Human Gene Module / Chromosome 12 / SOX5

SOX5SRY-box 5

SFARI Gene Score
1S
High Confidence, Syndromic Criteria 1.1, Syndromic
Autism Reports / Total Reports
9 / 24
Rare Variants / Common Variants
73 / 1
EAGLE Score
17.6
Strong Learn More
Aliases
SOX5, L-SOX5,  MGC35153
Associated Syndromes
Lamb-Shaffer syndrome, Lamb-Shaffer syndrome, DD, ID
Chromosome Band
12p12.1
Associated Disorders
ADHD, ID, ASD
Genetic Category
Rare Single Gene Mutation, Syndromic, Genetic Association
Relevance to Autism

Intragenic SOX5 deletions have been identified in an individual with ASD and individuals with developmental delay/intellectual disability (Rosenfeld et al. 2010; Lamb et al., 2012).

Molecular Function

This gene encodes a member of the SOX (SRY-related HMG-box) family of transcription factors involved in the regulation of embryonic development and in the determination of the cell fate. The encoded protein may act as a transcriptional regulator after forming a protein complex with other proteins. The encoded protein may play a role in chondrogenesis.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to SOX5 (24 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Copy number variations associated with autism spectrum disorders contribute to a spectrum of neurodevelopmental disorders Rosenfeld JA , et al. (2010) Yes -
2 Support Haploinsufficiency of SOX5 at 12p12.1 is associated with developmental delays with prominent language delay, behavior problems, and mild dysmorphic features Lamb AN , et al. (2012) No ASD, ADHD
3 Support Haploinsufficiency of SOX5, a member of the SOX (SRY-related HMG-box) family of transcription factors is a cause of intellectual disability Schanze I , et al. (2012) No -
4 Support Deletion 12p12 involving SOX5 in two children with developmental delay and dysmorphic features Lee RW , et al. (2013) No -
5 Support Exome sequencing expands the mechanism of SOX5-associated intellectual disability: A case presentation with review of sox-related disorders Nesbitt A , et al. (2015) No -
6 Recent Recommendation Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability Lelieveld SH et al. (2016) No -
7 Support Mutations in Human Accelerated Regions Disrupt Cognition and Social Behavior Doan RN , et al. (2016) Yes -
8 Support The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies Redin C , et al. (2016) No -
9 Support Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder C Yuen RK et al. (2017) Yes -
10 Support Using medical exome sequencing to identify the causes of neurodevelopmental disorders: Experience of 2 clinical units and 216 patients Chrot E , et al. (2017) Yes -
11 Support Diagnostic exome sequencing of syndromic epilepsy patients in clinical practice Tumien B , et al. (2017) No -
12 Support Clinical and genetic characterization of a patient with SOX5 haploinsufficiency caused by a de novo balanced reciprocal translocation Fukushi D , et al. (2018) No ID, autistic features
13 Positive Association Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection Pardias AF , et al. (2018) No -
14 Recent Recommendation Widening of the genetic and clinical spectrum of Lamb-Shaffer syndrome, a neurodevelopmental disorder due to SOX5 haploinsufficiency Zawerton A , et al. (2019) No ASD
15 Support - Woodbury-Smith M et al. (2022) Yes -
16 Support - Zhou X et al. (2022) Yes -
17 Recent Recommendation - Edgerley K et al. (2023) No ASD or autistic features, ADHD
18 Support - Hu C et al. (2023) Yes -
