NLGN4Xneuroligin 4, X-linked
Autism Reports / Total Reports
29 / 44Rare Variants / Common Variants
42 / 12Aliases
NLGN4X, HLNX, HNLX, NLGN, NLGN4, ASPGX2, AUTSX2, KIAA1260, MGC22376Associated Syndromes
-Chromosome Band
Xp22.32-p22.31Associated Disorders
ADHD, ID, ASD, EPSGenetic Category
Rare Single Gene Mutation, Syndromic, Genetic Association, FunctionalRelevance to Autism
Several studies have found rare variants in the NLGN4X gene in autism. Association was seen in Finnish and Caucasian population cohorts. However, several studies have found no rare variants in the NLGN4X gene in autistic patients in their cohorts (including Quebec population and IMGSAC cohorts).
Molecular Function
Neuroligins are cell-adhesion molecules at the postsynaptic side of the synapse .
External Links
SFARI Genomic Platforms
Reports related to NLGN4X (44 Reports)
| # | Type | Title | Author, Year | Autism Report | Associated Disorders |
|---|---|---|---|---|---|
| 1 | Primary | Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism | Jamain S , et al. (2003) | Yes | - |
| 2 | Highly Cited | X-linked mental retardation and autism are associated with a mutation in the NLGN4 gene, a member of the neuroligin family | Laumonnier F , et al. (2004) | No | ASD |
| 3 | Negative Association | Mutation screening of X-chromosomal neuroligin genes: no mutations in 196 autism probands | Vincent JB , et al. (2004) | Yes | - |
| 4 | Negative Association | NLGN3/NLGN4 gene mutations are not responsible for autism in the Quebec population | Gauthier J , et al. (2004) | Yes | - |
| 5 | Support | Analysis of the neuroligin 3 and 4 genes in autism and other neuropsychiatric patients | Yan J , et al. (2004) | Yes | - |
| 6 | Positive Association | Analysis of four neuroligin genes as candidates for autism | Ylisaukko-oja T , et al. (2005) | Yes | - |
| 7 | Negative Association | Absence of coding mutations in the X-linked genes neuroligin 3 and neuroligin 4 in individuals with autism from the IMGSAC collection | Blasi F , et al. (2006) | Yes | - |
| 8 | Recent Recommendation | Structure function and splice site analysis of the synaptogenic activity of the neurexin-1 beta LNS domain | Graf ER , et al. (2006) | No | - |
| 9 | Recent Recommendation | Reduced social interaction and ultrasonic communication in a mouse model of monogenic heritable autism | Jamain S , et al. (2008) | No | - |
| 10 | Support | Familial deletion within NLGN4 associated with autism and Tourette syndrome | Lawson-Yuen A , et al. (2008) | Yes | TS |
| 11 | Recent Recommendation | Unusually rapid evolution of Neuroligin-4 in mice | Bolliger MF , et al. (2008) | No | - |
| 12 | Support | Autism and nonsyndromic mental retardation associated with a de novo mutation in the NLGN4X gene promoter causing an increased expression level | Daoud H , et al. (2009) | Yes | MR |
| 13 | Positive Association | Genes related to sex steroids, neural growth, and social-emotional behavior are associated with autistic traits, empathy, and Asperger syndrome | Chakrabarti B , et al. (2009) | Yes | - |
| 14 | Positive Association | A substitution involving the NLGN4 gene associated with autistic behavior in the Greek population | Pampanos A , et al. (2009) | Yes | - |
| 15 | Support | A neuroligin-4 missense mutation associated with autism impairs neuroligin-4 folding and endoplasmic reticulum export | Zhang C , et al. (2009) | Yes | - |
| 16 | Support | Interpretation of clinical relevance of X-chromosome copy number variations identified in a large cohort of individuals with cognitive disorders and/or congenital anomalies | Willemsen MH , et al. (2012) | No | ASD, ADHD |
