Human Gene Module / Chromosome 21 / SON

SONSONDNA binding protein

SFARI Gene Score
1S
High Confidence, Syndromic Criteria 1.1, Syndromic
Autism Reports / Total Reports
8 / 26
Rare Variants / Common Variants
77 / 0
EAGLE Score
11
Moderate Learn More
Aliases
SON, BASS1,  C21orf50,  DBP-5,  NREBP3,  TOKIMS, SON
Associated Syndromes
ZTTK syndrome, ZTTK syndrome, DD, ZTTKsyndrome, DD, ID, epilepsy/seizures, ZTTK syndrome, DD, epilepsy/seizures
Chromosome Band
21q22.11
Associated Disorders
ID, ASD
Genetic Category
Rare Single Gene Mutation, Syndromic, Functional
Relevance to Autism

De novo missense variants in the SON gene have been identified in ASD probands from the Simons Simplex Collection (Iossifov et al., 2014) and the iHART cohort (Ruzzo et al., 2019). Mutations in the SON gene are also responsible for ZTTK syndrome (OMIM 617140), a severe multisystem developmental disorder characterized by delayed psychomotor development and intellectual disability; autism and autistic features have been observed in a subset of individuals with this disorder (Tokita et al., 2016; Kim et al., 2016).

Molecular Function

This gene encodes a protein that contains multiple simple repeats. The encoded protein binds RNA and promotes pre-mRNA splicing, particularly of transcripts with poor splice sites. The protein also recognizes a specific DNA sequence found in the human hepatitis B virus (HBV) and represses HBV core promoter activity.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to SON (26 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
2 Support - Takenouchi T et al. (2016) No DD, ID
3 Support De Novo Truncating Variants in SON Cause Intellectual Disability, Congenital Malformations, and Failure to Thrive Tokita MJ , et al. (2016) No ASD
4 Support De Novo Mutations in SON Disrupt RNA Splicing of Genes Essential for Brain Development and Metabolism, Causing an Intellectual-Disability Syndrome Kim JH , et al. (2016) No ASD or autistic features
5 Support - Kim JH et al. (2019) No ID
6 Support Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks Ruzzo EK , et al. (2019) Yes -
7 Support - Yang Y et al. (2019) No DD, ID
8 Support Autism risk in offspring can be assessed through quantification of male sperm mosaicism Breuss MW , et al. (2019) Yes -
9 Support - Quintana Castanedo L et al. (2020) No ID, epilepsy/seizures
10 Support - Tan Y et al. (2020) No DD, ID
11 Support Knockdown of Son, a mouse homologue of the ZTTK syndrome gene, causes neuronal migration defects and dendritic spine abnormalities Ueda M et al. (2020) No -
12 Support Phenotypic expansion in Zhu-Tokita-Takenouchi-Kim syndrome caused by de novo variants in the SON gene Slezak R et al. (2020) No ID, stereotypy
13 Support - Chen JS et al. (2021) Yes -
14 Support - Kushary ST et al. (2021) No ADHD, stereotypy
15 Support - Trakadis Y et al. (2021) No DD, epilepsy/seizures
16 Recent Recommendation - Dingemans AJM et al. (2021) No Epilepsy/seizures, ASD or autistic features
17 Support - Woodbury-Smith M et al. (2022) Yes -
18 Support - Levchenko O et al. (2022) No -
19 Support - Zhou X et al. (2022) Yes -
20 Support - More RP et al. (2023) Yes -
21 Support - Miyake N et al. (2023) Yes -
22 Support - Spataro N et al. (2023) No -
23 Recent Recommendation - Timberlake AT et al. (2023) No -
24 Support - Vasquez-Forero DM et al. (2023) No Stereotypy
25 Support - Isabelle Schrauwen et al. (2024) No -
26 Support - Axel Schmidt et al. (2024) No Cognitive impairment
Rare Variants   (77)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss Unknown - - 34521999 Dingemans AJM et al. (2021)
