SLC9A6solute carrier family 9 (sodium/hydrogen exchanger), member 6
Autism Reports / Total Reports
6 / 23Rare Variants / Common Variants
36 / 0Aliases
SLC9A6, MRSA, NHE6, KIAA0267Associated Syndromes
X-linked mental retardation syndrome, Angelman-like syndrome, Christianson syndromeChromosome Band
Xq26.3Associated Disorders
DD/NDD, ID, EP, EPS, ASDRelevance 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.
External Links
SFARI Genomic Platforms
Reports related to SLC9A6 (23 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 |
| 19 | Support | - | Mir A et al. (2021) | No | ASD |
| 20 | Support | - | Zhou X et al. (2022) | Yes | - |
| 21 | Support | - | Sanchis-Juan A et al. (2023) | No | - |
| 22 | Support | - | Mona Abdi et al. (2023) | Yes | DD, ID, epilepsy/seizures |
| 23 | Support | - | Alistair T Pagnamenta et al. (2024) | No | - |
Rare Variants (36)
| 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.680+3A>G | - | splice_region_variant | Familial | Maternal | - | 34797406 | Mir A et al. (2021) | |
| c.171C>G | p.Ile57Met | missense_variant | Unknown | - | Unknown | 32722525 | Yin J et al. (2020) | |
| - | - | inversion | Familial | Maternal | Simplex | 38776926 | Alistair T Pagnamenta et al. (2024) | |
| - | - | 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.1752G>T | p.Leu584Phe | missense_variant | Familial | Maternal | - | 34797406 | Mir A et al. (2021) | |
| c.25G>T | p.Ala9Ser | missense_variant | Familial | Maternal | - | 19471312 | Fichou Y , et al. (2009) | |
| c.454_459del | p.Glu152_Tyr153del | inframe_deletion | De novo | - | - | 35982159 | Zhou X et al. (2022) | |
| c.1568G>A | p.Trp523Ter | stop_gained | De novo | - | Simplex | 25044251 | Pescosolido MF , et al. (2014) | |
| c.1710G>A | p.Trp570Ter | stop_gained | De novo | - | Simplex | 25044251 | Pescosolido MF , et al. (2014) | |
| - | - | copy_number_gain | Familial | Maternal | Simplex | 38776926 | Alistair T Pagnamenta et al. (2024) | |
| c.1498C>T | p.Arg500Ter | stop_gained | Familial | Maternal | Simplex | 29100083 | Hamdan FF , et al. (2017) | |
| c.1148G>A | p.Gly383Asp | missense_variant | De novo | - | Simplex | 25044251 | Pescosolido MF , et al. (2014) | |
| c.681G>A | p.Gly227= | splice_site_variant | De novo | - | Simplex | 25044251 | Pescosolido MF , et al. (2014) | |
| c.617G>A | p.Arg206Gln | missense_variant | Familial | Maternal | Simplex | 37805537 | Mona Abdi et al. (2023) | |
| c.1402C>T | p.Leu468Phe | stop_gained | Familial | Maternal | Simplex | 18342287 | Gilfillan GD , et al. (2008) | |
| 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.1595_1613del | p.Met532ThrfsTer41 | frameshift_variant | Familial | Maternal | - | 34797406 | Mir A et al. (2021) | |
| 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 | - | Simplex | 25044251 | Pescosolido MF , et al. (2014) | |
| c.697_704dup | p.Leu236ValfsTer2 | frameshift_variant | De novo | - | 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.1299_1300del | p.Phe434HisfsTer8 | frameshift_variant | Unknown | - | Simplex | 37541188 | Sanchis-Juan A et al. (2023) | |
| 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
Score Delta: Score remained at 1S
criteria met
See SFARI Gene'scoring criteriaWe 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
1
1
Score remained at 1
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
1
1
Score remained at 1
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
1
1
Score remained at 1
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
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
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
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
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
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).
1/1/2016
S
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).
Reports Added
[Mutation in the SLC9A6 gene is not a frequent cause of sporadic Angelman-like syndrome.2009] [A mutation affecting the sodium/proton exchanger, SLC9A6, causes mental retardation with tau deposition.2010] [Genes for endosomal NHE6 and NHE9 are misregulated in autism brains.2013] [Novel mutation in SLC9A6 gene in a patient with Christianson syndrome and retinitis pigmentosum.2012] [Efficient strategy for the molecular diagnosis of intellectual disability using targeted high-throughput sequencing.2014] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [SLC9A6 mutations cause X-linked mental retardation, microcephaly, epilepsy, and ataxia, a phenotype mimicking Angelman syndrome.2008] [The Na? exchanger NHE6 in the endosomal recycling system is involved in the development of apical bile canalicular surface domains in HepG2 cells.2010] [Christianson syndrome protein NHE6 modulates TrkB endosomal signaling required for neuronal circuit development.2013] [Christianson syndrome protein NHE6 modulates TrkB endosomal signaling required for neuronal circuit development.2013] [Genetic and phenotypic diversity of NHE6 mutations in Christianson syndrome.2014]1/1/2015
S
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.
External PIN Data
Interactome
- Protein Binding
- DNA Binding
- RNA Binding
- Protein Modification
- Direct Regulation
- ASD-Linked Genes
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 |