Human Gene Module / Chromosome 1 / NTNG1

NTNG1netrin G1

SFARI Gene Score
2S
Strong Candidate, Syndromic Criteria 2.1, Syndromic
Autism Reports / Total Reports
2 / 8
Rare Variants / Common Variants
3 / 2
Aliases
NTNG1, Lmnt1,  KIAA0976
Associated Syndromes
Rett syndrome
Chromosome Band
1p13.3
Associated Disorders
-
Relevance to Autism

This gene has been identified with syndromic autism, where a subpopulation of individuals with a given syndrome develop autism. In particular, a rare mutation in the NTNG1 gene has been identified with Rett syndrome (Borg et al., 2005). In addition, genetic association has been found between the NTNG1 gene and schizophrenia in a Japanese population cohort (Ohtsuki et al., 2008), and rare mutations in the NTNG1 gene have been identified in individuals with ASD (ORoak et al., 2012).

Molecular Function

Netrin G1 (NTNG1) belongs to a conserved family of proteins that act as axon gui dance cues during vertebrate nervous system development

Reports related to NTNG1 (8 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Highly Cited The netrin-G1 ligand NGL-1 promotes the outgrowth of thalamocortical axons Lin JC , et al. (2003) No -
2 Primary Disruption of Netrin G1 by a balanced chromosome translocation in a girl with Rett syndrome Borg I , et al. (2005) No -
3 Recent Recommendation NGL family PSD-95-interacting adhesion molecules regulate excitatory synapse formation Kim S , et al. (2006) No -
4 Recent Recommendation Axonal netrin-Gs transneuronally determine lamina-specific subdendritic segments Nishimura-Akiyoshi S , et al. (2007) No -
5 Recent Recommendation Netrin-G2 and netrin-G2 ligand are both required for normal auditory responsiveness Zhang W , et al. (2007) No -
6 Recent Recommendation Association of polymorphisms in the haplotype block spanning the alternatively spliced exons of the NTNG1 gene at 1p13.3 with schizophrenia in Japanese populations Ohtsuki T , et al. (2008) No -
7 Support Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations O'Roak BJ , et al. (2012) Yes -
8 Support Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders O'Roak BJ , et al. (2012) Yes -
Rare Variants   (3)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - translocation - - - 15870826 Borg I , et al. (2005)
c.68A>G p.Tyr23Cys missense_variant De novo NA Simplex 22495309 O'Roak BJ , et al. (2012)
c.404C>T p.Thr135Ile missense_variant De novo NA Simplex 22495309 O'Roak BJ , et al. (2012)
Common Variants   (2)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
c.1390+10464A>G;c.1213+26120A>G;c.1088-33348A>G;c.1288+10464A>G;c.1516+10464A>G;c.915-33348A>G T/C intron_variant - - - 18384956 Ohtsuki T , et al. (2008)
c.1390+17685C>T;c.1214-26127C>T;c.1088-26127C>T;c.1288+17685C>T;c.1516+17685C>T;c.915-26127C>T G/A intron_variant - - - 18384956 Ohtsuki T , et al. (2008)
SFARI Gene score
2S

Strong Candidate, Syndromic

NTNG1 disrupted by chromosomal translocation in a female Rett syndrome patient (PMID 15870826), basis for syndromic designation); two de novo LoF missense variants identified in unrelated simplex ASD cases (PMID 22495309); genetic association found between NTNG1 and schizophrenia in a Japanese population cohort (PMID 18384956)

Score Delta: Decreased from 4S to 3S

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.

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."

10/1/2021
4S
icon
3S

Decreased from 4S to 3S

Description

NTNG1 disrupted by chromosomal translocation in a female Rett syndrome patient (PMID 15870826), basis for syndromic designation); two de novo LoF missense variants identified in unrelated simplex ASD cases (PMID 22495309); genetic association found between NTNG1 and schizophrenia in a Japanese population cohort (PMID 18384956)

7/1/2021
4S
icon
3S

Decreased from 4S to 3S

Description

NTNG1 disrupted by chromosomal translocation in a female Rett syndrome patient (PMID 15870826), basis for syndromic designation); two de novo LoF missense variants identified in unrelated simplex ASD cases (PMID 22495309); genetic association found between NTNG1 and schizophrenia in a Japanese population cohort (PMID 18384956)

4/1/2021
4S
icon
3S

Decreased from 4S to 3S

Description

NTNG1 disrupted by chromosomal translocation in a female Rett syndrome patient (PMID 15870826), basis for syndromic designation); two de novo LoF missense variants identified in unrelated simplex ASD cases (PMID 22495309); genetic association found between NTNG1 and schizophrenia in a Japanese population cohort (PMID 18384956)

1/1/2021
4S
icon
3S

Decreased from 4S to 3S

Description

NTNG1 disrupted by chromosomal translocation in a female Rett syndrome patient (PMID 15870826), basis for syndromic designation); two de novo LoF missense variants identified in unrelated simplex ASD cases (PMID 22495309); genetic association found between NTNG1 and schizophrenia in a Japanese population cohort (PMID 18384956)

10/1/2020
4S
icon
3S

Decreased from 4S to 3S

Description

NTNG1 disrupted by chromosomal translocation in a female Rett syndrome patient (PMID 15870826), basis for syndromic designation); two de novo LoF missense variants identified in unrelated simplex ASD cases (PMID 22495309); genetic association found between NTNG1 and schizophrenia in a Japanese population cohort (PMID 18384956)

