Human Gene Module / Chromosome 8 / RAD21

RAD21RAD21cohesin complex component

SFARI Gene Score
S
Syndromic Syndromic
Autism Reports / Total Reports
0 / 7
Rare Variants / Common Variants
3 / 0
Aliases
RAD21, CDLS4,  HR21,  HRAD21,  MCD1,  NXP1,  SCC1,  hHR21
Associated Syndromes
Cornelia de Lange syndrome-4 (CDLS4)
Chromosome Band
8q24.11
Associated Disorders
-
Relevance to Autism

Heterozygous mutations in the RAD21 gene are responsible for a form of Cornelia de Lange syndrome (Cornelia de Lange syndrome-4 ; OMIM 614701) (Deardorff et al., 2012; Ansari et al., 2014). A comparison of the primary clinical findings in individuals with molecularly confirmed Cornelia de Lange syndrome in Kline et al., 2018 determined that 20-49% of individuals with RAD21 mutations presented with autism spectrum disorder.

Molecular Function

Cleavable component of the cohesin complex, involved in chromosome cohesion during cell cycle, in DNA repair, and in apoptosis. The cohesin complex is required for the cohesion of sister chromatids after DNA replication. The cohesin complex apparently forms a large proteinaceous ring within which sister chromatids can be trapped. At metaphase-anaphase transition, this protein is cleaved by separase/ESPL1 and dissociates from chromatin, allowing sister chromatids to segregate. The cohesin complex may also play a role in spindle pole assembly during mitosis.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
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SFARI Genomic Platforms
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Reports related to RAD21 (7 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary RAD21 mutations cause a human cohesinopathy Deardorff MA , et al. (2012) No -
2 Support Genetic heterogeneity in Cornelia de Lange syndrome (CdLS) and CdLS-like phenotypes with observed and predicted levels of mosaicism Ansari M , et al. (2014) No -
3 Recent Recommendation Diagnosis and management of Cornelia de Lange syndrome: first international consensus statement Kline AD , et al. (2018) No -
4 Recent Recommendation Delineation of phenotypes and genotypes related to cohesin structural protein RAD21 Krab LC et al. (2020) No -
5 Support - Spataro N et al. (2023) No -
6 Support - Sanchis-Juan A et al. (2023) No -
7 Support - Tamam Khalaf et al. (2024) No -
Rare Variants   (3)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_gain Unknown - Simplex 37541188 Sanchis-Juan A et al. (2023)
c.497A>G p.Asp166Gly missense_variant Unknown - - 38438125 Tamam Khalaf et al. (2024)
c.628G>T p.Glu210Ter stop_gained Familial Maternal - 36980980 Spataro N et al. (2023)
Common Variants  

No common variants reported.

SFARI Gene score
S

Syndromic

Heterozygous mutations in the RAD21 gene are responsible for a form of Cornelia de Lange syndrome (Cornelia de Lange syndrome-4; OMIM 614701) (Deardorff et al., 2012; Ansari et al., 2014). A comparison of the primary clinical findings in individuals with molecularly confirmed Cornelia de Lange syndrome in Kline et al., 2018 determined that 20-49% of individuals with RAD21 mutations presented with autism spectrum disorder.

Score Delta: Score remained at S

criteria met
See SFARI Gene'scoring criteria
S

Syndromic

See all Category S Genes

The syndromic category includes mutations that are associated with a substantial degree of increased risk and consistently linked to additional characteristics not required for an ASD diagnosis. If there is independent evidence implicating a gene in idiopathic ASD, it will be listed as "#S" (e.g., 2S, 3S, etc.). If there is no such independent evidence, the gene will be listed simply as "S."

4/1/2020
S
icon
S

Score remained at S

Description

Heterozygous mutations in the RAD21 gene are responsible for a form of Cornelia de Lange syndrome (Cornelia de Lange syndrome-4; OMIM 614701) (Deardorff et al., 2012; Ansari et al., 2014). A comparison of the primary clinical findings in individuals with molecularly confirmed Cornelia de Lange syndrome in Kline et al., 2018 determined that 20-49% of individuals with RAD21 mutations presented with autism spectrum disorder.

Reports Added
[Delineation of phenotypes and genotypes related to cohesin structural protein RAD212020]
10/1/2019
S
icon
S

Score remained at S

New Scoring Scheme
Description

Heterozygous mutations in the RAD21 gene are responsible for a form of Cornelia de Lange syndrome (Cornelia de Lange syndrome-4; OMIM 614701) (Deardorff et al., 2012; Ansari et al., 2014). A comparison of the primary clinical findings in individuals with molecularly confirmed Cornelia de Lange syndrome in Kline et al., 2018 determined that 20-49% of individuals with RAD21 mutations presented with autism spectrum disorder.

Reports Added
[New Scoring Scheme]
Krishnan Probability Score

Score 0.53461246298184

Ranking 1500/25841 scored genes


[Show Scoring Methodology]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning approach on a human brain-specific gene network. The method was first presented in Nat Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed in column G of supplementary table 3 (see: http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at asd.princeton.edu.
Original Source
ExAC Score

Score 0.9995449494256

Ranking 918/18225 scored genes


[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of- function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of- function mutations in autism in such a gene would be more likely to confer risk. For a full list of pLI scores see: ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle aned_exac_nonTCGA_z_pli_rec_null_data.txt
Original Source
Sanders TADA Score

Score 0.93127871112398

Ranking 11656/18665 scored genes


[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013), and is a statistic that integrates evidence from both de novo and transmitted mutations. It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233 (2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper (the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
Original Source
Zhang D Score

Score 0.34825255821184

Ranking 2039/20870 scored genes


[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures), or D score, was developed to combine evidence from de novo loss-of- function mutation with evidence from cell-type- specific gene expression in the mouse brain (specifically translational profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with positive D scores are more likely to be associated with autism risk, with higher-confidence genes having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204- 215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in supplementary table 2 from that paper.
Original Source
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