Human Gene Module / Chromosome 15 / SIN3A

SIN3ASIN3 transcription regulator family member A

SFARI Gene Score
1S
High Confidence, Syndromic Criteria 1.1, Syndromic
Autism Reports / Total Reports
10 / 18
Rare Variants / Common Variants
69 / 0
Aliases
-
Associated Syndromes
Witteveen-Kolk syndrome, Witteveen-Kolk syndrome, DD, ID
Chromosome Band
15q24.2
Associated Disorders
ADHD, ASD, EPS
Relevance to Autism

De novo and inherited dominant variants in the SIN3A gene were identified in individuals presenting with a syndrome characterized by intellectual disability, ASD, brain abnormalities detected by MRI, dysmorphic facial features, microcephaly, and short stature; this phenotype is similar to that of individuals with atypical 15q24 microdeletions, whose shortest region of overlap (approximately 260 kb) includes the SIN3A gene (Witteveen et al., 2016). Knockdown of SIN3A in the developing mouse brain in Witteveen et al., 2016 resulted in a decrease in cortical progenitors, altered cortical neuronal identity, and aberrant corticocortical projections.

Molecular Function

The protein encoded by this gene is a transcriptional regulatory protein.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
Fruit fly
Entrez Gene
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to SIN3A (18 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Synaptic, transcriptional and chromatin genes disrupted in autism De Rubeis S , et al. (2014) Yes -
2 Support The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
3 Primary Haploinsufficiency of MeCP2-interacting transcriptional co-repressor SIN3A causes mild intellectual disability by affecting the development of cortical integrity Witteveen JS , et al. (2016) No ASD, epilepsy/seizures
4 Support Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability Lelieveld SH et al. (2016) No -
5 Support Candidate-gene criteria for clinical reporting: diagnostic exome sequencing identifies altered candidate genes among 8% of patients with undiagnosed diseases Farwell Hagman KD , et al. (2016) Yes -
6 Support Exome Pool-Seq in neurodevelopmental disorders Popp B , et al. (2017) No ADHD
7 Support Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model Guo H , et al. (2018) Yes -
8 Support Phenotype-to-genotype approach reveals head-circumference-associated genes in an autism spectrum disorder cohort Wu H , et al. (2019) Yes Microcephaly
9 Support Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism Satterstrom FK et al. (2020) Yes -
10 Support Transcriptional corepressor SIN3A regulates hippocampal synaptic plasticity via Homer1/mGluR5 signaling Bridi M , et al. (2020) No -
11 Support Behavior and cognitive functioning in Witteveen-Kolk syndrome van Dongen LCM et al. (2020) No ASD
12 Support Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders Wang T et al. (2020) Yes -
13 Support - Balasubramanian M et al. (2021) No ASD, ADHD, epilepsy/seizures
14 Support - Mahjani B et al. (2021) Yes -
15 Support - Zhou X et al. (2022) Yes -
16 Support - Spataro N et al. (2023) No -
17 Support - Hu C et al. (2023) Yes -
18 Support - Marina Giovannetti et al. (2024) No -
Rare Variants   (69)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss De novo - - 27399968 Witteveen JS , et al. (2016)
c.1657C>T p.Arg553Ter stop_gained Unknown - - 33004838 Wang T et al. (2020)
c.1091G>A p.Arg364His missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1424G>A p.Arg475Gln missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1490G>A p.Arg497His missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1793T>A p.Val598Glu missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.2002G>A p.Ala668Thr missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.2003C>T p.Ala668Val missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.2030C>T p.Ala677Val missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.2153G>A p.Arg718Gln missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.2254G>A p.Glu752Lys missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.2966T>A p.Ile989Asn missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.3034G>A p.Val1012Met missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.3139G>C p.Glu1047Gln missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.975del p.Tyr325Ter frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.1541T>A p.Leu514Ter stop_gained Unknown - Simplex 33004838 Wang T et al. (2020)
c.1855-3C>G - splice_region_variant Familial Maternal - 37007974 Hu C et al. (2023)
c.1852G>C p.Glu618Gln missense_variant Unknown - - 34615535 Mahjani B et al. (2021)
c.1675C>T p.Arg559Ter stop_gained Unknown - - 32783353 van Dongen LCM et al. (2020)
c.246T>C p.His82= synonymous_variant De novo - - 27479843 Lelieveld SH et al. (2016)
c.2585C>T p.Pro862Leu missense_variant De novo - - 25363760 De Rubeis S , et al. (2014)