7/1/2020
4S
icon
3S

Decreased from 4S to 3S

Description

NTNG1 disrupted by chromosomal translocation in a female Rett syndrome patient (PMID 15870826), basis for syndromic designation); two de novo LoF missense variants identified in unrelated simplex ASD cases (PMID 22495309); genetic association found between NTNG1 and schizophrenia in a Japanese population cohort (PMID 18384956)

4/1/2020
4S
icon
3S

Decreased from 4S to 3S

Description

NTNG1 disrupted by chromosomal translocation in a female Rett syndrome patient (PMID 15870826), basis for syndromic designation); two de novo LoF missense variants identified in unrelated simplex ASD cases (PMID 22495309); genetic association found between NTNG1 and schizophrenia in a Japanese population cohort (PMID 18384956)

1/1/2020
4S
icon
3S

Decreased from 4S to 3S

Description

NTNG1 disrupted by chromosomal translocation in a female Rett syndrome patient (PMID 15870826), basis for syndromic designation); two de novo LoF missense variants identified in unrelated simplex ASD cases (PMID 22495309); genetic association found between NTNG1 and schizophrenia in a Japanese population cohort (PMID 18384956)

10/1/2019
4S
icon
3S

Decreased from 4S to 3S

New Scoring Scheme
Description

NTNG1 disrupted by chromosomal translocation in a female Rett syndrome patient (PMID 15870826), basis for syndromic designation); two de novo LoF missense variants identified in unrelated simplex ASD cases (PMID 22495309); genetic association found between NTNG1 and schizophrenia in a Japanese population cohort (PMID 18384956)

Reports Added
[New Scoring Scheme]
7/1/2019
4S
icon
3S

Decreased from 4S to 3S

Description

NTNG1 disrupted by chromosomal translocation in a female Rett syndrome patient (PMID 15870826), basis for syndromic designation); two de novo LoF missense variants identified in unrelated simplex ASD cases (PMID 22495309); genetic association found between NTNG1 and schizophrenia in a Japanese population cohort (PMID 18384956)

4/1/2019
4S
icon
3S

Decreased from 4S to 3S

Description

NTNG1 disrupted by chromosomal translocation in a female Rett syndrome patient (PMID 15870826), basis for syndromic designation); two de novo LoF missense variants identified in unrelated simplex ASD cases (PMID 22495309); genetic association found between NTNG1 and schizophrenia in a Japanese population cohort (PMID 18384956)

1/1/2019
4S
icon
3S

Decreased from 4S to 3S

Description

NTNG1 disrupted by chromosomal translocation in a female Rett syndrome patient (PMID 15870826), basis for syndromic designation); two de novo LoF missense variants identified in unrelated simplex ASD cases (PMID 22495309); genetic association found between NTNG1 and schizophrenia in a Japanese population cohort (PMID 18384956)

10/1/2018
4S
icon
3S

Decreased from 4S to 3S

Description

NTNG1 disrupted by chromosomal translocation in a female Rett syndrome patient (PMID 15870826), basis for syndromic designation); two de novo LoF missense variants identified in unrelated simplex ASD cases (PMID 22495309); genetic association found between NTNG1 and schizophrenia in a Japanese population cohort (PMID 18384956)

10/1/2017
4S
icon
3S

Decreased from 4S to 3S

Description

NTNG1 disrupted by chromosomal translocation in a female Rett syndrome patient (PMID 15870826), basis for syndromic designation); two de novo LoF missense variants identified in unrelated simplex ASD cases (PMID 22495309); genetic association found between NTNG1 and schizophrenia in a Japanese population cohort (PMID 18384956)

10/1/2016
4S
icon
3S

Decreased from 4S to 3S

Description

NTNG1 disrupted by chromosomal translocation in a female Rett syndrome patient (PMID 15870826), basis for syndromic designation); two de novo LoF missense variants identified in unrelated simplex ASD cases (PMID 22495309); genetic association found between NTNG1 and schizophrenia in a Japanese population cohort (PMID 18384956)

10/1/2015
4S
icon
3S

Decreased from 4S to 3S

Description

NTNG1 disrupted by chromosomal translocation in a female Rett syndrome patient (PMID 15870826), basis for syndromic designation); two de novo LoF missense variants identified in unrelated simplex ASD cases (PMID 22495309); genetic association found between NTNG1 and schizophrenia in a Japanese population cohort (PMID 18384956)

10/1/2014
4S
icon
3S

Decreased from 4S to 3S

Description

NTNG1 disrupted by chromosomal translocation in a female Rett syndrome patient (PMID 15870826), basis for syndromic designation); two de novo LGD missense variants identified in unrelated simplex ASD cases (PMID 22495309); genetic association found between NTNG1 and schizophrenia in a Japanese population cohort (PMID 18384956)

7/1/2014
No data
icon
4S

Increased from No data to 4S

Description

NTNG1 disrupted by chromosomal translocation in a female Rett syndrome patient (PMID 15870826), basis for syndromic designation); two de novo LGD missense variants identified in unrelated simplex ASD cases (PMID 22495309); genetic association found between NTNG1 and schizophrenia in a Japanese population cohort (PMID 18384956)

4/1/2014
No data
icon
4S

Increased from No data to 4S

Description

NTNG1 disrupted by chromosomal translocation in a female Rett syndrome patient (PMID 15870826), basis for syndromic designation); two de novo LGD missense variants identified in unrelated simplex ASD cases (PMID 22495309); genetic association found between NTNG1 and schizophrenia in a Japanese population cohort (PMID 18384956)

Krishnan Probability Score

Score 0.60961917984334

Ranking 251/25841 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 0.4410311282378

Ranking 5764/18225 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 0.46410686440875

Ranking 377/18665 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 10

Ranking 190/461 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.
Zhang D Score

Score 0.16387833332263

Ranking 4914/20870 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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