- - copy_number_loss De novo - Simplex 27545680 Kim JH , et al. (2016)
c.394C>T p.Gln132Ter stop_gained De novo - - 31557424 Yang Y et al. (2019)
c.286C>T p.Gln96Ter stop_gained De novo - - 27545676 Tokita MJ , et al. (2016)
c.2763C>A p.Tyr921Ter stop_gained De novo - - 34331327 Kushary ST et al. (2021)
- - copy_number_loss Unknown - Simplex 38755281 Isabelle Schrauwen et al. (2024)
c.2051A>G p.Tyr684Cys missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.3408C>A p.Tyr1136Ter stop_gained Unknown - - 34331327 Kushary ST et al. (2021)
c.5761C>T p.Arg1921Ter stop_gained Unknown - - 34331327 Kushary ST et al. (2021)
c.3191G>A p.Arg1064His missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.2910del p.Tyr970Ter frameshift_variant De novo - - 35982159 Zhou X et al. (2022)
c.6022C>T p.Arg2008Ter stop_gained De novo - - 39039281 Axel Schmidt et al. (2024)
c.4779A>G p.Leu1593%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.3203C>G p.Ser1068Ter stop_gained Unknown - - 34521999 Dingemans AJM et al. (2021)
c.3334C>T p.Arg1112Ter stop_gained Unknown - - 34521999 Dingemans AJM et al. (2021)
c.3334C>T p.Arg1112Ter stop_gained De novo - Simplex 27545680 Kim JH , et al. (2016)
c.3214C>T p.Arg1072Cys missense_variant Unknown - - 34331327 Kushary ST et al. (2021)
c.1183C>T p.Gln395Ter stop_gained De novo - Simplex 31873310 Breuss MW , et al. (2019)
c.668C>T p.Ser223Leu missense_variant Unknown - - 34521999 Dingemans AJM et al. (2021)
c.1736C>G p.Thr579Ser missense_variant Unknown - - 34521999 Dingemans AJM et al. (2021)
c.5230del p.Arg1744ValfsTer29 frameshift_variant De novo - - 32291808 Tan Y et al. (2020)
c.4678del p.Glu1560LysfsTer63 frameshift_variant Unknown - - 31005274 Kim JH et al. (2019)
c.6925G>A p.Gly2309Arg missense_variant De novo - Simplex 36973392 Miyake N et al. (2023)
c.1085C>T p.Pro362Leu missense_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.2080A>G p.Thr694Ala missense_variant Familial - Multiplex 36702863 More RP et al. (2023)
c.3156del p.Met1053TrpfsTer6 frameshift_variant De novo - - 36980980 Spataro N et al. (2023)
c.2160del p.Met721TrpfsTer6 frameshift_variant De novo - - 34331327 Kushary ST et al. (2021)
c.3724T>G p.Ser1242Ala missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.4909A>T p.Thr1637Ser missense_variant De novo - Simplex 27545676 Tokita MJ , et al. (2016)
c.5528C>A p.Ser1843Tyr missense_variant De novo - Simplex 27545676 Tokita MJ , et al. (2016)
c.5515C>T p.Arg1839Cys missense_variant De novo - Multiplex 31398340 Ruzzo EK , et al. (2019)
c.6461del p.Asn2154IlefsTer2 frameshift_variant De novo - - 34331327 Kushary ST et al. (2021)
c.4663del p.Thr1555LeufsTer68 frameshift_variant De novo - - 34331327 Kushary ST et al. (2021)
c.457del p.Asp153IlefsTer4 frameshift_variant Unknown - - 34521999 Dingemans AJM et al. (2021)
c.5743C>T p.Arg1915Ter stop_gained De novo - Simplex 37476413 Vasquez-Forero DM et al. (2023)
c.5753_5756del p.Val1918GlufsTer87 frameshift_variant De novo - - 35982159 Zhou X et al. (2022)
c.268del p.Ser90ValfsTer59 frameshift_variant De novo - Simplex 27545680 Kim JH , et al. (2016)
c.384del p.Lys128AsnfsTer21 frameshift_variant Unknown - - 34521999 Dingemans AJM et al. (2021)
c.2365del p.Ser789AlafsTer8 frameshift_variant De novo - Simplex 27545680 Kim JH , et al. (2016)
c.326_329del p.Lys109SerfsTer39 frameshift_variant De novo - - 34331327 Kushary ST et al. (2021)
c.3711del p.Ser1238GlnfsTer3 frameshift_variant Unknown - - 34521999 Dingemans AJM et al. (2021)
c.6010del p.Val2004TrpfsTer2 frameshift_variant Unknown - - 34521999 Dingemans AJM et al. (2021)
