Human Gene Module / Chromosome 21 / ITSN1

ITSN1intersectin 1

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
8 / 10
Rare Variants / Common Variants
44 / 0
Aliases
ITSN1, ITSN,  SH3D1A,  SH3P17
Associated Syndromes
-
Chromosome Band
21q22.11
Associated Disorders
-
Relevance to Autism

A de novo likely gene-disruptive (LGD) variant in the ITSN1 gene was identified in an ASD proband from a simplex family from the ASD: Genomes to Outcome Study cohort (Yuen et al., 2017), while de novo damaging missense variants (defined by CADD score 25) in this gene were observed in an ASD proband from the Autism Sequencing Consortium (De Rubeis et al., 2014) and in two ASD probands from the SPARK cohort (Feliciano et al., 2019). A meta-analysis of de novo variants in 4773 published ASD trios and 465 SPARK trios using TADA in Feliciano et al., 2019 identified ITSN1 as an ASD candidate gene with a false discovery rate between 0.01 and 0.05 (0.01 < FDR 0.05). Rare singleton inherited LGD variants in the ITSN1 gene were also identified in ASD probands from the SPARK cohort and the Simons Simplex Collection (Krumm et al., 2015; Feliciano et al., 2019). Bruel et al., 2021 described the clinical presentation of 10 individuals from 8 families with heterozygous ITSN1 variants, all of whom presented with a neurodevelopmental disorder characterized by global developmental delay and delayed speech and language development; additional neurodevelopmental disorders such as autism spectrum disorders (90%), intellectual disability (86%), ADHD (50%), and epilepsy (30%) were also observed in this cohort. A two-stage analysis of rare de novo and inherited coding variants in 42,607 ASD cases, including 35,130 new cases from the SPARK cohort, in Zhou et al., 2022 identified ITSN1 as a gene reaching exome-wide significance (P < 2.5E-06); association of ITSN1 with ASD risk was primarily driven by rare inherited loss-of-function variants.

Molecular Function

The protein encoded by this gene is a cytoplasmic membrane-associated protein that indirectly coordinates endocytic membrane traffic with the actin assembly machinery. In addition, the encoded protein may regulate the formation of clathrin-coated vesicles and could be involved in synaptic vesicle recycling.

External Links
Gene CardOpen Targets PlatformgnomAD browserSynGO portalPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to ITSN1 (10 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Synaptic, transcriptional and chromatin genes disrupted in autism De Rubeis S , et al. (2014) Yes -
2 Support Excess of rare, inherited truncating mutations in autism Krumm N , et al. (2015) Yes -
3 Support Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder C Yuen RK et al. (2017) Yes -
4 Recent Recommendation Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes Feliciano P et al. (2019) Yes -
5 Recent Recommendation - Bruel AL et al. (2021) Yes ADHD, epilepsy/seizures
6 Support - Mosallaei M et al. (2022) No Autistic features
7 Recent Recommendation - Zhou X et al. (2022) Yes -
8 Support - Cirnigliaro M et al. (2023) Yes -
9 Support - Thomas V Fernandez et al. (2023) No -
10 Support - Khurram Liaqat et al. (2024) Yes -
Rare Variants   (44)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.934C>T p.Arg312Ter stop_gained Unknown - - 35982159 Zhou X et al. (2022)
c.1228G>T p.Glu410Ter stop_gained Unknown - - 35982159 Zhou X et al. (2022)
c.1504C>T p.Arg502Ter stop_gained De novo - - 35982159 Zhou X et al. (2022)
c.1885C>T p.Arg629Ter stop_gained Unknown - - 35982159 Zhou X et al. (2022)
c.789-2A>G - splice_site_variant De novo - - 34707297 Bruel AL et al. (2021)
c.1258G>T p.Glu420Ter stop_gained Unknown - - 34707297 Bruel AL et al. (2021)
c.1960C>T p.Gln654Ter stop_gained De novo - - 34707297 Bruel AL et al. (2021)
- p.Gln711Ter stop_gained Familial Paternal - 31452935 Feliciano P et al. (2019)
c.2894dup p.Tyr965Ter frameshift_variant Unknown - - 35982159 Zhou X et al. (2022)
c.527-1G>A - splice_site_variant Familial Maternal - 35982159 Zhou X et al. (2022)
c.4661+2T>G - splice_site_variant Familial Maternal - 35982159 Zhou X et al. (2022)
c.4354A>T p.Asn1452Tyr missense_variant De novo - - 34707297 Bruel AL et al. (2021)
c.1174G>T p.Glu392Ter stop_gained Familial Maternal - 35982159 Zhou X et al. (2022)
c.1504C>T p.Arg502Ter stop_gained Familial Paternal - 35982159 Zhou X et al. (2022)
c.2895C>G p.Tyr965Ter stop_gained Familial Paternal - 35982159 Zhou X et al. (2022)
c.2894dup p.Tyr965Ter frameshift_variant Unknown - - 34707297 Bruel AL et al. (2021)
c.3116G>A p.Trp1039Ter stop_gained Familial Paternal - 35982159 Zhou X et al. (2022)
c.3310C>T p.Arg1104Ter stop_gained Familial Maternal - 35982159 Zhou X et al. (2022)
c.1130G>A p.Arg377His missense_variant De novo - - 31452935 Feliciano P et al. (2019)
c.1726G>T p.Glu576Ter stop_gained Familial Paternal - 34707297 Bruel AL et al. (2021)
c.4841C>T p.Pro1614Leu missense_variant De novo - - 31452935 Feliciano P et al. (2019)
- p.Pro156fs frameshift_variant Familial Paternal - 31452935 Feliciano P et al. (2019)
c.1885C>T p.Arg629Ter stop_gained Unknown Not maternal - 35982159 Zhou X et al. (2022)
c.299del p.Pro100LeufsTer3 frameshift_variant Unknown - - 35982159 Zhou X et al. (2022)
c.300del p.Val101SerfsTer2 frameshift_variant De novo - - 35982159 Zhou X et al. (2022)
c.5099T>G p.Leu1700Arg missense_variant De novo - - 25363760 De Rubeis S , et al. (2014)
c.3271G>A p.Glu1091Lys missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.2847G>A p.Trp949Ter stop_gained De novo - Simplex 38346866 Khurram Liaqat et al. (2024)
c.1952+1del - splice_site_variant Familial Maternal Simplex 25961944 Krumm N , et al. (2015)
c.1300C>T p.Arg434Ter stop_gained Familial Maternal Multiplex 35982159 Zhou X et al. (2022)
c.1726G>T p.Glu576Ter stop_gained Familial Paternal Simplex 25961944 Krumm N , et al. (2015)
c.64dup p.Arg22LysfsTer5 frameshift_variant Familial Paternal - 35982159 Zhou X et al. (2022)
c.2842_2843del p.Met948ValfsTer41 frameshift_variant Unknown - - 35982159 Zhou X et al. (2022)
c.4652_4653del p.Ile1551LysfsTer2 frameshift_variant Unknown - - 35982159 Zhou X et al. (2022)
c.1389_1392del p.Lys463AsnfsTer5 frameshift_variant Unknown - - 34707297 Bruel AL et al. (2021)
c.472dup p.Leu158ProfsTer3 frameshift_variant Familial Maternal - 35982159 Zhou X et al. (2022)
c.3116G>A p.Trp1039Ter stop_gained Familial Paternal Multiplex 34707297 Bruel AL et al. (2021)
c.934C>T p.Arg312Ter stop_gained Familial Maternal Multiplex 37506195 Cirnigliaro M et al. (2023)
c.186-2A>G - splice_site_variant Familial Both parents Multiplex 35174982 Mosallaei M et al. (2022)
c.4379C>T p.Pro1460Leu missense_variant De novo - Simplex 37788244 Thomas V Fernandez et al. (2023)
c.2842_2843del p.Met948ValfsTer41 frameshift_variant Familial Maternal - 35982159 Zhou X et al. (2022)
c.2842_2843del p.Met948ValfsTer41 frameshift_variant De novo - Simplex 28263302 C Yuen RK et al. (2017)
c.3207_3208del p.Gly1070GlufsTer7 frameshift_variant Unknown Not maternal - 35982159 Zhou X et al. (2022)
c.490_491del p.Pro164CysfsTer22 frameshift_variant Familial Paternal Simplex 25961944 Krumm N , et al. (2015)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