| 17 | Support | Identification of Four Novel Synonymous Substitutions in the X-Linked Genes Neuroligin 3 and Neuroligin 4X in Japanese Patients with Autistic Spectrum Disorder | Yanagi K , et al. (2012) | Yes | - |
| 18 | Support | Identification of rare X-linked neuroligin variants by massively parallel sequencing in males with autism spectrum disorder | Steinberg KM , et al. (2012) | Yes | - |
| 19 | Support | A discovery resource of rare copy number variations in individuals with autism spectrum disorder | Prasad A , et al. (2013) | Yes | - |
| 20 | Support | Using whole-exome sequencing to identify inherited causes of autism | Yu TW , et al. (2013) | Yes | - |
| 21 | Recent Recommendation | The functional genetic link of NLGN4X knockdown and neurodevelopment in neural stem cells | Shi L , et al. (2013) | No | - |
| 22 | Positive Association | Variations analysis of NLGN3 and NLGN4X gene in Chinese autism patients | Xu X , et al. (2014) | Yes | - |
| 23 | Recent Recommendation | Integrated systems analysis reveals a molecular network underlying autism spectrum disorders | Li J , et al. (2015) | Yes | - |
| 24 | Recent Recommendation | Autism-associated mutation inhibits protein kinase C-mediated neuroligin-4X enhancement of excitatory synapses | Bemben MA , et al. (2015) | No | - |
| 25 | Recent Recommendation | Pathogenic mechanism of an autism-associated neuroligin mutation involves altered AMPA-receptor trafficking | Chanda S , et al. (2015) | No | - |
| 26 | Support | GABA/Glutamate synaptic pathways targeted by integrative genomic and electrophysiological explorations distinguish autism from intellectual disability | Bonnet-Brilhault F , et al. (2015) | Yes | - |
| 27 | Support | High diagnostic yield of syndromic intellectual disability by targeted next-generation sequencing | Martnez F , et al. (2016) | No | Autistic behavior |
| 28 | Support | Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder | C Yuen RK et al. (2017) | Yes | - |
| 29 | Negative Association | Not all neuroligin 3 and 4X missense variants lead to significant functional inactivation | Xu X , et al. (2017) | Yes | - |
| 30 | Positive Association | Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection | Pardias AF , et al. (2018) | No | - |
| 31 | Support | De Novo Sequence and Copy Number Variants Are Strongly Associated with Tourette Disorder and Implicate Cell Polarity in Pathogenesis | Wang S , et al. (2018) | No | - |
| 32 | Negative Association | Analysis of the SNP rs3747333 and rs3747334 in NLGN4X gene in autism spectrum disorder: a meta-analysis | Sun H , et al. (2019) | Yes | - |
| 33 | Recent Recommendation | Neuroligin-4 Regulates Excitatory Synaptic Transmission in Human Neurons | Marro SG , et al. (2019) | No | - |
| 34 | Recent Recommendation | A Cluster of Autism-Associated Variants on X-Linked NLGN4X Functionally Resemble NLGN4Y | Nguyen TA et al. (2020) | Yes | - |
| 35 | Support | Next-Generation Sequencing in Korean Children With Autism Spectrum Disorder and Comorbid Epilepsy | Lee J et al. (2020) | Yes | ID, epilepsy/seizures |
| 36 | Recent Recommendation | Autism-associated variants of neuroligin 4X impair synaptogenic activity by various molecular mechanisms | Yumoto T et al. (2020) | Yes | - |
| 37 | Support | - | Bruno LP et al. (2021) | No | Stereotypy |
| 38 | Support | - | Zhou X et al. (2022) | Yes | - |
| 39 | Support | - | Chan AJS et al. (2022) | Yes | ADHD, TS |
| 40 | Support | - | Toya A et al. (2023) | No | - |
| 41 | Support | - | Miyake N et al. (2023) | Yes | - |
| 42 | Support | - | Hu C et al. (2023) | Yes | - |
