SLC9A1 was first reported in relation to autosomal recessive Lichtenstein-Knorr syndrome in 2015 (Guissart et al, PMID: 25205112). Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data.
Four variants (missense, nonsense, frameshift) that have been reported in four probands in four publications (PMIDs: 25205112, 30018422, 30237576, 36561016) are included in this curation. Patients with recessive SLC9A1 variants have mainly been reported to exhibit early-onset cerebellar ataxia, seizures, cerebral atrophy and variable hearing loss (PMID: 25205112, 30018422, 36561016). Recently Pellerin, Ceravolo, and colleagues reported individuals from consanguineous families carrying recessive SLC9A1 variants presenting with amelogenesis imperfecta in addition to early-onset cerebellar ataxia associated with cerebellar atrophy, developmental delay, and variable sensorineural hearing loss (Journal of the Neurological Sciences, Volume 455, 121930).
This gene-disease relationship is supported by animal model and expression studies. SLC9A1 is shown to be ubiquitously expressed in various tissues throughout the body (PMID: 23715323, dbGaP Accession phs000424.v10.p2). Homozygous SLC9A1 null mutant mice models showed reduced postnatal growth, ataxia, and epileptic-like seizures without cerebellar atrophy (PMID: 10199808).
In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Cerebellar Ataxia GCEP on the meeting date July 9th, 2025 (SOP Version 11).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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