Human Gene Module / Chromosome 9 / NTNG2

NTNG2netrin G2

SFARI Gene Score
S
Syndromic Syndromic
Autism Reports / Total Reports
3 / 6
Rare Variants / Common Variants
14 / 0
Aliases
NTNG2, LHLL9381,  Lmnt2,  NTNG1,  bA479K20.1
Associated Syndromes
-
Chromosome Band
9q34.13
Associated Disorders
-
Relevance to Autism

Abu-Libdeh et al., 2019 identified a homozygous frameshift variant in the NTNG2 gene in eight individuals from four consanguineous families of Arab Muslim origin, all of whom presented with global developmental delay, hypotonia, absent speech, joint laxity, and autistic features such as poor eye contact and stereotypic hand movements. Dias et al., 2019 identified 16 individuals from seven unrelated families with ultra-rare homozygous missense variants in NTNG2 who presented with shared features of a neurodevelopmental disorder consisting of global developmental delay, severe to profound intellectual disability, muscle weakness and abnormal tone, autistic features (with all affected individuals in two families reported to have autism) and other behavioral abnormalities, and variable dysmorphic features; these missense variants were subsequently demonstrated to result in significantly reduced cell surface expression in functional studies.

Molecular Function

Involved in controlling patterning and neuronal circuit formation at the laminar, cellular, subcellular and synaptic levels. Promotes neurite outgrowth of both axons and dendrites.

External Links
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Human
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Mouse
Entrez GeneMouse Genome InformaticsAllen Brain Atlas
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to NTNG2 (6 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Homozygous frameshift variant in NTNG2, encoding a synaptic cell adhesion molecule, in individuals with developmental delay, hypotonia, and autistic features Abu-Libdeh B , et al. (2019) No -
2 Recent Recommendation Homozygous Missense Variants in NTNG2, Encoding a Presynaptic Netrin-G2 Adhesion Protein, Lead to a Distinct Neurodevelopmental Disorder Dias CM , et al. (2019) Yes -
3 Support Netrin-G2 dysfunction causes a Rett-like phenotype with areflexia Heimer G , et al. (2019) No Stereotypies
4 Support - Zhou X et al. (2022) Yes -
5 Support - Cirnigliaro M et al. (2023) Yes -
6 Support - Balasar et al. (2023) No -
Rare Variants   (14)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.1548C>T p.Leu516%3D synonymous_variant De novo - Multiplex 35982159 Zhou X et al. (2022)
c.591G>C p.Glu197Asp missense_variant De novo - Multiplex 37506195 Cirnigliaro M et al. (2023)
c.599C>T p.Ser200Leu missense_variant Familial Both parents Simplex 31668703 Dias CM , et al. (2019)
c.1368C>G p.Cys456Trp missense_variant Familial Both parents Simplex 37524782 Balasar et al. (2023)
c.446T>C p.Met149Thr missense_variant Familial Both parents Multiplex 31668703 Dias CM , et al. (2019)
c.1065G>G p.Cys355Trp missense_variant Familial Both parents Multiplex 31668703 Dias CM , et al. (2019)
c.1076C>G p.Ser359Cys missense_variant Familial Both parents Multiplex 31668703 Dias CM , et al. (2019)
c.1367G>A p.Cys456Tyr missense_variant Familial Both parents Multiplex 31668703 Dias CM , et al. (2019)
c.242G>A p.Cys81Tyr missense_variant Familial Both parents Extended multiplex 31668703 Dias CM , et al. (2019)
c.319T>G p.Trp107Gly missense_variant Familial Both parents Extended multiplex 31668703 Dias CM , et al. (2019)
c.376dup p.Ser126PhefsTer241 frameshift_variant Familial Both parents Simplex 31692205 Heimer G , et al. (2019)
c.376dup p.Ser126PhefsTer241 frameshift_variant Familial Both parents Multiplex 31692205 Heimer G , et al. (2019)
c.376dup p.Ser126PhefsTer241 frameshift_variant Familial Both parents Simplex 31372774 Abu-Libdeh B , et al. (2019)
c.376dup p.Ser126PhefsTer241 frameshift_variant Familial Both parents Multiplex 31372774 Abu-Libdeh B , et al. (2019)
Common Variants  

No common variants reported.

SFARI Gene score
S

Syndromic

Abu-Libdeh et al., 2019 identified a homozygous frameshift variant in the NTNG2 gene in eight individuals from four consanguineous families of Arab Muslim origin, all of whom presented with global developmental delay, hypotonia, absent speech, joint laxity, and autistic features such as poor eye contact and stereotypic hand movements. Dias et al., 2019 identified 16 individuals from seven unrelated families with ultra-rare homozygous missense variants in NTNG2 who presented with shared features of a neurodevelopmental disorder consisting of global developmental delay, severe to profound intellectual disability, muscle weakness and abnormal tone, autistic features (with all affected individuals in two families reported to have autism) and other behavioral abnormalities, and variable dysmorphic features; these missense variants were subsequently demonstrated to result in significantly reduced cell surface expression in functional studies.

Score Delta: Score remained at S

criteria met
See SFARI Gene'scoring criteria
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
S

Score remained at S

New Scoring Scheme
Description

Abu-Libdeh et al., 2019 identified a homozygous frameshift variant in the NTNG2 gene in eight individuals from four consanguineous families of Arab Muslim origin, all of whom presented with global developmental delay, hypotonia, absent speech, joint laxity, and autistic features such as poor eye contact and stereotypic hand movements. Dias et al., 2019 identified 16 individuals from seven unrelated families with ultra-rare homozygous missense variants in NTNG2 who presented with shared features of a neurodevelopmental disorder consisting of global developmental delay, severe to profound intellectual disability, muscle weakness and abnormal tone, autistic features (with all affected individuals in two families reported to have autism) and other behavioral abnormalities, and variable dysmorphic features; these missense variants were subsequently demonstrated to result in significantly reduced cell surface expression in functional studies.

Reports Added
[New Scoring Scheme]
Krishnan Probability Score

Score 0.49571762017302

Ranking 2832/25841 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 0.8295832300383

Ranking 3755/18225 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 0.93886182131812

Ranking 14009/18665 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 0.17865432933407

Ranking 4630/20870 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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