Human Gene Module / Chromosome X / SLC9A6

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

Score
1
High Confidence Criteria 1.1
Autism Reports / Total Reports
2 / 16
Rare Variants / Common Variants
25 / 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, ASD, EP, ID, EPS
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 (16 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? 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 -
Rare Variants   (25)
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)
- - copy_number_loss Familial Maternal Simplex 25044251 Pescosolido MF , et al. (2014)
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.1498C>T p.Arg500Ter stop_gained Familial Maternal Simplex 25044251 Pescosolido MF , et al. (2014)
c.681G>A p.Gly227%3D splice_site_variant De novo NA 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
1

High Confidence

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.

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
S

Score remained at S

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

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).

4/1/2019
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).

10/1/2017
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).

7/1/2016
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).

1/1/2015
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).

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
Submit New Gene

Report an Error

SFARI Gene Update

We are pleased to announce some changes to the ongoing curation of the data in SFARI Gene. In the context of a continued effort to develop the human gene module and its manually curated list of autism risk genes, we are modifying other aspects of the site to focus on the information that is of greatest interest to the research community. The version of SFARI Gene that has been developed until now will be frozen and will remain available as “SFARI Gene Archive”. Please see the announcement for more details.
Close