Human Gene Module / Chromosome X / SMC1A

SMC1Astructural maintenance of chromosomes 1A

SFARI Gene Score
S
Syndromic Syndromic
Autism Reports / Total Reports
4 / 19
Rare Variants / Common Variants
35 / 0
Aliases
SMC1A, CDLS2,  DXS423E,  SB1.8,  SMC1,  SMC1L1,  SMC1alpha,  SMCB
Associated Syndromes
Cornelia de Lange syndrome-2 (CDLS2)
Chromosome Band
Xp11.22
Associated Disorders
DD/NDD, EPS
Relevance to Autism

Mutations in the SMC1A gene are responsible for a form of Cornelia de Lange syndrome (Cornelia de Lange syndrome 2; OMIM 300590), a clinically heterogeneous developmental disorder characterized by malformations affecting multiple systems (Deardorff et al., 2007). Phenotypic characterization of 51 individuals with SMC1A variants demonstrated that 6/6 individuals displayed socialization deficits (ranging from mild to profound) and 20/31 individuals (65%) exhibited stereotypic movements (Huisman et al., 2017); furthermore, 5 females from a cohort of 13 Dutch individuals with SMC1A variants presented with a phenotype similar to Rett syndrome: epileptic encephalopathy, severe or profound intellectual disability, stereotypic movements, and, in some cases, developmental regression.