| 43 | Support | - | Lucie Sedlackova et al. (2024) | No | - |
| 44 | Support | - | Omri Bar et al. (2024) | Yes | ID |
Rare Variants (42)
| Status | Allele Change | Residue Change | Variant Type | Inheritance Pattern | Parental Transmission | Family Type | PubMed ID | Author, Year |
|---|---|---|---|---|---|---|---|---|
| - | - | copy_number_loss | Unknown | - | - | 32477112 | Lee J et al. (2020) | |
| - | - | copy_number_gain | Unknown | - | Unknown | 23275889 | Prasad A , et al. (2013) | |
| c.1601+5G>A | - | splice_site_variant | De novo | - | - | 35982159 | Zhou X et al. (2022) | |
| c.1805C>T | p.(=) | synonymous_variant | - | - | - | 15274046 | Vincent JB , et al. (2004) | |
| - | - | copy_number_gain | Familial | Maternal | - | 22796527 | Willemsen MH , et al. (2012) | |
| C2241TC2243G | p.(=) | synonymous_variant | - | - | - | 15274046 | Vincent JB , et al. (2004) | |
| c.1271A>C | p.Tyr424Ser | missense_variant | De novo | - | - | 37007974 | Hu C et al. (2023) | |
| c.1310G>A | p.Arg437Gln | synonymous_variant | - | - | - | 15274046 | Vincent JB , et al. (2004) | |
| c.1397C>T | p.Pro466Leu | synonymous_variant | - | - | - | 15274046 | Vincent JB , et al. (2004) | |
| c.-335G>A | - | 2KB_upstream_variant | De novo | - | Simplex | 19545860 | Daoud H , et al. (2009) | |
| c.484C>A | p.Gln162Lys | missense_variant | De novo | - | Simplex | 24570023 | Xu X , et al. (2014) | |
| c.392A>G | p.Asn131Ser | missense_variant | Unknown | - | Unknown | 25549968 | Li J , et al. (2015) | |
| - | - | copy_number_loss | Familial | Maternal | Multiplex | 18231125 | Lawson-Yuen A , et al. (2008) | |
| c.1564G>A | p.Val522Met | missense_variant | De novo | - | Simplex | 30257206 | Wang S , et al. (2018) | |
| c.281C>T | p.Pro94Leu | missense_variant | Unknown | - | Unknown | 32243781 | Nguyen TA et al. (2020) | |
| c.297C>T | p.Gly99= | synonymous_variant | Unknown | - | Unknown | 22934180 | Yanagi K , et al. (2012) | |
| c.2167C>T | p.His723Tyr | missense_variant | De novo | - | Simplex | 34948243 | Bruno LP et al. (2021) | |
| c.259C>T | p.Arg87Trp | missense_variant | De novo | - | Multiplex | 19726642 | Zhang C , et al. (2009) | |
| c.516C>T | p.Ile172= | synonymous_variant | Unknown | - | Unknown | 22934180 | Yanagi K , et al. (2012) | |
| c.985C>T | p.Gln329Ter | stop_gained | Familial | Maternal | Simplex | 23352163 | Yu TW , et al. (2013) | |
| c.659del | p.Gly220AlafsTer29 | frameshift_variant | Unknown | - | - | 36309498 | Chan AJS et al. (2022) | |
| c.1590C>T | p.Phe530= | synonymous_variant | Unknown | - | Unknown | 22934180 | Yanagi K , et al. (2012) | |
| c.632del | p.Leu211Ter | frameshift_variant | Unknown | - | Simplex | 28263302 | C Yuen RK et al. (2017) | |
| c.250G>A | p.Gly84Arg | missense_variant | Familial | Maternal | Simplex | 24570023 | Xu X , et al. (2014) | |
| c.820C>T | p.Gln274Ter | stop_gained | Familial | Maternal | Simplex | 28263302 | C Yuen RK et al. (2017) | |
| c.847G>A | p.Ala283Thr | missense_variant | Familial | Maternal | Simplex | 24570023 | Xu X , et al. (2014) | |
| c.1133A>G | p.Lys378Arg | missense_variant | Familial | Maternal | - | 19645625 | Pampanos A , et al. (2009) | |
| c.1133A>G | p.Lys378Arg | missense_variant | Familial | Maternal | Simplex | 15622415 | Yan J , et al. (2004) | |
| c.2297G>A | p.Arg766Gln | missense_variant | Familial | Maternal | Simplex | 23352163 | Yu TW , et al. (2013) | |
| c.295G>A | p.Gly99Ser | missense_variant | Familial | Maternal | Multiplex | 15622415 | Yan J , et al. (2004) | |
| c.1361_1372del | p.Val454_Ala457del | inframe_deletion | De novo | - | - | 27620904 | Martnez F , et al. (2016) | |