c.4549dup p.Glu1517GlyfsTer6 frameshift_variant De novo - Simplex 27545680 Kim JH , et al. (2016)
c.4865_4869del p.Leu1622Ter frameshift_variant De novo - Simplex 32705777 Slezak R et al. (2020)
c.4055del p.Pro1352GlnfsTer14 frameshift_variant De novo - Simplex 27545680 Kim JH , et al. (2016)
c.4640del p.His1547LeufsTer76 frameshift_variant De novo - Simplex 27545680 Kim JH , et al. (2016)
c.6087del p.Ser2029ArgfsTer22 frameshift_variant De novo - Simplex 27545680 Kim JH , et al. (2016)
c.3135_3157del p.Glu1046GlyfsTer2 frameshift_variant De novo - - 34331327 Kushary ST et al. (2021)
c.4448_4452del p.Val1483GlufsTer4 frameshift_variant Unknown - - 34331327 Kushary ST et al. (2021)
c.3963del p.Ala1322ProfsTer13 frameshift_variant De novo - Simplex 32705777 Slezak R et al. (2020)
c.4777_4778del p.Leu1593IlefsTer11 frameshift_variant De novo - - 34331327 Kushary ST et al. (2021)
c.4779_4782del p.Ser1594LeufsTer28 frameshift_variant De novo - - 34331327 Kushary ST et al. (2021)
c.5753_5756del p.Val1918GlufsTer87 frameshift_variant De novo - - 34331327 Kushary ST et al. (2021)
c.5753_5756del p.Val1918GlufsTer87 frameshift_variant Unknown - - 34331327 Kushary ST et al. (2021)
c.5753_5756del p.Val1918GlufsTer87 frameshift_variant De novo - - 34363551 Trakadis Y et al. (2021)
c.348_351del p.Asn116LysfsTer32 frameshift_variant Unknown - - 34521999 Dingemans AJM et al. (2021)
c.3073dup p.Met1025AsnfsTer6 frameshift_variant De novo - Simplex 27545676 Tokita MJ , et al. (2016)
c.6233del p.Pro2078HisfsTer4 frameshift_variant De novo - Simplex 27545676 Tokita MJ , et al. (2016)
c.5753_5756del p.Val1918GlufsTer87 frameshift_variant De novo - - 27256762 Takenouchi T et al. (2016)
c.1881_1882del p.Val629AlafsTer56 frameshift_variant Unknown - - 34521999 Dingemans AJM et al. (2021)
c.4151_4174del p.Leu1384_Val1391del inframe_deletion Unknown - Simplex 27545680 Kim JH , et al. (2016)
c.4999_5013del p.Asp1667_Asn1671del inframe_deletion De novo - Simplex 27545680 Kim JH , et al. (2016)
c.1881_1882del p.Val629AlafsTer56 frameshift_variant De novo - Simplex 27545680 Kim JH , et al. (2016)
c.3852_3856del p.Met1284IlefsTer2 frameshift_variant De novo - Simplex 27545680 Kim JH , et al. (2016)
c.5549_5550del p.Arg1850IlefsTer3 frameshift_variant De novo - Simplex 27545680 Kim JH , et al. (2016)
c.5753_5756del p.Val1918GlufsTer87 frameshift_variant Unknown - - 34521999 Dingemans AJM et al. (2021)
c.1444del p.Leu482CysfsTer4 frameshift_variant De novo - - 32045494 Quintana Castanedo L et al. (2020)
c.3597_3598dup p.Pro1200ArgfsTer17 frameshift_variant De novo - Simplex 27545680 Kim JH , et al. (2016)
c.4358_4359del p.Thr1453SerfsTer11 frameshift_variant De novo - Simplex 27545680 Kim JH , et al. (2016)
c.5753_5756del p.Val1918GlufsTer87 frameshift_variant De novo - Simplex 27545680 Kim JH , et al. (2016)
c.5753_5756del p.Val1918GlufsTer87 frameshift_variant Unknown - Unknown 33753861 Chen JS et al. (2021)
c.5031_5032insAA p.Asp1678LysfsTer9 frameshift_variant De novo - Simplex 27545680 Kim JH , et al. (2016)
c.6002_6003insCC p.Arg2002GlnfsTer5 frameshift_variant De novo - Simplex 27545680 Kim JH , et al. (2016)
c.3852_3856del p.Met1284IlefsTer2 frameshift_variant De novo - Simplex 27545676 Tokita MJ , et al. (2016)
c.4641_4642del p.His1547GlnfsTer9 frameshift_variant De novo - Simplex 35887114 Levchenko O et al. (2022)
c.5753_5756delTTAG p.Val1918GlufsTer87 frameshift_variant De novo - Simplex 27545680 Kim JH , et al. (2016)
c.5753_5756delTTAG p.Val1918GlufsTer87 frameshift_variant De novo - Simplex 27545676 Tokita MJ , et al. (2016)
Common Variants  

