Human Gene Module / Chromosome X / SLC9A6

SLC9A6solute carrier family 9 (sodium/hydrogen exchanger), member 6

SFARI Gene Score
1S
High Confidence, Syndromic Criteria 1.1, Syndromic
Autism Reports / Total Reports
4 / 18
Rare Variants / Common Variants
28 / 0
Aliases
SLC9A6, MRSA,  NHE6,  KIAA0267
Associated Syndromes
X-linked mental retardation syndrome, Angelman-like syndrome, Christianson syndrome
Genetic Category
Rare Single Gene Mutation, Syndromic, Functional
Chromosome Band
Xq26.3
Associated Disorders
DD/NDD, EPS, ID, ASD, EP
Relevance to Autism

This gene has been identified with syndromic autism, where a subpopulation of individuals with a given syndrome develop autism. In particular, studies have found SLC9A6 variants to be identified with X-linked mental retardation and Angelman-like phenotypes. As well, mutation in the SLC9A6 gene has been identified with autism (Garbern et al., 2010).

Molecular Function

This gene encodes a sodium-hydrogen exchanger that is a member of the solute carrier family 9. The encoded protein may be involved in regulating endosomal pH and volume.

Reports related to SLC9A6 (18 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Highly Cited SLC9A6 mutations cause X-linked mental retardation, microcephaly, epilepsy, and ataxia, a phenotype mimicking Angelman syndrome Gilfillan GD , et al. (2008) No -
2 Recent Recommendation Mutation in the SLC9A6 gene is not a frequent cause of sporadic Angelman-like syndrome Fichou Y , et al. (2009) No -
3 Recent Recommendation The Na+/H+ exchanger NHE6 in the endosomal recycling system is involved in the development of apical bile canalicular surface domains in HepG2 cells Ohgaki R , et al. (2010) No -
4 Primary A mutation affecting the sodium/proton exchanger, SLC9A6, causes mental retardation with tau deposition Garbern JY , et al. (2010) No ASD, ID, epilepsy, dystonia
5 Recent Recommendation Novel mutation in SLC9A6 gene in a patient with Christianson syndrome and retinitis pigmentosum Mignot C , et al. (2012) No ID, Epilepsy
6 Support Genes for endosomal NHE6 and NHE9 are misregulated in autism brains Schwede M , et al. (2013) Yes -
7 Recent Recommendation Christianson syndrome protein NHE6 modulates TrkB endosomal signaling required for neuronal circuit development Ouyang Q , et al. (2013) No -
8 Support Genetic and phenotypic diversity of NHE6 mutations in Christianson syndrome Pescosolido MF , et al. (2014) No ID, epilepsy, ASD
9 Support Efficient strategy for the molecular diagnosis of intellectual disability using targeted high-throughput sequencing Redin C , et al. (2014) No -
10 Support Large-scale discovery of novel genetic causes of developmental disorders Deciphering Developmental Disorders Study (2014) No Microcephaly
11 Support A new family with an SLC9A6 mutation expanding the phenotypic spectrum of Christianson syndrome Masurel-Paulet A , et al. (2016) No -
12 Support High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies Hamdan FF , et al. (2017) No DD/ID
13 Support Elucidation of the phenotypic spectrum and genetic landscape in primary and secondary microcephaly Boonsawat P , et al. (2019) No DD, epilepsy/seizures
14 Support Lessons Learned from Large-Scale, First-Tier Clinical Exome Sequencing in a Highly Consanguineous Population Monies D , et al. (2019) Yes -
15 Support A Christianson syndrome-linked deletion mutation (?287ES288) in SLC9A6 impairs hippocampal neuronal plasticity Gao AYL , et al. (2019) No -
16 Support Targeted Next-Generation Sequencing in Patients with Suggestive X-Linked Intellectual Disability Ibarluzea N , et al. (2020) No -
17 Support The diagnostic yield of intellectual disability: combined whole genome low-coverage sequencing and medical exome sequencing Wang J et al. (2020) Yes -
18 Support Next Generation Sequencing of 134 Children with Autism Spectrum Disorder and Regression Yin J et al. (2020) Yes Developmental regression, epilepsy/seizures
Rare Variants   (28)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- p.(=) intron_variant - - - 19471312 Fichou Y , et al. (2009)
c.1462+8G>A - intron_variant - - - 19471312 Fichou Y , et al. (2009)
c.616C>T p.Arg206Ter stop_gained - - - 31130284 Monies D , et al. (2019)
c.916C>T p.Gln306Ter stop_gained - - Simplex 22541666 Mignot C , et al. (2012)
c.171C>G p.Ile57Met missense_variant Unknown - Unknown 32722525 Yin J et al. (2020)
- - copy_number_loss Familial Maternal Simplex 25044251 Pescosolido MF , et al. (2014)
c.1777C>G p.Leu593Val missense_variant Unknown - Unknown 32722525 Yin J et al. (2020)
c.286G>A p.Ala96Thr missense_variant Familial Maternal - 32429945 Wang J et al. (2020)
c.25G>T p.Ala9Ser missense_variant Familial Maternal - 19471312 Fichou Y , et al. (2009)
c.1568G>A p.Trp523Ter stop_gained De novo NA Simplex 25044251 Pescosolido MF , et al. (2014)
c.1710G>A p.Trp570Ter stop_gained De novo NA Simplex 25044251 Pescosolido MF , et al. (2014)
c.1498C>T p.Arg500Ter stop_gained Familial Maternal Simplex 29100083 Hamdan FF , et al. (2017)
c.1402C>T p.Leu468Phe stop_gained Familial Maternal Simplex 18342287 Gilfillan GD , et al. (2008)
c.1148G>A p.Gly383Asp missense_variant De novo NA Simplex 25044251 Pescosolido MF , et al. (2014)
c.681G>A p.Gly227= splice_site_variant De novo NA Simplex 25044251 Pescosolido MF , et al. (2014)
c.1498C>T p.Arg500Ter stop_gained Familial Maternal Simplex 25044251 Pescosolido MF , et al. (2014)
c.190G>T p.Glu64Ter stop_gained Familial Maternal Multiplex 25044251 Pescosolido MF , et al. (2014)
c.1639G>T p.Glu547Ter stop_gained Familial Maternal Multiplex 25044251 Pescosolido MF , et al. (2014)
c.615dup p.Arg206SerfsTer58 frameshift_variant Familial Maternal - 30842647 Boonsawat P , et al. (2019)
c.1570dup p.Val524GlyfsTer20 frameshift_variant De novo NA Simplex 25044251 Pescosolido MF , et al. (2014)
c.526-9_526-5del - splice_site_variant Familial Maternal Multi-generational 25167861 Redin C , et al. (2014)
c.697_704dup p.Leu236ValfsTer2 frameshift_variant De novo NA Simplex 25044251 Pescosolido MF , et al. (2014)
c.316A>G p.Met106Val missense_variant Familial Maternal Multi-generational 31906484 Ibarluzea N , et al. (2020)
c.509del p.Asn170MetfsTer30 splice_site_variant Familial Maternal Multiplex 18342287 Gilfillan GD , et al. (2008)
c.513_514del p.Glu171AspfsTer3 frameshift_variant Familial Maternal Multiplex 18342287 Gilfillan GD , et al. (2008)
c.1148-2A>G - splice_site_variant Familial Maternal Simplex 25533962 Deciphering Developmental Disorders Study (2014)
c.764_769del p.Phe255_Ala257delinsSer inframe_deletion Familial Maternal Multiplex 18342287 Gilfillan GD , et al. (2008)
c.1012_1020del p.Gly338_Ala340del inframe_deletion Familial Maternal Multi-generational 20395263 Garbern JY , et al. (2010)
Common Variants  

