleus, and cohesin antagonized Brd2 binding to chromatin and counteracted its ability to promote interactions between ACDs. In the absence of cohesin, the affinity of Brd2 for active chromatin increased. In addition to cohesin, Brd4 (608749) competed with Brd2 to inhibit its activities in genome organization, implying a division of labor for BET proteins to govern distinct regulatory processes in the accessible genome. Polymer simulation supported a model of Brd2-cohesin interplay for nuclear topology, where genome compartmentalization resulted from competition between loop extrusion and chromatin state-specific affinity interactions.
Crystal Structure
Gligoris et al. (2014) showed that the N-terminal domain of yeast Scc1 contains 2 alpha-helices, forming a 4-helix bundle with the coiled coil emerging from the adenosine triphosphatase head of Smc3 (606062). Mutations affecting this interaction compromise cohesin's association with chromosomes. The interface is far from Smc3 residues, whose acetylation prevents cohesin's dissociation from chromosomes. Gligoris et al. (2014) concluded that cohesin complexes holding chromatids together in vivo do indeed have the configuration of heterotrimeric rings, and sister DNAs are entrapped within these.
By somatic cell hybrid analysis, Nomura et al. (1994) mapped the RAD21 gene to chromosome 8. Using FISH, McKay et al. (1996) refined the localization to 8q24.
Cornelia de Lange Syndrome 4 with or without Midline Brain Defects
In 2 unrelated patients with Cornelia de Lange syndrome-4 (CDLS4; 614701), Deardorff et al. (2012) identified different de novo heterozygous mutations in the RAD21 gene (P376R; 606462.0001 and C585R; 606462.0002). These mutations were identified by screening of the RAD21 gene in 258 individuals with a CDLS-like phenotype after genomewide copy-number analysis had identified a different patient with a de novo deletion of chromosome 8q24.1 that included RAD21. In vitro studies showed that the P376R mutation resulted in altered activity of the mutant protein rather than a loss of function. Patient cells showed decreased sister chromatid separation, increased aneuploidy, and defective DNA repair, as well as abnormal transcriptional activity in a zebrafish model. In contrast, functional studies of the C585R mutation suggested a loss of function, similar to patients with deletion of the RAD21 gene. Three additional patients with overlapping deletions were also studied. Although the phenotype of all patients overlapped that of CDLS, there was some divergence in facial features and the cognitive defects in most were not as severe. Common features included short stature, synophrys, micrognathia, brachydactyly, mild radioulnar differences, vertebral anomalies, and mild cognitive involvement, although the boy with the P376R mutation had more severe mental retardation, tetralogy of Fallot, and hearing loss. Deardorff et al. (2012) concluded that dominant RAD21 missense mutations result in more severe functional defects and a worse phenotype than loss-of-function (LOF) mutations or deletions.
In 3 unrelated patients with CDLS4 with midline brain defects in the holoprosencephaly (HPE) spectrum, Kruszka et al. (2019) identified heterozygous frameshift or nonsense mutations in the RAD21 gene (606462.0004-606462.0006). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, were identified from a cohort of over 277 patients with HPE who underwent exome sequencing. All of the mutations were predicted to result in a loss of function, although functional studies of the variants and studies of patient cells were not performed. A father of 1 of the patients with milder symptoms also carried the heterozygous mutation; the inheritance pattern of the other 2 patients was unknown. The authors noted that the RAD21 gene is intolerant to LOF variation based on data from gnomAD.
Goel and Parasivam (2020) identified a de novo heterozygous nonsense mutation in the RAD21 gene (E615X; 606462.0007) in a female fetus with CDLS4 and lobar holoprosencephaly. The mutation was identified by clinical exome analysis of 4,702 genes. No functional studies were performed.
In a 26-year-old woman with mild CDLS4, Boyle et al. (2017) identified a heterozygous mutation in the RAD21 gene (606462.0008). The woman's mother and 2 maternal aunts, who were also heterozygous for the mutation, had variable, milder features seen in CDLS4 but did not meet clinical criteria for the disorder. Boyle et al. (2017) concluded that the intrafamilial phenotypic variation suggested incomplete penetrance.
In a mother and son and an unrelated patient with CDLS4, Minor et al. (2014) identified heterozygous mutations in the RAD21 gene (606462.0009 and 606462.0010, respectively).
In a 5-year-old boy with CDLS4, Dorval et al. (2020) identified a heterozygous frameshift mutation in the RAD21 gene (606462.0011).
In a 15-month-old boy with CDLS4, Gudmundsson et al. (2019) identified a de novo heterozygous mutation in the RAD21 gene (606462.0012). Molecular modeling predicted that the mutation disrupted the interaction of RAD21 with SMC1A (300040).
Mungan Syndrome
In a large Turkish family with intestinal pseudoobstruction mapping to chromosome 8q23-q24 (Mungan syndrome, MGS; 611376), Bonora et al. (2015) identified homozygosity for a missense mutation in the RAD21 gene (A622T; 606462.0003) that segregated fully with disease in the family and was not found in 500 Turkish controls or in public variant databases.