19 Support - Wang J et al. (2023) Yes -
20 Support - Cirnigliaro M et al. (2023) Yes -
21 Support - Sanchis-Juan A et al. (2023) No -
22 Support - Jair Tenorio-Castano et al. (2023) No -
23 Support - Alistair T Pagnamenta et al. (2024) No -
24 Support - Axel Schmidt et al. (2024) No ID, cognitive impairment
Rare Variants   (73)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - translocation De novo - - 27841880 Redin C , et al. (2016)
- - translocation De novo - - 29477873 Fukushi D , et al. (2018)
- - copy_number_loss Unknown - - 22290657 Lamb AN , et al. (2012)
- - copy_number_loss De novo - - 27841880 Redin C , et al. (2016)
- - copy_number_loss De novo - - 36861937 Edgerley K et al. (2023)
- - copy_number_loss Unknown - - 36861937 Edgerley K et al. (2023)
- - translocation De novo - Simplex 22290657 Lamb AN , et al. (2012)
- - copy_number_loss De novo - - 20808228 Rosenfeld JA , et al. (2010)
- - copy_number_loss De novo - Simplex 22290657 Lamb AN , et al. (2012)
- - copy_number_loss De novo - Unknown 22290657 Lamb AN , et al. (2012)
G>A - stop_gained De novo - Multiplex 28263302 C Yuen RK et al. (2017)
- - copy_number_loss De novo - Simplex 23220431 Schanze I , et al. (2012)
- - copy_number_loss De novo - Simplex 31578471 Zawerton A , et al. (2019)
- - copy_number_loss Unknown - Simplex 31578471 Zawerton A , et al. (2019)
- - copy_number_loss Familial Maternal - 36861937 Edgerley K et al. (2023)
c.231+14275dup - intron_variant - - Unknown 27667684 Doan RN , et al. (2016)
c.1613C>G p.Ser538Ter stop_gained De novo - - 35982159 Zhou X et al. (2022)
- - inversion De novo - Simplex 38776926 Alistair T Pagnamenta et al. (2024)
- - copy_number_loss Familial Paternal Simplex 22290657 Lamb AN , et al. (2012)
- - copy_number_loss Familial Maternal Simplex 31578471 Zawerton A , et al. (2019)
c.1002C>T p.Gly334%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.1895C>A p.Thr632Asn missense_variant De novo - - 28708303 Chrot E , et al. (2017)
c.865C>T p.Pro289Ser missense_variant De novo - - 29286531 Tumien B , et al. (2017)
c.1676C>T p.Pro559Leu missense_variant De novo - - 36861937 Edgerley K et al. (2023)
c.1711C>T p.Arg571Trp missense_variant De novo - - 31578471 Zawerton A , et al. (2019)
c.1786G>C p.Ala596Pro missense_variant De novo - - 31578471 Zawerton A , et al. (2019)
c.532C>T p.Leu178Phe missense_variant Familial Maternal - 37007974 Hu C et al. (2023)
c.472G>A p.Glu158Lys missense_variant De novo - Simplex 37393044 Wang J et al. (2023)
c.1477C>T p.Arg493Ter stop_gained De novo - Simplex 36861937 Edgerley K et al. (2023)
c.1534C>T p.Gln512Ter stop_gained De novo - Simplex 36861937 Edgerley K et al. (2023)
c.622C>T p.Gln208Ter stop_gained De novo - Simplex 31578471 Zawerton A , et al. (2019)
c.637C>T p.Arg213Ter stop_gained De novo - Simplex 31578471 Zawerton A , et al. (2019)
c.820C>T p.Gln274Ter stop_gained De novo - Simplex 31578471 Zawerton A , et al. (2019)
c.1234+2T>A - splice_site_variant De novo - Simplex 31578471 Zawerton A , et al. (2019)
c.1489-1G>A - splice_site_variant De novo - Simplex 31578471 Zawerton A , et al. (2019)
c.1814A>C p.Tyr605Ser missense_variant De novo - - 39039281 Axel Schmidt et al. (2024)
c.1477C>T p.Arg493Ter stop_gained De novo - Simplex 31578471 Zawerton A , et al. (2019)
c.1613C>G p.Ser538Ter stop_gained De novo - Simplex 31578471 Zawerton A , et al. (2019)
c.1782G>A p.Trp594Ter stop_gained De novo - Simplex 31578471 Zawerton A , et al. (2019)
c.1819G>T p.Glu607Ter stop_gained De novo - Simplex 31578471 Zawerton A , et al. (2019)