Molecular Function

The cohesin multiprotein complex is required for sister chromatid cohesion, a prerequisite for the correct segregation of chromosomes during cell division, and is composed partly of two structural maintenance of chromosomes (SMC) proteins: SMC3 and either SMC1B or the protein encoded by this gene. Most of the cohesin complexes dissociate from the chromosomes before mitosis, although those complexes at the kinetochore remain. Therefore, the encoded protein is thought to be an important part of functional kinetochores.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to SMC1A (19 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Highly Cited Mutations in cohesin complex members SMC3 and SMC1A cause a mild variant of cornelia de Lange syndrome with predominant mental retardation Deardorff MA , et al. (2007) No -
2 Support Cornelia de Lange syndrome mutations in SMC1A or SMC3 affect binding to DNA Revenkova E , et al. (2008) No -
3 Primary Phenotypes and genotypes in individuals with SMC1A variants Huisman S , et al. (2017) No -
4 Recent Recommendation Diagnosis and management of Cornelia de Lange syndrome: first international consensus statement Kline AD , et al. (2018) No -
5 Support Clinical genome sequencing in an unbiased pediatric cohort Thiffault I , et al. (2018) No DD, epilepsy/seizures, microcephaly
6 Support Lessons Learned from Large-Scale, First-Tier Clinical Exome Sequencing in a Highly Consanguineous Population Monies D , et al. (2019) Yes -
7 Support - Alonso-Gonzalez A et al. (2021) Yes -
8 Support - Brunet T et al. (2021) No -
9 Support - Zou D et al. (2021) No -
10 Support - Pode-Shakked B et al. (2021) No ADHD, epilepsy/seizures
11 Support - Álvarez-Mora MI et al. (2022) No -
12 Support - Brea-Fernández AJ et al. (2022) No -
13 Support - Hieu NLT et al. (2022) No -
14 Support - Chuan Z et al. (2022) No DD, ID
15 Support - Zhou X et al. (2022) Yes -
16 Support - Ko YJ et al. (2023) No -
17 Support - Karthika Ajit Valaparambil et al. () Yes -
18 Support - Luigi Vetri et al. (2024) No -
19 Support - Axel Schmidt et al. (2024) No -
Rare Variants   (35)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.694G>T p.Glu232Ter stop_gained Unknown - - 28548707 Huisman S , et al. (2017)
c.3219+1G>C - splice_site_variant De novo - Simplex 37645600 Ko YJ et al. (2023)
c.1903C>T p.Arg635Cys missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.31A>T p.Asn11Tyr missense_variant Unknown - - 28548707 Huisman S , et al. (2017)
c.1192C>T p.Arg398Ter stop_gained Unknown - - 39039281 Axel Schmidt et al. (2024)
c.3103C>T p.Arg1035Ter stop_gained De novo - Simplex 37645600 Ko YJ et al. (2023)
c.358G>T p.Glu120Ter stop_gained De novo - Simplex 35365919 Hieu NLT et al. (2022)
c.397T>G p.Phe133Val missense_variant De novo - - 17273969 Deardorff MA , et al. (2007)
c.587G>A p.Arg196His missense_variant De novo - - 17273969 Deardorff MA , et al. (2007)
c.607A>G p.Lys203Glu missense_variant De novo - Simplex 35571021 Chuan Z et al. (2022)
c.52C>T p.Arg18Ter stop_gained Familial Maternal - 30008475 Thiffault I , et al. (2018)
c.1487G>A p.Arg496His missense_variant Unknown - - 17273969 Deardorff MA , et al. (2007)
c.2131C>T p.Arg711Trp missense_variant De novo - - 17273969 Deardorff MA , et al. (2007)
c.2369G>A p.Arg790Gln missense_variant De novo - - 17273969 Deardorff MA , et al. (2007)
c.261_263del p.Asn87del inframe_deletion De novo - Simplex 37645600 Ko YJ et al. (2023)
c.587G>C p.Arg196Pro missense_variant De novo - Unknown 33619735 Brunet T et al. (2021)
c.3364T>C p.Phe1122Leu missense_variant De novo - - 17273969 Deardorff MA , et al. (2007)
c.3497A>C p.Asn1166Thr missense_variant De novo - Unknown 33619735 Brunet T et al. (2021)
c.1171C>T p.Gln391Ter stop_gained De novo - Simplex 34580403 Pode-Shakked B et al. (2021)
c.547C>T p.Gln183Ter stop_gained Unknown - - 37943464 Karthika Ajit Valaparambil et al. ()
c.3617A>T p.Glu1206Val missense_variant Unknown - Simplex 31130284 Monies D , et al. (2019)
c.157dup p.Thr53AsnfsTer34 frameshift_variant Unknown - - 28548707 Huisman S , et al. (2017)
c.107del p.Val36GlufsTer7 inframe_deletion De novo - - 17273969 Deardorff MA , et al. (2007)
c.2364_2379del p.Asn788LysfsTer5 frameshift_variant Unknown - - 34145886 Zou D et al. (2021)
c.2357del p.Leu786TrpfsTer21 frameshift_variant Unknown - - 28548707 Huisman S , et al. (2017)
c.2364del p.Asn788LysfsTer10 frameshift_variant Unknown - - 28548707 Huisman S , et al. (2017)
c.2095C>T p.Arg699Cys missense_variant De novo - - 35322241 Brea-Fernández AJ et al. (2022)
c.2341T>C p.Cys781Arg missense_variant De novo - Simplex 34580403 Pode-Shakked B et al. (2021)
c.611_612del p.Glu204GlyfsTer3 frameshift_variant De novo - - 38256219 Luigi Vetri et al. (2024)
c.1421G>A p.Arg474His missense_variant Familial - Multiplex 17273969 Deardorff MA , et al. (2007)
c.802_804del p.Lys268del inframe_deletion De novo - Simplex 34580403 Pode-Shakked B et al. (2021)
c.2369G>A p.Arg790Gln missense_variant De novo - Simplex 33431980 Alonso-Gonzalez A et al. (2021)
c.1405C>T p.Arg469Cys missense_variant Familial Maternal - 35183220 Álvarez-Mora MI et al. (2022)
c.1486C>T p.Arg496Cys missense_variant Familial Maternal Multiplex 17273969 Deardorff MA , et al. (2007)
c.1487G>A p.Arg496His missense_variant De novo (germline mosaicism) - Multiplex 17273969 Deardorff MA , et al. (2007)
Common Variants  

No common variants reported.

SFARI Gene score
S

Syndromic

Mutations in the SMC1A gene are responsible for a form of Cornelia de Lange syndrome (Cornelia de Lange syndrome 2; OMIM 300590), a clinically heterogeneous developmental disorder characterized by malformations affecting multiple systems (Deardorff et al., 2007). Phenotypic characterization of 51 individuals with SMC1A variants demonstrated that 6/6 individuals displayed socialization deficits (ranging from mild to profound) and 20/31 individuals (65%) exhibited stereotypic movements (Huisman et al., 2017); furthermore, 5 females from a cohort of 13 Dutch individuals with SMC1A variants presented with a phenotype similar to Rett syndrome: epileptic encephalopathy, severe or profound intellectual disability, stereotypic movements, and, in some cases, developmental regression. 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 SMC1A 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."