| c.295G>A | p.Gly99Ser | missense_variant | Familial | Maternal | - | 38008000 | Lucie Sedlackova et al. (2024) | |
| c.1207G>A | p.Val403Met | missense_variant | Familial | Maternal | Multiplex | 15622415 | Yan J , et al. (2004) | |
| c.2110C>T | p.Arg704Cys | missense_variant | Familial | Maternal | Multiplex | 15622415 | Yan J , et al. (2004) | |
| c.302G>A | p.Arg101Gln | missense_variant | Familial | Maternal | Unknown | 32243781 | Nguyen TA et al. (2020) | |
| c.325G>C | p.Val109Leu | missense_variant | Familial | Maternal | Unknown | 32243781 | Nguyen TA et al. (2020) | |
| c.1360G>C | p.Val454Leu | missense_variant | Familial | Maternal | Multiplex | 38256266 | Omri Bar et al. (2024) | |
| c.1601+969del | - | 3_prime_UTR_variant | Familial | Maternal | Multiplex | 23020841 | Steinberg KM , et al. (2012) | |
| c.1601+2982T>C | - | 3_prime_UTR_variant | Familial | Maternal | Multiplex | 23020841 | Steinberg KM , et al. (2012) | |
| c.1186_1187insT | p.Asp396ValfsTer16 | frameshift_variant | Familial | Maternal | Multiplex | 12669065 | Jamain S , et al. (2003) | |
| c.1581_1582delinsTT | p.Trp527_Thr528delinsCysSer | inframe_indel | Familial | Maternal | Simplex | 36973392 | Miyake N et al. (2023) | |
| c.1254_1255del | p.Glu418AspfsTer12 | frameshift_variant | Familial | Maternal | Multi-generational | 14963808 | Laumonnier F , et al. (2004) |
Common Variants (12)
| Status | Allele Change | Residue Change | Variant Type | Inheritance Pattern | Paternal Transmission | Family Type | PubMed ID | Author, Year |
|---|---|---|---|---|---|---|---|---|
| c.1777C>T;c.1837C>T | p.Leu593Phe;p.Leu613Phe | missense_variant | - | - | - | 16508939 | Blasi F , et al. (2006) | |
| c.1777C>T;c.1837C>T | p.Leu593Phe;p.Leu613Phe | missense_variant | - | - | - | 15389766 | Gauthier J , et al. (2004) | |
| c.-306+6390T>C;c.-305-29322T>C;c.-306+5679T>C | - | intron_variant | - | - | - | 19598235 | Chakrabarti B , et al. (2009) | |
| c.-613+640G>A;c.-1327G>A;c.-518G>A;c.-306+640G>A;c.-1572G>A;c.-1341G>A;c.-2250G>A | G to A | intron_variant, 2KB_upstream_variant | - | - | - | 16508939 | Blasi F , et al. (2006) | |
| c.-613+727G>C;c.-1240G>C;c.-431G>C;c.-306+727G>C;c.-1485G>C;c.-1254G>C;c.-2163G>C | G34C | intron_variant, 2KB_upstream_variant, 5_prime_UTR_variant | - | - | - | 16508939 | Blasi F , et al. (2006) | |
| - | - | intron_variant, microsatellite | - | - | - | 16077734 | Ylisaukko-oja T , et al. (2005) | |
| c.1779C>G;c.1839C>G | p.(=) | synonymous_variant | - | - | - | 24570023 | Xu X , et al. (2014) | |
| c.1779C>G;c.1839C>G | p.(=) | synonymous_variant | - | - | - | 16508939 | Blasi F , et al. (2006) | |
| c.1779C>G;c.1839C>G | p.(=) | synonymous_variant | - | - | - | 15389766 | Gauthier J , et al. (2004) | |
| c.625+26439T>C;c.685+26439T>C | - | intron_variant | - | - | - | 29483656 | Pardias AF , et al. (2018) | |
| c.1397C>T;c.933C>T;c.993C>T | p.(=) | synonymous_variant | - | - | - | 16508939 | Blasi F , et al. (2006) | |
| c.1777C>T;c.1837C>T | p.Leu593Phe;p.Leu613Phe | missense_variant | - | - | - | 24570023 | Xu X , et al. (2014) |
SFARI Gene score
1
High Confidence
Score Delta: Score remained at 1
criteria met
See SFARI Gene'scoring criteriaWe 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.
7/1/2020
1
1
Score remained at 1
Description
Several studies have observed rare variants in the NLGN4X gene with autism. In addition, association was seen in Finnish and Caucasian population cohorts. However, several studies have found no rare variants in the NLGN4X gene in autistic patients in their cohorts (including Quebec population and IMGSAC cohorts). NLGN4X interacts with another ASD gene, NRXN1.