- - copy_number_loss Familial Maternal Multi-generational 22290657 Lamb AN , et al. (2012)
c.2051C>A p.Ala684Asp missense_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.1477C>T p.Arg493Ter stop_gained Unknown Not maternal - 36861937 Edgerley K et al. (2023)
c.703C>T p.Arg235Cys missense_variant De novo - Simplex 31578471 Zawerton A , et al. (2019)
c.928T>A p.Cys310Ser missense_variant De novo - Simplex 31578471 Zawerton A , et al. (2019)
c.1678A>G p.Met560Val missense_variant De novo - Simplex 31578471 Zawerton A , et al. (2019)
c.1712G>T p.Arg571Leu missense_variant De novo - Simplex 31578471 Zawerton A , et al. (2019)
c.1814A>G p.Tyr605Cys missense_variant De novo - Simplex 31578471 Zawerton A , et al. (2019)
c.1868A>G p.Tyr623Cys missense_variant De novo - Simplex 31578471 Zawerton A , et al. (2019)
c.1895C>A p.Thr632Asn missense_variant De novo - Simplex 31578471 Zawerton A , et al. (2019)
c.2078C>T p.Ser693Leu missense_variant De novo - Simplex 31578471 Zawerton A , et al. (2019)
c.405dup p.Lys136GlnfsTer6 frameshift_variant De novo - - 39039281 Axel Schmidt et al. (2024)
- - copy_number_loss De novo (germline mosaicism) - Multiplex 36861937 Edgerley K et al. (2023)
c.1681A>C p.Asn561His missense_variant De novo - Multiplex 31578471 Zawerton A , et al. (2019)
c.1711C>T p.Arg571Trp missense_variant Unknown - Multiplex 31578471 Zawerton A , et al. (2019)
- - copy_number_loss De novo (germline mosaicism) - Multiplex 31578471 Zawerton A , et al. (2019)
c.1495dup p.Thr499AsnfsTer13 frameshift_variant De novo - - 27479843 Lelieveld SH et al. (2016)
c.1788dup p.Met597TyrfsTer11 frameshift_variant De novo - - 27479843 Lelieveld SH et al. (2016)
c.1711C>T p.Arg571Trp missense_variant Unknown - Simplex 37541188 Sanchis-Juan A et al. (2023)
c.622C>T p.Gln208Ter stop_gained De novo - Multi-generational 31578471 Zawerton A , et al. (2019)
c.979-1G>A - splice_site_variant Familial Maternal Multiplex 37506195 Cirnigliaro M et al. (2023)
c.1477C>T p.Arg493Ter stop_gained Unknown Not maternal Simplex 31578471 Zawerton A , et al. (2019)
c.737_738insT p.Glu246AspfsTer41 frameshift_variant De novo - - 27479843 Lelieveld SH et al. (2016)
c.1465dup p.Leu489ProfsTer3 frameshift_variant De novo - Simplex 31578471 Zawerton A , et al. (2019)
c.1348C>T p.Arg450Trp missense_variant De novo - Multi-generational 31578471 Zawerton A , et al. (2019)
c.1678A>G p.Met560Val missense_variant De novo - Multi-generational 31578471 Zawerton A , et al. (2019)
c.747_748del p.Arg250ThrfsTer36 frameshift_variant Unknown - Simplex 31578471 Zawerton A , et al. (2019)
c.518G>A p.Trp173Ter stop_gained Familial Maternal Multi-generational 31578471 Zawerton A , et al. (2019)
c.637C>T p.Arg213Ter stop_gained De novo - Multiplex (monozygotic twins) 36861937 Edgerley K et al. (2023)
c.1411C>T p.Arg471Ter stop_gained Familial Maternal Multi-generational 31578471 Zawerton A , et al. (2019)
c.637C>T p.Arg213Ter stop_gained De novo (germline mosaicism) - Multiplex 31578471 Zawerton A , et al. (2019)
c.1711C>T p.Arg571Trp missense_variant De novo (germline mosaicism) - Multiplex 31578471 Zawerton A , et al. (2019)
c.1616_1617del p.Glu539ValfsTer5 frameshift_variant De novo - Multiplex (monozygotic twins) 36861937 Edgerley K et al. (2023)
Common Variants   (1)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
T>G - intergenic_variant - - - 29483656 Pardias AF , et al. (2018)
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."