c.3811A>G p.Lys1271Glu missense_variant De novo - Simplex 31674007 Wu H , et al. (2019)
c.1511T>A p.Val504Asp missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.3016dup p.Arg1006LysfsTer9 frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.1813T>C p.Tyr605His missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
- p.Gln827LysfsTer3 frameshift_variant De novo - - 27513193 Farwell Hagman KD , et al. (2016)
c.46C>T p.Gln16Ter stop_gained Familial Maternal - 33437032 Balasubramanian M et al. (2021)
c.889C>T p.Gln297Ter stop_gained De novo - Simplex 33437032 Balasubramanian M et al. (2021)
c.2809_2810del p.Lys937GlufsTer2 frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.95G>A p.Arg32Gln missense_variant Familial Maternal Simplex 30564305 Guo H , et al. (2018)
c.1675C>T p.Arg559Ter stop_gained De novo - Simplex 33437032 Balasubramanian M et al. (2021)
c.1773G>A p.Trp591Ter stop_gained De novo - Simplex 33437032 Balasubramanian M et al. (2021)
c.2764C>T p.Arg922Ter stop_gained De novo - Simplex 33437032 Balasubramanian M et al. (2021)
c.2803C>T p.Arg935Ter stop_gained De novo - Simplex 33437032 Balasubramanian M et al. (2021)
c.3698_3702del p.Trp1233TyrfsTer3 frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.3179A>G p.Asp1060Gly missense_variant Familial - Multiplex 36980980 Spataro N et al. (2023)
c.3303C>G p.Tyr1101Ter stop_gained De novo - Simplex 33437032 Balasubramanian M et al. (2021)
c.3323C>G p.Ser1108Ter stop_gained De novo - Simplex 33437032 Balasubramanian M et al. (2021)
c.3490A>T p.Lys1164Ter stop_gained De novo - Simplex 33437032 Balasubramanian M et al. (2021)
c.3706_3709del p.Gly1236ArgfsTer21 frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.803dup p.Leu269ThrfsTer37 frameshift_variant De novo - - 27399968 Witteveen JS , et al. (2016)
c.377C>T p.Ala126Val missense_variant De novo - Simplex 33437032 Balasubramanian M et al. (2021)
c.463A>G p.Lys155Glu missense_variant De novo - Simplex 33437032 Balasubramanian M et al. (2021)
c.2983_2984insGTAA p.Phe995CysfsTer21 frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.3785_3791del p.Tyr1262SerfsTer70 frameshift_variant De novo - - 36980980 Spataro N et al. (2023)
c.3317T>C p.Met1106Thr missense_variant De novo - Simplex 33437032 Balasubramanian M et al. (2021)
c.1010_1013del p.Lys337SerfsTer16 frameshift_variant De novo - - 27399968 Witteveen JS , et al. (2016)
c.2955_2956del p.Glu985AspfsTer29 frameshift_variant De novo - - 27399968 Witteveen JS , et al. (2016)
c.3310C>T p.Arg1104Ter stop_gained Familial Maternal Multiplex 27399968 Witteveen JS , et al. (2016)
c.1489_1499del p.Arg497CysfsTer13 frameshift_variant Unknown - - 32783353 van Dongen LCM et al. (2020)
c.588del p.Asn197MetfsTer4 frameshift_variant De novo - Simplex 33437032 Balasubramanian M et al. (2021)
c.775dup p.His259ProfsTer47 frameshift_variant De novo - Simplex 33437032 Balasubramanian M et al. (2021)
c.824del p.Pro275HisfsTer12 frameshift_variant De novo - Simplex 33437032 Balasubramanian M et al. (2021)
c.1462del p.Val488LeufsTer7 frameshift_variant De novo - Simplex 33437032 Balasubramanian M et al. (2021)
c.1888dup p.Ile630AsnfsTer17 frameshift_variant De novo - Simplex 33437032 Balasubramanian M et al. (2021)
c.2339del p.Ala780GlyfsTer14 frameshift_variant De novo - Simplex 33437032 Balasubramanian M et al. (2021)
c.3118_3119del p.Gln1040GlufsTer15 frameshift_variant Unknown Not maternal - 29158550 Popp B , et al. (2017)
c.1010_1013del p.Lys337SerfsTer16 frameshift_variant De novo - Simplex 31981491 Satterstrom FK et al. (2020)
c.2185_2186del p.Leu729GlyfsTer8 frameshift_variant De novo - Simplex 33437032 Balasubramanian M et al. (2021)
c.2809_2810del p.Lys937GlufsTer2 frameshift_variant De novo - Simplex 33437032 Balasubramanian M et al. (2021)
c.1245_1246del p.Asn415LysfsTer24 frameshift_variant De novo - Simplex 33437032 Balasubramanian M et al. (2021)
c.1489_1499del p.Arg497CysfsTer13 frameshift_variant De novo - Simplex 33437032 Balasubramanian M et al. (2021)
c.1570_1577del p.Tyr524ValfsTer26 frameshift_variant De novo - Simplex 33437032 Balasubramanian M et al. (2021)
c.2248_2251del p.Leu750MetfsTer43 frameshift_variant De novo - Simplex 33437032 Balasubramanian M et al. (2021)
c.3441_3445del p.Lys1148ArgfsTer12 frameshift_variant De novo - Simplex 33437032 Balasubramanian M et al. (2021)
c.1759del p.Ser587ProfsTer12 frameshift_variant Familial Paternal Multiplex 27399968 Witteveen JS , et al. (2016)
c.2248_2249insCTCTTAC p.Leu750ProfsTer5 frameshift_variant De novo - Simplex 31981491 Satterstrom FK et al. (2020)
c.1715_1722delinsCCCAAGTGTA p.Gly572AlafsTer11 frameshift_variant De novo - Simplex 33437032 Balasubramanian M et al. (2021)
c.1319_1320insGAAGAAACCCAAACTGCTCAATCTGAAGGATTCTTCTATGGCAGATGCCAGCAAACATGGTGGTGGAACAGAATCGTTATTTTTTG p.Pro442LysfsTer34 frameshift_variant De novo - Simplex 33437032 Balasubramanian M et al. (2021)
Common Variants  