No common variants reported.

SFARI Gene score
1S

High Confidence, Syndromic

A nonsense mutation in the SLC9A6 gene was identified in a 22 year-old male with Christianson syndrome, which is characterized by mental retardation, ASD, and epilepsy (PMID 20395263).

Score Delta: Score remained at S

1

High Confidence

See all Category 1 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."

7/1/2020
S
icon
S

Score remained at S

Description

A nonsense mutation in the SLC9A6 gene was identified in a 22 year-old male with Christianson syndrome, which is characterized by mental retardation, ASD, and epilepsy (PMID 20395263).

4/1/2020
S
icon
S

Score remained at S

Description

A nonsense mutation in the SLC9A6 gene was identified in a 22 year-old male with Christianson syndrome, which is characterized by mental retardation, ASD, and epilepsy (PMID 20395263).

1/1/2020
S
icon
S

Score remained at S

Description

A nonsense mutation in the SLC9A6 gene was identified in a 22 year-old male with Christianson syndrome, which is characterized by mental retardation, ASD, and epilepsy (PMID 20395263).

10/1/2019
S
icon
1

Increased from S to 1

New Scoring Scheme
Description

A nonsense mutation in the SLC9A6 gene was identified in a 22 year-old male with Christianson syndrome, which is characterized by mental retardation, ASD, and epilepsy (PMID 20395263).

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

Increased from S to S

Description

A nonsense mutation in the SLC9A6 gene was identified in a 22 year-old male with Christianson syndrome, which is characterized by mental retardation, ASD, and epilepsy (PMID 20395263).

4/1/2019
S
icon
S

Increased from S to S

Description

A nonsense mutation in the SLC9A6 gene was identified in a 22 year-old male with Christianson syndrome, which is characterized by mental retardation, ASD, and epilepsy (PMID 20395263).

10/1/2017
S
icon
S

Increased from S to S

Description

A nonsense mutation in the SLC9A6 gene was identified in a 22 year-old male with Christianson syndrome, which is characterized by mental retardation, ASD, and epilepsy (PMID 20395263).

7/1/2016
S
icon
S

Increased from S to S

Description

A nonsense mutation in the SLC9A6 gene was identified in a 22 year-old male with Christianson syndrome, which is characterized by mental retardation, ASD, and epilepsy (PMID 20395263).

1/1/2015
S
icon
S

Increased from S to S

Description

A nonsense mutation in the SLC9A6 gene was identified in a 22 year-old male with Christianson syndrome, which is characterized by mental retardation, ASD, and epilepsy (PMID 20395263).

Krishnan Probability Score

Score 0.56969439323276

Ranking 1007/25841 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 0.97566793350017

Ranking 2241/18225 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 0.93674211803233

Ranking 13295/18665 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).
Zhang D Score

Score 0.2228058475066

Ranking 3891/20870 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.
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
CDK20 Cyclin-dependent kinase 20 Human Protein Binding 23552 Q8IZL9
DNAJC30 DnaJ homolog subfamily C member 30 Human Protein Binding 84277 Q96LL9
FNDC4 Fibronectin type III domain-containing protein 4 Human Protein Binding 64838 Q9H6D8
MAP1LC3B2 Microtubule-associated proteins 1A/1B light chain 3 beta 2 Human Protein Binding 643246 A6NCE7
RELL2 RELT-like protein 2 Human Protein Binding 285613 Q8NC24
SLC22A9 Solute carrier family 22 member 9 Human Protein Binding 114571 Q8IVM8
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