ClinGen Dosage Sensitivity Curation Page

SLC9A6

Curation Status: Complete

Gene Information

Location Information

Evidence for Loss Phenotypes

Evidence for loss of function phenotype
PubMed ID Description
18342287 Gilfillan et al. (2008) first identified SLC9A6 variants in 4 families with phenotypes associated with microcephaly, seizures, ataxia, and absent speech resembling Angelman syndrome. Family 1 with 3 affected males from Norway had p.E255_S256del c.764_769delAAAGTG. This deletion results in the loss of two highly conserved amino acid residues. Family 2 with 2 affected males from Sweden had p.R468X,c.1402C/T . The variant creates an stop codon that prematurely truncates the predicted protein (p.R468X), removing the final transmembrane domain and C terminus. Alternatively, the stop codon could also initiate a nonsense-mediated mRNA decay (NMD). Two female carriers had no reported clinical symptom; one had severe dysplexia. Family 3 with 3 affected males from United Kingdom had p.V144_R169del c.507 ? 1delGTAA. This splice-site mutation was said to cause skipping of exon 3. This variant removes the entire predicted fourth transmembrane domain of the protein, and therefore also likely affects the folding of the protein within the membrane. Carrier mother had no clinical symptoms reported. Family 4 with 16 affected males from South Africa had p.H171fs, c.512_513delAT. This family was originally reported as having a diagnosis of Christianson syndrome by Christianson et al. in 1999 (PMID: 10528855). The deletion is predicted to introduce a frameshift, truncating the NHE6 polypeptide at residue 171 (p.H171fs) and introducing 59 residues of nonsense-derived sequence. Of the 10 female carriers in this family, three were described as having intellectual disability or learning problems. All X-inactivation studies performed on female carriers were normal for their age. It seems the range of carrier phenotypes possible with SLC9A6 mutation could depend on the severity of the variant, functional overlap with other solute carrier proteins, or genetic-modifier effects.
21812100 Takahashi et al. (2011) identified a frameshift SLC9A6 variant in exon 2, NM_001042537c.441delG, p.S147fs, from a cohort of 22 Japanese male Angelman syndrome-like patients with negative SNURF-SNRPN DNA methylation test (which identifies a deletion, uniparental disomy, or imprinting defect) and UBE3A variant screening to rule out Angelman syndrome. This variant was inherited from his healthy mother, who was heterozygous. No other SLC9A6 variants were identified from a different cohort of 100 male patients with X-linked intellectual disability, but two common polymorphisms (rs2291639, rs2307131) and one putative novel polymorphism intron 12 (c.1692 ?10 A>G) were detected. This frameshift variant causes PTC (premature translation termination codon) by nonsense mediated mRNA decay (NMD). Reverse transcriptase PCR demonstrated that SLC9A6 variant mRNA expression decreased, Western blotting demonstrated no NHE6.1 protein in this patient. The authors concluded that SLC9A6 is not a major cause of AS-like cases and SLC9A6 is likely to account for only small proportion of X-linked intellectual disability cases.
24630051 Zanni et al. (2014) reported a novel splice site variant (IVS10-1G>A) in SLC9A6 in a 7 year old boy with characteristic clinical and neuroimaging features of Christianson syndrome and epileptic encephalopathy with continuous spikes and waves during sleep. The authors propose that SLC9A6 dysfunction is a new cause of electrical status epilepticus during slow-wave sleep (ESES).

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.

Evidence for Triplosenstive Phenotype

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.

NOTE:The loss of function score should be used to evaluate deletions, and the triplosensitivity score should be used to evaluated duplications. CNVs encompassing more than one gene must be evaluated in their totality (e.g. overall size, gain vs. loss, presence of other genes, etc). The rating of a single gene within the CNV should not necessarily be the only criteria by which one defines a clinical interpretation. Individual interpretations must take into account the phenotype described for the patient as well as issues of penetrance and expressivity of the disorder. ACMG has published guidelines for the characterization of postnatal CNVs, and these recommendations should be utilized (Genet Med (2011)13: 680-685). Exceptions to these interpretive correlations will occur, and clinical judgment should always be exercised.