4/1/2020
1
1
Score remained at 1
Description
Several studies have observed rare variants in the NLGN4X gene with autism. In addition, association was seen in Finnish and Caucasian population cohorts. However, several studies have found no rare variants in the NLGN4X gene in autistic patients in their cohorts (including Quebec population and IMGSAC cohorts). NLGN4X interacts with another ASD gene, NRXN1.
10/1/2019
3
1
Decreased from 3 to 1
New Scoring Scheme
Description
Several studies have observed rare variants in the NLGN4X gene with autism. In addition, association was seen in Finnish and Caucasian population cohorts. However, several studies have found no rare variants in the NLGN4X gene in autistic patients in their cohorts (including Quebec population and IMGSAC cohorts). NLGN4X interacts with another ASD gene, NRXN1.
Reports Added
[New Scoring Scheme]7/1/2019
3
3
Decreased from 3 to 3
Description
Several studies have observed rare variants in the NLGN4X gene with autism. In addition, association was seen in Finnish and Caucasian population cohorts. However, several studies have found no rare variants in the NLGN4X gene in autistic patients in their cohorts (including Quebec population and IMGSAC cohorts). NLGN4X interacts with another ASD gene, NRXN1.
Reports Added
[Not all neuroligin 3 and 4X missense variants lead to significant functional inactivation.2017] [Analysis of the SNP rs3747333 and rs3747334 in NLGN4X gene in autism spectrum disorder: a meta-analysis.2019] [Neuroligin-4 Regulates Excitatory Synaptic Transmission in Human Neurons.2019]10/1/2018
3
3
Decreased from 3 to 3
Description
Several studies have observed rare variants in the NLGN4X gene with autism. In addition, association was seen in Finnish and Caucasian population cohorts. However, several studies have found no rare variants in the NLGN4X gene in autistic patients in their cohorts (including Quebec population and IMGSAC cohorts). NLGN4X interacts with another ASD gene, NRXN1.
4/1/2017
3
3
Decreased from 3 to 3
Description
Several studies have observed rare variants in the NLGN4X gene with autism. In addition, association was seen in Finnish and Caucasian population cohorts. However, several studies have found no rare variants in the NLGN4X gene in autistic patients in their cohorts (including Quebec population and IMGSAC cohorts). NLGN4X interacts with another ASD gene, NRXN1.
Reports Added
[Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism.2003] [Mutation screening of X-chromosomal neuroligin genes: no mutations in 196 autism probands.2004] [NLGN3/NLGN4 gene mutations are not responsible for autism in the Quebec population.2004] [Analysis of four neuroligin genes as candidates for autism.2005] [Absence of coding mutations in the X-linked genes neuroligin 3 and neuroligin 4 in individuals with autism from the IMGSAC collection.2006] [Familial deletion within NLGN4 associated with autism and Tourette syndrome.2008] [Autism and nonsyndromic mental retardation associated with a de novo mutation in the NLGN4X gene promoter causing an increased expression level.2009] [Genes related to sex steroids, neural growth, and social-emotional behavior are associated with autistic traits, empathy, and Asperger syndrome.2009] [A substitution involving the NLGN4 gene associated with autistic behavior in the Greek population.2009] [Identification of Four Novel Synonymous Substitutions in the X-Linked Genes Neuroligin 3 and Neuroligin 4X in Japanese Patients with Autistic Spect...2012] [Identification of rare X-linked neuroligin variants by massively parallel sequencing in males with autism spectrum disorder.2012] [A discovery resource of rare copy number variations in individuals with autism spectrum disorder.2013] [Using whole-exome sequencing to identify inherited causes of autism.2013] [Variations analysis of NLGN3 and NLGN4X gene in Chinese autism patients.2014] [Integrated systems analysis reveals a molecular network underlying autism spectrum disorders.2015] [Analysis of the neuroligin 3 and 4 genes in autism and other neuropsychiatric patients.2004] [Interpretation of clinical relevance of X-chromosome copy number variations identified in a large cohort of individuals with cognitive disorders an...2012] [Structure function and splice site analysis of the synaptogenic activity of the neurexin-1 beta LNS domain.2006] [Reduced social interaction and ultrasonic communication in a mouse model of monogenic heritable autism.2008] [Unusually rapid evolution of Neuroligin-4 in mice.2008] [A