No common variants reported.

SFARI Gene score
1S

High Confidence, Syndromic

De novo missense variants in the SIN3A gene were observed in ASD probands from the Autism Sequencing Consortium and the Simons Simplex Collection (a predicted benign missense variant in De Rubeis et al., 2014, and a predicted damaging missense variant in Iossifov et al., 2014); a predicted benign missense variant in SIN3A was also observed in an unaffected sibing in Iossifov et al., 2014. De novo and inherited dominant variants in the SIN3A gene were identified in individuals presenting with a syndrome characterized by intellectual disability, ASD, brain abnormalities detected by MRI, dysmorphic facial features, microcephaly, and short stature; this phenotype is similar to that of individuals with atypical 15q24 microdeletions, whose shortest region of overlap (approximately 260 kb) includes the SIN3A gene (Witteveen et al., 2016). ASD was observed in 3 individuals with de novo loss-of-function SIN3A variants and 1 individual with a de novo 15q24 microdeletion involving SIN3A in this report. Knockdown of SIN3A in the developing mouse brain in Witteveen et al., 2016 resulted in a decrease in cortical progenitors, altered cortical neuronal identity, and aberrant corticocortical projections. A de novo frameshift variant in SIN3A was identified in a patient with a primary reason for referral of ASD in Farwell Hagman et al., 2016.