1/1/2021
S
icon
S

Score remained at S

Description

Mutations in the SMC1A gene are responsible for a form of Cornelia de Lange syndrome (Cornelia de Lange syndrome 2; OMIM 300590), a clinically heterogeneous developmental disorder characterized by malformations affecting multiple systems (Deardorff et al., 2007). Phenotypic characterization of 51 individuals with SMC1A variants demonstrated that 6/6 individuals displayed socialization deficits (ranging from mild to profound) and 20/31 individuals (65%) exhibited stereotypic movements (Huisman et al., 2017); furthermore, 5 females from a cohort of 13 Dutch individuals with SMC1A variants presented with a phenotype similar to Rett syndrome: epileptic encephalopathy, severe or profound intellectual disability, stereotypic movements, and, in some cases, developmental regression. 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 SMC1A mutations presented with autism spectrum disorder.

Reports Added
[Exploring the biological role of postzygotic and germinal de novo mutations in ASD2021] [De novo variants in neurodevelopmental disorders-experiences from a tertiary care center2021]
10/1/2019
S
icon
S

Score remained at S

New Scoring Scheme
Description

Mutations in the SMC1A gene are responsible for a form of Cornelia de Lange syndrome (Cornelia de Lange syndrome 2; OMIM 300590), a clinically heterogeneous developmental disorder characterized by malformations affecting multiple systems (Deardorff et al., 2007). Phenotypic characterization of 51 individuals with SMC1A variants demonstrated that 6/6 individuals displayed socialization deficits (ranging from mild to profound) and 20/31 individuals (65%) exhibited stereotypic movements (Huisman et al., 2017); furthermore, 5 females from a cohort of 13 Dutch individuals with SMC1A variants presented with a phenotype similar to Rett syndrome: epileptic encephalopathy, severe or profound intellectual disability, stereotypic movements, and, in some cases, developmental regression. 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 SMC1A mutations presented with autism spectrum disorder.

Reports Added
[New Scoring Scheme]
7/1/2019
S
icon
S

Score remained at S

Description

Mutations in the SMC1A gene are responsible for a form of Cornelia de Lange syndrome (Cornelia de Lange syndrome 2; OMIM 300590), a clinically heterogeneous developmental disorder characterized by malformations affecting multiple systems (Deardorff et al., 2007). Phenotypic characterization of 51 individuals with SMC1A variants demonstrated that 6/6 individuals displayed socialization deficits (ranging from mild to profound) and 20/31 individuals (65%) exhibited stereotypic movements (Huisman et al., 2017); furthermore, 5 females from a cohort of 13 Dutch individuals with SMC1A variants presented with a phenotype similar to Rett syndrome: epileptic encephalopathy, severe or profound intellectual disability, stereotypic movements, and, in some cases, developmental regression. 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 SMC1A mutations presented with autism spectrum disorder.

Reports Added
[Lessons Learned from Large-Scale, First-Tier Clinical Exome Sequencing in a Highly Consanguineous Population.2019]
7/1/2018
S
icon
S

Score remained at S

Description

Mutations in the SMC1A gene are responsible for a form of Cornelia de Lange syndrome (Cornelia de Lange syndrome 2; OMIM 300590), a clinically heterogeneous developmental disorder characterized by malformations affecting multiple systems (Deardorff et al., 2007). Phenotypic characterization of 51 individuals with SMC1A variants demonstrated that 6/6 individuals displayed socialization deficits (ranging from mild to profound) and 20/31 individuals (65%) exhibited stereotypic movements (Huisman et al., 2017); furthermore, 5 females from a cohort of 13 Dutch individuals with SMC1A variants presented with a phenotype similar to Rett syndrome: epileptic encephalopathy, severe or profound intellectual disability, stereotypic movements, and, in some cases, developmental regression. 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 SMC1A mutations presented with autism spectrum disorder.

Reports Added
[Diagnosis and management of Cornelia de Lange syndrome: first international consensus statement.2018] [Clinical genome sequencing in an unbiased pediatric cohort.2018]
Krishnan Probability Score

Score 0.44757487379508

Ranking 12199/25841 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 0.99998849372004

Ranking 466/18225 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 0.91106563748341

Ranking 7673/18665 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 0.4349527442894

Ranking 1077/20870 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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