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The voltage-gated sodium channel gene SCN8A encodes Nav1.6, a key mediator of neuronal excitability. Heterozygous pathogenic variants in SCN8A underlie a spectrum of disorders, including developmental and epileptic encephalopathy type 13 and cognitive impairment with or without cerebellar ataxia (MONDO:0013680).
Two independent exome sequencing studies describe eight individuals from six unrelated families presenting with cognitive impairment with or without cerebellar ataxia harboring heterozygous SCN8A variants (PMID:37609289; PMID:38233770). Clinical features ranged from isolated ataxia to global developmental delay, variably accompanied by epilepsy.
Genetic analysis identified seven distinct SCN8A variants: six missense changes (c.971G>A (p.Cys324Tyr), c.986A>G (p.Asp329Gly), c.773C>T (p.Thr258Ile), c.5630A>G (p.Asn1877Ser), c.4447G>A (p.Glu1483Lys), c.1238C>A (p.Ala413Asp)) and one nonsense variant (c.1723C>T (p.Arg575Ter)). All occurred in heterozygous state, consistent with an autosomal dominant inheritance model.
No additional affected family members segregating these variants were reported, suggesting de novo occurrence or reduced penetrance in relatives.
Missense substitutions predominated (6/7), with a single truncating allele predicted to undergo nonsense-mediated decay. There was no evidence of recurrent or population-specific founder variants in the cohorts.
Electrophysiological analyses in transfected cells demonstrated that the missense variant c.971G>A (p.Cys324Tyr) results in markedly reduced sodium current amplitude, confirming a loss-of-function mechanism consistent with SCN8A haploinsufficiency (PMID:37609289).
The convergence of genetic findings in multiple unrelated probands and concordant in vitro functional data supports a mechanism of heterozygous loss-of-function of SCN8A leading to cognitive impairment and cerebellar dysfunction.
Key Take-home: Heterozygous SCN8A loss-of-function variants cause cognitive impairment with or without cerebellar ataxia; targeted SCN8A sequencing and functional assays should be considered for diagnosis and therapeutic decision-making.
Gene–Disease AssociationModerateEight unrelated probands with consistent phenotypes across six families (PMID:37609289; PMID:38233770) and concordant functional data Genetic EvidenceModerateSeven distinct heterozygous variants in eight probands, meeting ClinGen genetic evidence criteria Functional EvidenceModerateElectrophysiological assays demonstrate loss-of-function for c.971G>A (p.Cys324Tyr) in transfected cells (PMID:37609289) |