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."

1/1/2021
1
icon
1

Score remained at 1

Description

De novo missense variants in the SIN3A gene were observed in ASD probands from the Autism Sequencing Consortium and the Simons Simplex Collection (a predicted benign missense variant in De Rubeis et al., 2014, and a predicted damaging missense variant in Iossifov et al., 2014); a predicted benign missense variant in SIN3A was also observed in an unaffected sibing in Iossifov et al., 2014. De novo and inherited dominant variants in the SIN3A gene were identified in individuals presenting with a syndrome characterized by intellectual disability, ASD, brain abnormalities detected by MRI, dysmorphic facial features, microcephaly, and short stature; this phenotype is similar to that of individuals with atypical 15q24 microdeletions, whose shortest region of overlap (approximately 260 kb) includes the SIN3A gene (Witteveen et al., 2016). ASD was observed in 3 individuals with de novo loss-of-function SIN3A variants and 1 individual with a de novo 15q24 microdeletion involving SIN3A in this report. Knockdown of SIN3A in the developing mouse brain in Witteveen et al., 2016 resulted in a decrease in cortical progenitors, altered cortical neuronal identity, and aberrant corticocortical projections. A de novo frameshift variant in SIN3A was identified in a patient with a primary reason for referral of ASD in Farwell Hagman et al., 2016.

Reports Added
[Comprehensive study of 28 individuals with SIN3A-related disorder underscoring the associated mild cognitive and distinctive facial phenotype2021]
10/1/2020
1
icon
1

Score remained at 1

Description

De novo missense variants in the SIN3A gene were observed in ASD probands from the Autism Sequencing Consortium and the Simons Simplex Collection (a predicted benign missense variant in De Rubeis et al., 2014, and a predicted damaging missense variant in Iossifov et al., 2014); a predicted benign missense variant in SIN3A was also observed in an unaffected sibing in Iossifov et al., 2014. De novo and inherited dominant variants in the SIN3A gene were identified in individuals presenting with a syndrome characterized by intellectual disability, ASD, brain abnormalities detected by MRI, dysmorphic facial features, microcephaly, and short stature; this phenotype is similar to that of individuals with atypical 15q24 microdeletions, whose shortest region of overlap (approximately 260 kb) includes the SIN3A gene (Witteveen et al., 2016). ASD was observed in 3 individuals with de novo loss-of-function SIN3A variants and 1 individual with a de novo 15q24 microdeletion involving SIN3A in this report. Knockdown of SIN3A in the developing mouse brain in Witteveen et al., 2016 resulted in a decrease in cortical progenitors, altered cortical neuronal identity, and aberrant corticocortical projections. A de novo frameshift variant in SIN3A was identified in a patient with a primary reason for referral of ASD in Farwell Hagman et al., 2016.

Reports Added
[Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders2020]
7/1/2020
1
icon
1

Score remained at 1

Description

De novo missense variants in the SIN3A gene were observed in ASD probands from the Autism Sequencing Consortium and the Simons Simplex Collection (a predicted benign missense variant in De Rubeis et al., 2014, and a predicted damaging missense variant in Iossifov et al., 2014); a predicted benign missense variant in SIN3A was also observed in an unaffected sibing in Iossifov et al., 2014. De novo and inherited dominant variants in the SIN3A gene were identified in individuals presenting with a syndrome characterized by intellectual disability, ASD, brain abnormalities detected by MRI, dysmorphic facial features, microcephaly, and short stature; this phenotype is similar to that of individuals with atypical 15q24 microdeletions, whose shortest region of overlap (approximately 260 kb) includes the SIN3A gene (Witteveen et al., 2016). ASD was observed in 3 individuals with de novo loss-of-function SIN3A variants and 1 individual with a de novo 15q24 microdeletion involving SIN3A in this report. Knockdown of SIN3A in the developing mouse brain in Witteveen et al., 2016 resulted in a decrease in cortical progenitors, altered cortical neuronal identity, and aberrant corticocortical projections. A de novo frameshift variant in SIN3A was identified in a patient with a primary reason for referral of ASD in Farwell Hagman et al., 2016.