neuroligin-4 missense mutation associated with autism impairs neuroligin-4 folding and endoplasmic reticulum export.2009] [The functional genetic link of NLGN4X knockdown and neurodevelopment in neural stem cells.2013] [Autism-associated mutation inhibits protein kinase C-mediated neuroligin-4X enhancement of excitatory synapses.2015] [Pathogenic mechanism of an autism-associated neuroligin mutation involves altered AMPA-receptor trafficking.2015] [GABA/Glutamate synaptic pathways targeted by integrative genomic and electrophysiological explorations distinguish autism from intellectual disabil...2015] [X-linked mental retardation and autism are associated with a mutation in the NLGN4 gene, a member of the neuroligin family.2004] [High diagnostic yield of syndromic intellectual disability by targeted next-generation sequencing.2016] [Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder2017]10/1/2016
3
3
Decreased from 3 to 3
Description
Several studies have observed rare variants in the NLGN4X gene with autism. In addition, association was seen in Finnish and Caucasian population cohorts. However, several studies have found no rare variants in the NLGN4X gene in autistic patients in their cohorts (including Quebec population and IMGSAC cohorts). NLGN4X interacts with another ASD gene, NRXN1.
4/1/2015
3
3
Decreased from 3 to 3
Description
Several studies have observed rare variants in the NLGN4X gene with autism. In addition, association was seen in Finnish and Caucasian population cohorts. However, several studies have found no rare variants in the NLGN4X gene in autistic patients in their cohorts (including Quebec population and IMGSAC cohorts). NLGN4X interacts with another ASD gene, NRXN1.
Reports Added
[Pathogenic mechanism of an autism-associated neuroligin mutation involves altered AMPA-receptor trafficking.2015] [GABA/Glutamate synaptic pathways targeted by integrative genomic and electrophysiological explorations distinguish autism from intellectual disabil...2015] [X-linked mental retardation and autism are associated with a mutation in the NLGN4 gene, a member of the neuroligin family.2004]1/1/2015
3
3
Decreased from 3 to 3
Description
Several studies have observed rare variants in the NLGN4X gene with autism. In addition, association was seen in Finnish and Caucasian population cohorts. However, several studies have found no rare variants in the NLGN4X gene in autistic patients in their cohorts (including Quebec population and IMGSAC cohorts). NLGN4X interacts with another ASD gene, NRXN1.
Reports Added
[Integrated systems analysis reveals a molecular network underlying autism spectrum disorders.2015] [Analysis of the neuroligin 3 and 4 genes in autism and other neuropsychiatric patients.2004] [Autism-associated mutation inhibits protein kinase C-mediated neuroligin-4X enhancement of excitatory synapses.2015]7/1/2014
No data
3
Increased from No data to 3
Description
Several studies have observed rare variants in the NLGN4X gene with autism. In addition, association was seen in Finnish and Caucasian population cohorts. However, several studies have found no rare variants in the NLGN4X gene in autistic patients in their cohorts (including Quebec population and IMGSAC cohorts). NLGN4X interacts with another ASD gene, NRXN1.
4/1/2014
No data
3
Increased from No data to 3
Description
Several studies have observed rare variants in the NLGN4X gene with autism. In addition, association was seen in Finnish and Caucasian population cohorts. However, several studies have found no rare variants in the NLGN4X gene in autistic patients in their cohorts (including Quebec population and IMGSAC cohorts). NLGN4X interacts with another ASD gene, NRXN1.
Krishnan Probability Score
Score 0.49662832886019
Ranking 2551/25841 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.
ExAC Score
Score 0.93229855900972
Ranking 2901/18225 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
Sanders TADA Score
Score 0.94481636431511
Ranking 16224/18665 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).
Larsen Cumulative Evidence Score
Score 41
Ranking 46/461 scored genes
[Show Scoring Methodology]
Larsen and colleagues generated gene scores based on the sum of evidence for all available
ASD-associated variants in a gene, with assessments based on mode of inheritance, effect size,
and variant frequency in the general population. The approach was first presented in Mol Autism
7:44 (2016), and scores for 461 genes can be found in column I in supplementary table 4 from
that paper.