A de novo likely gene-disruptive (LGD) variant in the ITSN1 gene was identified in an ASD proband from a simplex family from the ASD: Genomes to Outcome Study cohort (Yuen et al., 2017), while de novo damaging missense variants (defined by CADD score 25) in this gene were observed in an ASD proband from the Autism Sequencing Consortium (De Rubeis et al., 2014) and in two ASD probands from the SPARK cohort (Feliciano et al., 2019). A meta-analysis of de novo variants in 4773 published ASD trios and 465 SPARK trios using TADA identified ITSN1 as an ASD candidate gene with a q-value 0.1. Rare singleton inherited LGD variants in the ITSN1 gene were also identified in ASD probands from the SPARK cohort and the Simons Simplex Collection (Krumm et al., 2015; Feliciano et al., 2019).

Score Delta: Score remained at 2

criteria met
See SFARI Gene'scoring criteria
2

Strong Candidate

See all Category 2 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.

4/1/2022
3
icon
2

Decreased from 3 to 2

Description

A de novo likely gene-disruptive (LGD) variant in the ITSN1 gene was identified in an ASD proband from a simplex family from the ASD: Genomes to Outcome Study cohort (Yuen et al., 2017), while de novo damaging missense variants (defined by CADD score 25) in this gene were observed in an ASD proband from the Autism Sequencing Consortium (De Rubeis et al., 2014) and in two ASD probands from the SPARK cohort (Feliciano et al., 2019). A meta-analysis of de novo variants in 4773 published ASD trios and 465 SPARK trios using TADA identified ITSN1 as an ASD candidate gene with a q-value 0.1. Rare singleton inherited LGD variants in the ITSN1 gene were also identified in ASD probands from the SPARK cohort and the Simons Simplex Collection (Krumm et al., 2015; Feliciano et al., 2019).

10/1/2019
icon
3

Increased from to 3

New Scoring Scheme
Description

A de novo likely gene-disruptive (LGD) variant in the ITSN1 gene was identified in an ASD proband from a simplex family from the ASD: Genomes to Outcome Study cohort (Yuen et al., 2017), while de novo damaging missense variants (defined by CADD score 25) in this gene were observed in an ASD proband from the Autism Sequencing Consortium (De Rubeis et al., 2014) and in two ASD probands from the SPARK cohort (Feliciano et al., 2019). A meta-analysis of de novo variants in 4773 published ASD trios and 465 SPARK trios using TADA identified ITSN1 as an ASD candidate gene with a q-value 0.1. Rare singleton inherited LGD variants in the ITSN1 gene were also identified in ASD probands from the SPARK cohort and the Simons Simplex Collection (Krumm et al., 2015; Feliciano et al., 2019).

Reports Added
[New Scoring Scheme]
Krishnan Probability Score

Score 0.52134155925362

Ranking 1679/25841 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 0.99999997363569

Ranking 159/18225 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 0.78582221879538

Ranking 1983/18665 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 -0.22445506295386

Ranking 15907/20870 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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