ClinGen Dosage Sensitivity Curation Page

SLC9A6

  • Curation Status: Complete

Location Information

Select assembly: (NC_000023.10) (NC_000023.11)
Evidence for haploinsufficiency 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).

Haploinsufficiency phenotype comments:

Additional evidence includes: PMID: 22931061 Riess A et al. (2013) described two German families with Christianson syndrome and variants in SLC9A6. An insertion of one nucleotide (T) in exon 12 of SLC9A6 (c.1464_1465insT, p.Thr489TyrfsX23) was identified in 3 affected male patients and their mother in one family. A variant involving the first intronic nucleotide at the boundary of exon 4 to intron 4 (c.584+1G>T) of SLC9A6 was identified in another index patient and his mother. The clinical features of the male patients reported here are in accordance with previous reports. Female carriers of SLC9A6 mutations have been reported to have either no clinical problems or mild cognitive deficits. The obligate carrier grandmother in the first family had developed neurological problems in her fifties which can be classified as parkinsonism, and signs of parkinsonism were also present in her mother. PMID: 20949524 Schroer et al. (2010) described two families with Christianson syndrome who also presented with an Angelman-like phenotype. Family 1 has 6 affected males across three generations, and was found to have the variant c.1402C>T p.R468X. The same variant was also found in a Swedish family described by Gilfillan et al. (2008). The mother is an obligate carrier and was described as having ?learning problems?. The proband of family 2 had a de novo variant, c.1219C>T p.Q407X. The mother was found to have two normal copies of the SLC9A6 gene. PMID: 27256868 Masurel-Paulet A et al. (2016) reported a splicing variant (c.526-9_526-5del) in the SLC9A6 gene in a 9-year-old boy with mild intellectual disability (ID), microcephaly, and social interaction disabilities. This intronic 5-bp deletion is located upstream to the splice acceptor site of exon 3, leading to abnormal SLC9A6 splicing, skipping of exon 3, and an in-frame deletion of 26 amino acids in the TM4 domain. It segregates with cognitive impairment or learning difficulties in other members of the family. PMID 19377476 Tarpey et al. (2009) reported two families with X-linked intellectual disability. The frameshift variant, c.511_512delAT p.H171fs*59, in family 197 and the nonsense variant, c.1402C>T p.R468*, in family 227 segregated with the phenotypes in their respective families. Carrier females were normal. PMID: 25044251 Pescosolido MF et al. (2014) reported 9 single nucleotide variants, 2 indels and 1 copy number deletion from 14 boys age of 4-19 years old in 12 independent pedigrees. The majority of variants were protein truncations (10/12, 83%) and occurred in exons 1, 3, 11, 12, 13 and 14. In contrast to prior literature regarding NHE6 mutations wherein variants have been largely inherited, a majority of variants in this study (58%) were de novo. They are C.1148 G>A(p.G383D) in family 1; c.1414dupA (p.R472fsX4) in family 2;c.1710G>A (p.W570X) in family 3 and 7; c.1568 G>A(p.W523X) in family 4; c.540_547dupAGAAGTAT (p.F183fsX1) in family 5; IVS c.526-1,G>A in family 6. Variants were not found in the mothers. Variants c.190G>T (p.E64X) in family 8; c.1498C>T (p.500X) in family 9 and family 12; IVS c.1237-557_UTR del in family 10; and c.1639G>T (p.E547X) in family 11 are inherited. The copy number loss in Family 10 spans from ChrX:135098247-135218938 (c.1237-557), predicting to delete exons 10 through 16 and the 3?-untranslated region (UTR). Variants c.1498C>T (p.R500X) in family 3 and c.1710G>A (p.W570X) in family 7 are recurrent. These Christianson syndrome participants demonstrated profound developmental delays in most or all domains, including gross and fine motor, social, language and cognitive domains. Female carriers presented with diverse clinical presentations that included neurotypical functioning, mild to moderate ID and psychiatric illness. PMID: 22541666 Mignot et al. (2013) reported a 22 year old male patient with Christianson syndrome and retinitis pigmentosum carrying the novel p.Gln306X variant. PMID: 30937176 Leda D et al. (2019) reported identified a novel splicing variant (NM_006359.2:c.1141-8C>A) in SLC9A6 in a seven-year-old boy with microcephaly, severe developmental delay, and intractable epilepsy. Functional analysis found multiple aberrant transcripts, none of which maintained the canonical open reading frame. This variant resulted in a new AG acceptor site six nucleotides upstream of the canonical acceptor site of exon 10. PMID: 25649377 Tzschach A et al. (2015) reported a deletion of 336 bp including exon 1 of SLC9A6 [NG_017160.1: g.135067656_135067991del (GRCh37/hg19)] in an individual with sporadic X linked intellectual disability (XLID).

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.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

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.