No common variants reported.

SFARI Gene score
1S

High Confidence, Syndromic

Score Delta: Score remained at 1S

criteria met
See SFARI Gene'scoring criteria
1

High Confidence

See all Category 1 Genes

We considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.

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."

4/1/2021
1
icon
1

Score remained at 1

Description

De novo missense variants in the SON gene have been identified in ASD probands from the Simons Simplex Collection (Iossifov et al., 2014) and the iHART cohort (Ruzzo et al., 2019). Mutations in the SON gene are also responsible for ZTTK syndrome (OMIM 617140), a severe multisystem developmental disorder characterized by delayed psychomotor development and intellectual disability; autism and autistic features have been observed in a subset of individuals with this disorder (Tokita et al., 2016; Kim et al., 2016).

Reports Added
[Comorbidities associated with genetic abnormalities in children with intellectual disability2021]
7/1/2020
1
icon
1

Score remained at 1

Description

De novo missense variants in the SON gene have been identified in ASD probands from the Simons Simplex Collection (Iossifov et al., 2014) and the iHART cohort (Ruzzo et al., 2019). Mutations in the SON gene are also responsible for ZTTK syndrome (OMIM 617140), a severe multisystem developmental disorder characterized by delayed psychomotor development and intellectual disability; autism and autistic features have been observed in a subset of individuals with this disorder (Tokita et al., 2016; Kim et al., 2016).

Reports Added
[Phenotypic expansion in Zhu-Tokita-Takenouchi-Kim syndrome caused by de novo variants in the SON gene2020]
4/1/2020
1
icon
1

Score remained at 1

Description

De novo missense variants in the SON gene have been identified in ASD probands from the Simons Simplex Collection (Iossifov et al., 2014) and the iHART cohort (Ruzzo et al., 2019). Mutations in the SON gene are also responsible for ZTTK syndrome (OMIM 617140), a severe multisystem developmental disorder characterized by delayed psychomotor development and intellectual disability; autism and autistic features have been observed in a subset of individuals with this disorder (Tokita et al., 2016; Kim et al., 2016).

Reports Added
[Knockdown of Son, a mouse homologue of the ZTTK syndrome gene, causes neuronal migration defects and dendritic spine abnormalities2020]
1/1/2020
1
icon
1

Score remained at 1

Description

De novo missense variants in the SON gene have been identified in ASD probands from the Simons Simplex Collection (Iossifov et al., 2014) and the iHART cohort (Ruzzo et al., 2019). Mutations in the SON gene are also responsible for ZTTK syndrome (OMIM 617140), a severe multisystem developmental disorder characterized by delayed psychomotor development and intellectual disability; autism and autistic features have been observed in a subset of individuals with this disorder (Tokita et al., 2016; Kim et al., 2016).

Reports Added
[Autism risk in offspring can be assessed through quantification of male sperm mosaicism.2019]
10/1/2019
icon
1

Increased from to 1

New Scoring Scheme
Description

De novo missense variants in the SON gene have been identified in ASD probands from the Simons Simplex Collection (Iossifov et al., 2014) and the iHART cohort (Ruzzo et al., 2019). Mutations in the SON gene are also responsible for ZTTK syndrome (OMIM 617140), a severe multisystem developmental disorder characterized by delayed psychomotor development and intellectual disability; autism and autistic features have been observed in a subset of individuals with this disorder (Tokita et al., 2016; Kim et al., 2016).

Reports Added
[New Scoring Scheme]
Krishnan Probability Score

Score 0.59389299228488

Ranking 455/25841 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 0.99999991013254

Ranking 193/18225 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
Iossifov Probability Score

Score 0.944

Ranking 91/239 scored genes


[Show Scoring Methodology]
Supplementary dataset S2 in the paper by Iossifov et al. (PNAS 112, E5600-E5607 (2015)) lists 239 genes with a probability of at least 0.8 of being associated with autism risk (column I). This probability metric combines the evidence from de novo likely-gene- disrupting and missense mutations and assesses it against the background mutation rate in unaffected individuals from the University of Washington’s Exome Variant Sequence database (evs.gs.washington.edu/EVS/). The list of probability scores can be found here: www.pnas.org/lookup/suppl/doi:10.1073/pnas.1516376112/- /DCSupplemental/pnas.1516376112.sd02.xlsx
Original Source
Sanders TADA Score

Score 0.94965387003432

Ranking 18178/18665 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 0.35216619344413

Ranking 1990/20870 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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