(175) Functional data of variants at analogous positions in sodium channel genes can serve as surrogate for variant effects in related sodium channel epilepsies

This abstract has been invited to present during the Investigators Workshop Platform poster session

Rationale: Genes in the voltage-gated sodium channel family (SCN) are conserved in sequence composition and biophysical function. Variants in different SCN-genes are associated with epilepsy, neurodevelopmental disorders, autism, cardiac arrhythmia, skeletal muscle channelopathies and peripheral neuropathies. We investigated functional effects of amino acid substitutions across SCN-gene paralogs, taking a broader perspective on precision treatment than on an individual gene level alone.

Methods: We performed a PubMed search (up until June 15, 2020) to collect functionally assessed variants within all genes in the SCN-family and the term “clamp”. We included missense variants that had been electrophysiologically characterised in mammalian cells with whole-cell patch-clamp recordings. As controls, we integrated variants identified in the general population (gnomAD) by applying clinically plausible allele frequency thresholds. We compared substitutions of analogous amino acids across the alignment index position for all SCN-genes. Variants were analysed for their overall functional effect and correlated with clinical phenotypes.

Results: Four hundred twenty-six SCN-variants met our inclusion criteria. Of these, 127 variants were epilepsy-associated (SCN1/2/3/8A), 123 were associated with a cardiac phenotype (SCN5/10A), 61 with a neuromuscular phenotype (SCN4/9/10/11A) and 115 were assumed benign. We detected 38 pairs of missense variants with an analogous (identical) disease-associated variant in a different SCN-gene. The missense variants in each of those pairs (37/38 = 97%) produce similar functional consequences. SCN1A loss-of-function (LoF) is associated with Dravet Syndrome, however, the corresponding LoF SCN2A and SCN8A variants lead to primary neurodevelopmental disorders and autism, whereas gain-of-function (GoF) variants result in severe early onset epilepsy (DEE). Corresponding variants in SCN1/2/8A have similar functional impact on the channel but result in different phenotypes depending on their expression profiles in different neuron subtypes. Across SCN-subtypes, 91% of variants occurring at S5-6 pore-loop regions displayed LoF, while 92% of variants in the fast inactivation gate displayed GoF effects. Variants distributed across voltage-sensing regions (S3-4, S4 and S4-5) displayed a mixture of GoF (56%), LoF (31%) and mixed (13%) effects (figure 1). Variants identified in the general population are clustered in cytoplasmic domains and rarely occurred at conserved channel locations.

Conclusions: Our findings suggest that functional characterisation of variants in one SCN-gene may serve as a valuable surrogate for corresponding variants at the same position across different SCN-genes where subtype-specific functional data are not available. We outline shared patterns of functional effects across the SCN-gene paralogs, revealing a framework that aids variant interpretation and show evidence that knowledge of the underlying channel function can inform precision treatment depending on mutation effect.

Funding: Please list any funding that was received in support of this abstract.: None
Click here to view image/table