Reports Added
[Behavior and cognitive functioning in Witteveen-Kolk syndrome2020]
1/1/2020
1
icon
1

Score remained at 1

Description

De novo missense variants in the SIN3A gene were observed in ASD probands from the Autism Sequencing Consortium and the Simons Simplex Collection (a predicted benign missense variant in De Rubeis et al., 2014, and a predicted damaging missense variant in Iossifov et al., 2014); a predicted benign missense variant in SIN3A was also observed in an unaffected sibing in Iossifov et al., 2014. De novo and inherited dominant variants in the SIN3A gene were identified in individuals presenting with a syndrome characterized by intellectual disability, ASD, brain abnormalities detected by MRI, dysmorphic facial features, microcephaly, and short stature; this phenotype is similar to that of individuals with atypical 15q24 microdeletions, whose shortest region of overlap (approximately 260 kb) includes the SIN3A gene (Witteveen et al., 2016). ASD was observed in 3 individuals with de novo loss-of-function SIN3A variants and 1 individual with a de novo 15q24 microdeletion involving SIN3A in this report. Knockdown of SIN3A in the developing mouse brain in Witteveen et al., 2016 resulted in a decrease in cortical progenitors, altered cortical neuronal identity, and aberrant corticocortical projections. A de novo frameshift variant in SIN3A was identified in a patient with a primary reason for referral of ASD in Farwell Hagman et al., 2016.

Reports Added
[Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism2020] [Transcriptional corepressor SIN3A regulates hippocampal synaptic plasticity via Homer1/mGluR5 signaling.2020]
10/1/2019
4S
icon
1

Decreased from 4S to 1

New Scoring Scheme
Description

De novo missense variants in the SIN3A gene were observed in ASD probands from the Autism Sequencing Consortium and the Simons Simplex Collection (a predicted benign missense variant in De Rubeis et al., 2014, and a predicted damaging missense variant in Iossifov et al., 2014); a predicted benign missense variant in SIN3A was also observed in an unaffected sibing in Iossifov et al., 2014. De novo and inherited dominant variants in the SIN3A gene were identified in individuals presenting with a syndrome characterized by intellectual disability, ASD, brain abnormalities detected by MRI, dysmorphic facial features, microcephaly, and short stature; this phenotype is similar to that of individuals with atypical 15q24 microdeletions, whose shortest region of overlap (approximately 260 kb) includes the SIN3A gene (Witteveen et al., 2016). ASD was observed in 3 individuals with de novo loss-of-function SIN3A variants and 1 individual with a de novo 15q24 microdeletion involving SIN3A in this report. Knockdown of SIN3A in the developing mouse brain in Witteveen et al., 2016 resulted in a decrease in cortical progenitors, altered cortical neuronal identity, and aberrant corticocortical projections. A de novo frameshift variant in SIN3A was identified in a patient with a primary reason for referral of ASD in Farwell Hagman et al., 2016.