10/1/2019
S
icon
1

Increased from S to 1

New Scoring Scheme
Description

A SOX5 deletion was found in one ASD subject out of nearly 1500 subjects referred for clinical genetic testing (PMID 20808228). In addition, nine individuals with single-gene deletions of SOX5, of which 2 have PDD, and seven larger deletions, of which one has autism, have been found (Lamb et al., 2012). Other common associated features include ID, speech delay, dysmorphic features, and behavioral abnormalities. As a result of these initial findings and subsequent findings in patients with SOX5 variants (Schanze et al., 2013; Lee et al., 2013; Nesbitt et al., 2015), SOX5 is considered to be responsible for a neurodevelopmental disorder designated Lamb-Shaffer syndrome (OMIM 616803). As well, an additional report identified exon-including deletions and duplications of SOX5 in controls (Wong et al., 2007). Zawerton et al., 2019 collected genetic and clinical information from 41 novel patients with SOX5-associated Lamb-Shaffer syndrome and determined that, of the 25 patients evaluated for autism spectrum disorder, 6 were positively diagnosed (24%) and 11 had other behavioral disturbances including stereotypies, isolation, tantrums, and hyperactivity.

Reports Added
[Widening of the genetic and clinical spectrum of Lamb-Shaffer syndrome, a neurodevelopmental disorder due to SOX5 haploinsufficiency.2019] [New Scoring Scheme]
7/1/2017
S
icon
S

Increased from S to S

Description

A SOX5 deletion was found in one ASD subject out of nearly 1500 subjects referred for clinical genetic testing (PMID 20808228). In addition, nine individuals with single-gene deletions of SOX5, of which 2 have PDD, and seven larger deletions, of which one has autism, have been found (Lamb et al., 2012). Other common associated features include ID, speech delay, dysmorphic features, and behavioral abnormalities. As a result of these initial findings and subsequent findings in patients with SOX5 variants (Schanze et al., 2013; Lee et al., 2013; Nesbitt et al., 2015), SOX5 is considered to be responsible for a neurodevelopmental disorder designated Lamb-Shaffer syndrome (OMIM 616803). As well, an additional report identified exon-including deletions and duplications of SOX5 in controls (Wong et al., 2007).

Reports Added
[Using medical exome sequencing to identify the causes of neurodevelopmental disorders: experience of two clinical units and 216 patients.2017]
4/1/2017
S
icon
S

Increased from S to S

Description

A SOX5 deletion was found in one ASD subject out of nearly 1500 subjects referred for clinical genetic testing (PMID 20808228). In addition, nine individuals with single-gene deletions of SOX5, of which 2 have PDD, and seven larger deletions, of which one has autism, have been found (Lamb et al., 2012). Other common associated features include ID, speech delay, dysmorphic features, and behavioral abnormalities. As a result of these initial findings and subsequent findings in patients with SOX5 variants (Schanze et al., 2013; Lee et al., 2013; Nesbitt et al., 2015), SOX5 is considered to be responsible for a neurodevelopmental disorder designated Lamb-Shaffer syndrome (OMIM 616803). As well, an additional report identified exon-including deletions and duplications of SOX5 in controls (Wong et al., 2007).

Reports Added
[Copy number variations associated with autism spectrum disorders contribute to a spectrum of neurodevelopmental disorders.2010] [Haploinsufficiency of SOX5 at 12p12.1 is associated with developmental delays with prominent language delay, behavior problems, and mild dysmorphic...2012] [Haploinsufficiency of SOX5, a member of the SOX (SRY-related HMG-box) family of transcription factors is a cause of intellectual disability.2012] [Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability2016] [Mutations in Human Accelerated Regions Disrupt Cognition and Social Behavior.2016] [The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies.2016] [Haploinsufficiency of SOX5, a member of the SOX (SRY-related HMG-box) family of transcription factors is a cause of intellectual disability.2012] [Deletion 12p12 involving SOX5 in two children with developmental delay and dysmorphic features.2013] [Exome sequencing expands the mechanism of SOX5-associated intellectual disability: A case presentation with review of sox-related disorders.2015] [Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder2017]
1/1/2017
4
icon
S