Bonora et al. (2015) injected zebrafish embryos with a rad21a slice-blocking morpholino and observed recapitulation of the chronic intestinal pseudoobstruction phenotype seen in their patients with Mungan syndrome. The morphants showed delayed food transit compared to wildtype zebrafish, and quantitative analysis of the zebrafish gut revealed marked depletion of enteric neurons at 4 and 5 days postfertilization in the morphants compared to controls, suggesting a neurogenic cause of the observed motility defects.
In a boy with Cornelia de Lange syndrome-4 (CDLS4; 614701), Deardorff et al. (2012) identified a de novo heterozygous 1127C-G transversion in the RAD21 gene, resulting in a pro376-to-arg (P376R) substitution in a highly conserved residue within a region essential for the interaction of RAD21 with STAG proteins. The mutation was not found in 600 control chromosomes. The patient had microcephaly and a characteristic facial appearance, with thick, bushy, arched eyebrows, synophrys, prominent eyelashes, broad nasal bridge, smooth philtrum, upturned nose, and thin upper lip. He also had a number of additional congenital anomalies, including submucosal cleft palate, stapes fixation and hearing loss, thin fingers, left radioulnar synostosis, delayed skeletal age, vertebral clefting, pectus carinatum, short femoral neck, tetralogy of Fallot, intestinal malrotation, gastroesophageal reflux, and severe cognitive delay. In vitro studies showed that the P376R mutation resulted in an increased interaction of RAD21 with STAG1 (604358) and STAG2 (300826), potentially causing delayed sister chromatid separation or altered transcription. Analysis of metaphase spreads from the patient showed a higher percentage of sister chromatids with a closed-arm phenotype compared to controls. Patient cells showed increased aneuploidy, with a substantial gain or loss of 1 or more chromosomes compared to controls, causing a delay in cell cycle progression during mitosis from G2/M to G1 phase. Patient lymphoblastoid cells also showed decreased survival, increased chromosome breakage, and defective DNA repair after irradiation compared to control cells.
Rad21-null zebrafish show absent tissue-specific expression of Runx1 (151385). Deardorff et al. (2012) showed that zebrafish P377R (corresponding to human P376R) rescued transcriptional expression of Runx1 in 65% of Rad21-null zebrafish embryos, indicating partial function. However, this variant also caused altered transcription in wildtype embryos, causing 50% more atypical Runx1 expression than wildtype Rad21. These findings suggested altered activity of the mutant protein rather than a loss of function.
In a girl with Cornelia de Lange syndrome-4 (CDLS4; 614701), Deardorff et al. (2012) identified a de novo heterozygous 1753T-C transition in the RAD21 gene, resulting in a cys585-to-arg (C585R) substitution in a residue conserved in vertebrates. The mutation was not found in 600 control chromosomes. Structural modeling suggested that the C585R mutation is within the C terminus of RAD21 positioned near the interface of RAD21 and the C-terminal residues of SMC1 (300040), and may interfere with the interaction between these 2 cohesion proteins, causing a defect in formation of functional cohesin complexes. The patient had microcephaly and a characteristic facial appearance, with thick, bushy, arched eyebrows, synophrys, long eyelashes, broad nasal bridge, smooth philtrum, thin upper lip, short nose, and upslanted palpebral fissures. Other features included short fingers, fifth finger clinodactyly, small prominent first toe, long fourth metacarpal, cutis marmorata, and mild neurodevelopmental defects. Zebrafish C597R (corresponding to human C585R) failed to rescue Runx1 expression in Rad21-null embryos and showed only background levels of activity in wildtype embryos, consistent with a loss of function.
In affected members of a large Turkish family with intestinal pseudoobstruction (MGS; 611376), originally described by Mungan et al. (2003), Bonora et al. (2015) identified homozygosity for a c.1864G-A transition (c.1864G-A, NM_006265.2) in the RAD21 gene, resulting in an ala622-to-thr (A622T) substitution at a highly conserved residue. The mutation segregated fully with disease in the family and was not found in 500 Turkish controls or in the dbSNP, 1000 Genomes Project, or NHLBI Exome Sequencing Project databases. Although expression of RAD21 in patient lymphoblastoid cells was similar to that of controls, expression of the RAD21 target gene RUNX1 (151385) was significantly reduced both in patient cells and in HEK293 cells transfected with the A622T mutant. Zebrafish embryos injected with a morpholino blocking the ortholog gene rad21a showed partial or complete absence of runx1 expression, which could not be rescued with coinjection of the A622T mutant, indicating a loss-of-function effect in vivo. Bonora et al. (2015) identified 2 RAD21 binding sites in the APOB (107730) proximal promoter and observed that nuclear extracts from wildtype cells formed a specific complex with either region, whereas no complex was observed in the presence of mutant RAD21. In addition, gut-specific APOB48 levels were increased in patient serum compared to controls; however, sera from sporadic patients with intestinal pseudoobstruction who were negative for mutation in RAD21 also showed consistently increased APOB48 levels compared to controls. Bonora et al. (2015) suggested that APOB48 expression might represent a marker for the degree of neuronal loss or symptom severity.
