Compound heterozygous SLC12A5 variants expand the molecular and functional spectrum of KCC2-developmental and epileptic encephalopathy

SLC12A5 (biallelic compound heterozygotes — 4 novel variants including 1 splice site + 3 missense)

Mechanistic spectrum expansion: one variant (p.Arg420Cys) preserves KCC2 ion transport but abolishes KCC2-dependent glutamatergic synaptogenesis (chloride-independent mechanism) — ion transport loss and NMD for the other variants

Report of two new patients with severe neonatal-onset DEE caused by biallelic compound heterozygous SLC12A5 variants, bringing the total of documented cases to 11. Case A: two missense variants (p.Phe117Ile + p.Arg420Cys); the first abolishes ion transport while the second preserves it or even increases it, yet destroys excitatory synapse formation and dendritic spine density via a chloride-independent mechanism. Case B: a splice site variant (NMD → loss of expression) + a missense (p.Leu766Arg) with partial LOF. Both patients had migrating seizures within hours of birth and died early (9 years and 6 months).

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

Major mechanistic finding: the severity of KCC2-DEE cannot be predicted by ion transport testing alone — a variant preserving ion transport can still be highly pathogenic via non-canonical functions (synaptogenesis). Direct impact on SLC12A5 VUS interpretation: a variant with preserved ion transport cannot be classified as benign without specific synaptogenesis functional testing. Add to DEE panels and SLC12A5 pathogenicity arguments.

known gene +0; biallelic AR compound het +2; full functional (transport, phosphorylation, minigene, patch-clamp, dendritic spines) +2; novel chloride-independent mechanism +2; spectrum expansion 2 cases +1; Epilepsia +1