Decreased from 4 to S

Description

A SOX5 deletion was found in one ASD subject out of nearly 1500 subjects referred for clinical genetic testing (PMID 20808228). In addition, nine individuals with single-gene deletions of SOX5, of which 2 have PDD, and seven larger deletions, of which one has autism, have been found (Lamb et al., 2012). Other common associated features include ID, speech delay, dysmorphic features, and behavioral abnormalities. As a result of these initial findings and subsequent findings in patients with SOX5 variants (Schanze et al., 2013; Lee et al., 2013; Nesbitt et al., 2015), SOX5 is considered to be responsible for a neurodevelopmental disorder designated Lamb-Shaffer syndrome (OMIM 616803). As well, an additional report identified exon-including deletions and duplications of SOX5 in controls (Wong et al., 2007).

Reports Added
[Deletion 12p12 involving SOX5 in two children with developmental delay and dysmorphic features.2013] [Exome sequencing expands the mechanism of SOX5-associated intellectual disability: A case presentation with review of sox-related disorders.2015]
10/1/2016
4
icon
4

Decreased from 4 to 4

Description

A SOX5 deletion was found in one ASD subject out of nearly 1500 subjects referred for clinical genetic testing (PMID 20808228). In addition, nine individuals with single-gene deletions of SOX5, of which 2 have PDD, and seven larger deletions, of which one has autism, have been found (PMID 22290657). Other common associated features include ID, speech delay, dysmorphic features, and behavioral abnormalities. As well, an additional report exists that found exon-including deletion and duplication of SOX5 in controls (Wong et al., 2007).

Reports Added
[Mutations in Human Accelerated Regions Disrupt Cognition and Social Behavior.2016] [The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies.2016]
7/1/2016
4
icon
4

Decreased from 4 to 4

Description

A SOX5 deletion was found in one ASD subject out of nearly 1500 subjects referred for clinical genetic testing (PMID 20808228). In addition, nine individuals with single-gene deletions of SOX5, of which 2 have PDD, and seven larger deletions, of which one has autism, have been found (PMID 22290657). Other common associated features include ID, speech delay, dysmorphic features, and behavioral abnormalities. As well, an additional report exists that found exon-including deletion and duplication of SOX5 in controls (Wong et al., 2007).

Reports Added
[Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability2016]
7/1/2014
No data
icon
4

Increased from No data to 4

Description

A SOX5 deletion was found in one ASD subject out of nearly 1500 subjects referred for clinical genetic testing (PMID 20808228). In addition, nine individuals with single-gene deletions of SOX5, of which 2 have PDD, and seven larger deletions, of which one has autism, have been found (PMID 22290657). Other common associated features include ID, speech delay, dysmorphic features, and behavioral abnormalities. As well, an additional report exists that found exon-including deletion and duplication of SOX5 in controls (Wong et al., 2007).

4/1/2014
No data
icon
4

Increased from No data to 4

Description

A SOX5 deletion was found in one ASD subject out of nearly 1500 subjects referred for clinical genetic testing (PMID 20808228). In addition, nine individuals with single-gene deletions of SOX5, of which 2 have PDD, and seven larger deletions, of which one has autism, have been found (PMID 22290657). Other common associated features include ID, speech delay, dysmorphic features, and behavioral abnormalities. As well, an additional report exists that found exon-including deletion and duplication of SOX5 in controls (Wong et al., 2007).

Krishnan Probability Score

Score 0.57254780058653

Ranking 704/25841 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 0.99939888448761

Ranking 971/18225 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 0.94944162089237

Ranking 18092/18665 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 0.16599059168542

Ranking 4873/20870 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
Interactome
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
FAM46B family with sequence similarity 46, member B Human Protein Binding 115572 Q96A09
SOX1 Transcription factor SOX-1 Human Protein Binding 6656 O00570
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