Human Gene Module / Chromosome 3 / SLC9A9

SLC9A9solute carrier family 9 (sodium/hydrogen exchanger), member 9

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
10 / 17
Rare Variants / Common Variants
17 / 6
Aliases
SLC9A9, NHE9
Associated Syndromes
-
Chromosome Band
3q24
Associated Disorders
ID
Relevance to Autism

Rare variants in the SLC9A9 gene have been identified with autism in the HMCA cohort (Morrow et al., 2008). In addition, rare variants in SLC9A9 have been identified with ADHD and genetic association has been found with age of onset of ADHD.

Molecular Function

enzyme involved in pH regulation

SFARI Genomic Platforms
Reports related to SLC9A9 (17 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Highly Cited Disruption of a novel member of a sodium/hydrogen exchanger family and DOCK3 is associated with an attention deficit hyperactivity disorder-like phenotype de Silva MG , et al. (2003) No ID
2 Recent Recommendation Vestibular hair bundles control pH with (Na+, K+)/H+ exchangers NHE6 and NHE9 Hill JK , et al. (2006) No -
3 Recent Recommendation Cell surface levels of organellar Na+/H+ exchanger isoform 6 are regulated by interaction with RACK1 Ohgaki R , et al. (2007) No -
4 Primary Identifying autism loci and genes by tracing recent shared ancestry Morrow EM , et al. (2008) Yes -
5 Recent Recommendation Genome-wide association scan of the time to onset of attention deficit hyperactivity disorder Lasky-Su J , et al. (2008) No -
6 Support Genes for endosomal NHE6 and NHE9 are misregulated in autism brains Schwede M , et al. (2013) Yes -
7 Recent Recommendation Haplotype structure enables prioritization of common markers and candidate genes in autism spectrum disorder Vardarajan BN , et al. (2013) No -
8 Recent Recommendation Functional evaluation of autism-associated mutations in NHE9 Kondapalli KC , et al. (2013) Yes -
9 Support Exonic deletion of SLC9A9 in autism with epilepsy Cardon M , et al. (2016) Yes -
10 Support SLC9A9 Co-expression modules in autism-associated brain regions Patak J , et al. (2016) No -
11 Support A mouse model of autism implicates endosome pH in the regulation of presynaptic calcium entry Ullman JC , et al. (2018) No -
12 Support Effect of disease-associated SLC9A9 mutations on protein-protein interaction networks: implications for molecular mechanisms for ADHD and autism Zhang-James Y , et al. (2019) Yes -
13 Support - Mir A et al. (2021) Yes -
14 Support - Woodbury-Smith M et al. (2022) Yes -
15 Support - Zhou X et al. (2022) Yes -
16 Support - Cirnigliaro M et al. (2023) Yes -
17 Support - Sheth F et al. (2023) Yes DD, ID
Rare Variants   (17)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - inversion Familial - Multiplex 14569117 de Silva MG , et al. (2003)
A>G - splice_site_variant Unknown - Unknown 18621663 Morrow EM , et al. (2008)
c.1195G>A p.Gly399Arg missense_variant De novo - - 34797406 Mir A et al. (2021)
- - copy_number_loss Familial Both parents Simplex 18621663 Morrow EM , et al. (2008)
c.63G>C p.Ala21%3D synonymous_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.992-2A>G p.? splice_site_variant Unknown - Unknown 18621663 Morrow EM , et al. (2008)
c.1485G>A p.Leu495= missense_variant Unknown - Unknown 18621663 Morrow EM , et al. (2008)
c.1583T>C p.Met528Thr missense_variant Unknown - Multiplex 37543562 Sheth F et al. (2023)
- - copy_number_loss Familial Paternal Multi-generational 27123481 Cardon M , et al. (2016)
c.349C>A p.Pro117Thr missense_variant Unknown - Unknown 18621663 Morrow EM , et al. (2008)
c.526G>A p.Val176Ile missense_variant Unknown - Unknown 18621663 Morrow EM , et al. (2008)
c.707T>C p.Leu236Ser missense_variant Unknown - Unknown 18621663 Morrow EM , et al. (2008)
c.171G>T p.Val57%3D synonymous_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.1312T>C p.Ser438Pro missense_variant Unknown - Unknown 18621663 Morrow EM , et al. (2008)
c.1824C>A p.Asp608Glu missense_variant Unknown - Unknown 18621663 Morrow EM , et al. (2008)
c.1267C>T p.Arg423Ter stop_gained Familial Maternal Multiplex 18621663 Morrow EM , et al. (2008)
c.1267C>T p.Arg423Ter stop_gained Familial Maternal Multiplex 37506195 Cirnigliaro M et al. (2023)
Common Variants   (6)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
- - intergenic_variant - - - 18937294 Lasky-Su J , et al. (2008)
- N/A downstream_gene_variant - - - 18937294 Lasky-Su J , et al. (2008)
c.534-25975A>G - intron_variant - - - 18937294 Lasky-Su J , et al. (2008)
c.534-30711G>A N/A intron_variant - - - 18937294 Lasky-Su J , et al. (2008)
c.756-16398A>G;c.108-16398A>G - intron_variant - - - 18937294 Lasky-Su J , et al. (2008)
c.755+12312T>C;c.107+12312T>C N/A intron_variant - - - 18937294 Lasky-Su J , et al. (2008)
SFARI Gene score
2

Strong Candidate

Rare sequence variants in the SLC9A9 gene were observed in autism.

Score Delta: Score remained at 2

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

Rare sequence variants in the SLC9A9 gene were observed in autism.

10/1/2019
4
icon
3

Decreased from 4 to 3

New Scoring Scheme
Description

Rare sequence variants in the SLC9A9 gene were observed in autism.

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

Decreased from 4 to 4

Description

Rare sequence variants in the SLC9A9 gene were observed in autism.

7/1/2016
4
icon
4

Decreased from 4 to 4

Description

Rare sequence variants in the SLC9A9 gene were observed in autism.

7/1/2014
No data
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4

Increased from No data to 4

Description

Rare sequence variants in the SLC9A9 gene were observed in autism.

4/1/2014
No data
icon
4

Increased from No data to 4

Description

Rare sequence variants in the SLC9A9 gene were observed in autism.

Krishnan Probability Score

Score 0.48603578662928

Ranking 7256/25841 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 2.4774052099267E-8

Ranking 16012/18225 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 0.69134306423758

Ranking 1104/18665 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 38

Ranking 56/461 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 -0.15653683105804

Ranking 14324/20870 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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