In a 7-year-old girl (patient 12) with Cornelia de Lange syndrome-4 with midline brain defects (CDLS4; 614701), Kruszka et al. (2019) identified a heterozygous c.1548delinsTC mutation in the RAD21 gene, predicted to result in a frameshift and premature termination (Glu518ArgfsTer19). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was inherited from her mildly affected father. Functional studies of the variant and studies of patient cells were not performed, but the variant was predicted to result in a loss of function (LOF). The authors noted that the RAD21 gene is intolerant to LOF variation based on data from gnomAD.
In a 14-year-old boy (patient 13) with Cornelia de Lange syndrome-4 with midline brain defects (CDLS4; 614701), Kruszka et al. (2019) identified a heterozygous c.589C-T transition (chr8.117869605G-A, GRCh37) in the RAD21 gene, resulting in a gln197-to-ter (Q197X) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was predicted to result in a loss of function (LOF), although functional studies of the variant and studies of patient cells were not performed. The inheritance pattern could not be determined because parental DNA was unavailable. The authors noted that the RAD21 gene is intolerant to LOF variation based on data from gnomAD.
In a 2-year-old boy (patient 14) with Cornelia de Lange syndrome-4 with midline brain defects (CDLS4; 614701), Kruszka et al. (2019) identified a heterozygous 8-bp deletion (c.1217_1224del; chr8.117,864,885del8, GRCh37), predicted to result in a frameshift and premature termination (Lys406ArgfsTer4). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was predicted to result in a loss of function (LOF), although functional studies of the variant and studies of patient cells were not performed. The inheritance pattern could not be determined because parental DNA was unavailable. The authors noted that the RAD21 gene is intolerant to LOF variation based on data from gnomAD.
In a female fetus with Cornelia de Lange syndrome-4 with midline brain defects (CDLS4; 614701), Goel and Parasivam (2020) identified a de novo heterozygous c.1843G-T transversion in the RAD21 gene, resulting in a glu615-to-ter (E615X) substitution. The mutation was identified by clinical whole-exome sequencing. Functional studies were not performed. The patient had lobar holoprosencephaly.
In a 26-year-old woman with mild Cornelia de Lange syndrome-4 (CDLS4; 614701), Boyle et al. (2017) identified heterozygosity for a 1-bp deletion (c.704delG, NM_0062625.2) in exon 13 of the RAD21 gene, predicted to result in a frameshift and premature termination (Ser235IlefsTer19), leading to a nonfunctional protein or nonsense-mediated mRNA decay. The mutation, which was identified by targeted next-generation sequencing, was also present in heterozygous state in the patient's mother and 2 maternal aunts, who had variable, milder features seen in CDLS4 but did not fulfill the clinical criteria for CDLS. Functional studies were not performed.
In a 3-year-old boy (patient 1) and his mother with mild Cornelia de Lange syndrome-4 (CDLS4; 614701), Minor et al. (2014) identified a heterozygous 665-bp deletion (chr8.(117,860,090_117,861,110)_(117,861,670_117,861,700)del) in the RAD21 gene with a 2-bp microhomology (TT) at the breakpoint junction, resulting in an in-frame deletion of exon 13. The deletion was identified by targeted array-CGH and confirmed by real-time quantitative PCR and breakpoint sequencing. The deletion was not detected in an in-house database of 452 patients tested for diagnostic purposes. The mutation was predicted to affect the interaction of RAD21 with SMC1A (300040) and alter the function of the cohesion complex.
In a 12-year-old boy (patient 2) with mild Cornelia de Lange syndrome-4 (CDLS4; 614701), Minor et al. (2014) identified a heterozygous 2-bp duplication (c.592_593dup, NM_006265) in exon 6 of the RAD21 gene, resulting in a frameshift and premature termination (Ser198ArgfsTer6). The mutation was identified by sequence analysis of the RAD21 gene. The mutation was not present in the mother, but the father was not available for testing. The mutation was predicted to result in either nonsense-mediated decay or a truncated protein missing functional domains necessary for the interaction with WAPL (610754), PDS5B (605333), and STAG1 (604358).
In a 5-year-old by with mild Cornelia de Lange syndrome-4 (CDLS4; 614701), Dorval et al. (2020) identified a de novo heterozygous 4-bp deletion (c.943_946del, NM_006265) in exon 9 of the RAD21 gene, resulting in a frameshift and premature termination (Glu315GlnfsTer9). The mutation was identified by sequencing of a multigene panel containing 5 known CDLS genes and confirmed by Sanger sequencing. The mutation was not present in the ExAC and gnomAD databases. Functional studies were not performed.
In a 15-month-old boy with mild Cornelia de Lange syndrome-4 (CDLS4; 614701), Gudmundsson et al. (2019) identified a de novo heterozygous 3-bp deletion (c.1774_1776del, NM_006265) in the RAD21 gene, resulting in deletion of Gln592, a conserved residue. The de novo mutation was identified by trio whole-exome sequencing and confirmed by Sanger sequencing. The mutation was not present in the ExAC, SweGen, and gnomAD databases. Molecular modeling predicted that the mutation disrupted the interaction of RAD21 with SMC1A (300040).
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