Loss-of-function variants of in intellectual disability without seizures.

OBJECTIVE

To determine the functional effect of missense mutations in 2 children with intellectual disability and developmental delay but no seizures.

METHODS

Genomic DNA was analyzed by next-generation sequencing. variants were introduced into the Na1.6 complementary DNA by site-directed mutagenesis. Channel activity was measured electrophysiologically in transfected ND7/23 cells. The stability of the mutant channels was assessed by Western blot.

RESULTS

Both children were heterozygous for novel missense variants that altered conserved residues in transmembrane segments of Na1.6, p.Gly964Arg in D2S6 and p.Glu1218Lys in D3S1. Both altered amino acids are evolutionarily conserved in vertebrate and invertebrate channels and are predicted to be deleterious. Neither was observed in the general population. Both variants completely prevented the generation of sodium currents in transfected cells. The abundance of Na1.6 protein was reduced by the Glu1218Lys substitution.

CONCLUSIONS

Haploinsufficiency of is associated with cognitive impairment. These observations extend the phenotypic spectrum of mutations beyond their established role in epileptic encephalopathy (OMIM#614558) and other seizure disorders. should be considered as a candidate gene for intellectual disability, regardless of seizure status.