Reports Added
[Phenotype-to-genotype approach reveals head-circumference-associated genes in an autism spectrum disorder cohort.2019] [New Scoring Scheme]
1/1/2019
4S
icon
4S

Decreased from 4S to 4S

Description

De novo missense variants in the SIN3A gene were observed in ASD probands from the Autism Sequencing Consortium and the Simons Simplex Collection (a predicted benign missense variant in De Rubeis et al., 2014, and a predicted damaging missense variant in Iossifov et al., 2014); a predicted benign missense variant in SIN3A was also observed in an unaffected sibing in Iossifov et al., 2014. De novo and inherited dominant variants in the SIN3A gene were identified in individuals presenting with a syndrome characterized by intellectual disability, ASD, brain abnormalities detected by MRI, dysmorphic facial features, microcephaly, and short stature; this phenotype is similar to that of individuals with atypical 15q24 microdeletions, whose shortest region of overlap (approximately 260 kb) includes the SIN3A gene (Witteveen et al., 2016). ASD was observed in 3 individuals with de novo loss-of-function SIN3A variants and 1 individual with a de novo 15q24 microdeletion involving SIN3A in this report. Knockdown of SIN3A in the developing mouse brain in Witteveen et al., 2016 resulted in a decrease in cortical progenitors, altered cortical neuronal identity, and aberrant corticocortical projections. A de novo frameshift variant in SIN3A was identified in a patient with a primary reason for referral of ASD in Farwell Hagman et al., 2016.

Reports Added
[Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model.2018]
10/1/2017
4S
icon
4S

Decreased from 4S to 4S

Description

De novo missense variants in the SIN3A gene were observed in ASD probands from the Autism Sequencing Consortium and the Simons Simplex Collection (a predicted benign missense variant in De Rubeis et al., 2014, and a predicted damaging missense variant in Iossifov et al., 2014); a predicted benign missense variant in SIN3A was also observed in an unaffected sibing in Iossifov et al., 2014. De novo and inherited dominant variants in the SIN3A gene were identified in individuals presenting with a syndrome characterized by intellectual disability, ASD, brain abnormalities detected by MRI, dysmorphic facial features, microcephaly, and short stature; this phenotype is similar to that of individuals with atypical 15q24 microdeletions, whose shortest region of overlap (approximately 260 kb) includes the SIN3A gene (Witteveen et al., 2016). ASD was observed in 3 individuals with de novo loss-of-function SIN3A variants and 1 individual with a de novo 15q24 microdeletion involving SIN3A in this report. Knockdown of SIN3A in the developing mouse brain in Witteveen et al., 2016 resulted in a decrease in cortical progenitors, altered cortical neuronal identity, and aberrant corticocortical projections. A de novo frameshift variant in SIN3A was identified in a patient with a primary reason for referral of ASD in Farwell Hagman et al., 2016.

Reports Added
[Exome Pool-Seq in neurodevelopmental disorders.2017]
7/1/2016
icon
4S

Increased from to 4S

Description

De novo missense variants in the SIN3A gene were observed in ASD probands from the Autism Sequencing Consortium and the Simons Simplex Collection (a predicted benign missense variant in De Rubeis et al., 2014, and a predicted damaging missense variant in Iossifov et al., 2014); a predicted benign missense variant in SIN3A was also observed in an unaffected sibing in Iossifov et al., 2014. De novo and inherited dominant variants in the SIN3A gene were identified in individuals presenting with a syndrome characterized by intellectual disability, ASD, brain abnormalities detected by MRI, dysmorphic facial features, microcephaly, and short stature; this phenotype is similar to that of individuals with atypical 15q24 microdeletions, whose shortest region of overlap (approximately 260 kb) includes the SIN3A gene (Witteveen et al., 2016). ASD was observed in 3 individuals with de novo loss-of-function SIN3A variants and 1 individual with a de novo 15q24 microdeletion involving SIN3A in this report. Knockdown of SIN3A in the developing mouse brain in Witteveen et al., 2016 resulted in a decrease in cortical progenitors, altered cortical neuronal identity, and aberrant corticocortical projections. A de novo frameshift variant in SIN3A was identified in a patient with a primary reason for referral of ASD in Farwell Hagman et al., 2016.

Krishnan Probability Score

Score 0.49158213177016

Ranking 5383/25841 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 0.99999994122779

Ranking 179/18225 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 0.945

Ranking 87/239 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 0.83494560608985

Ranking 2985/18665 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 0.10459779424042

Ranking 6026/20870 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.
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