Abstract
Dominant gain-of-function mutations of the KCNMA1 gene, encoding the pore-forming subunit of the large conductance voltage- and Ca
-activated K+ channel, have been described in a few patients with the syndrome of epilepsy, paroxysmal dyskinesias and developmental delay. In this report, we describe the loss-of-function phenotype of this newly described disease gene. In two siblings from a consanguineous family with epilepsy, developmental delay and severe cerebellar atrophy, combined exome/autozygome analysis identified a homozygous frameshift duplication in KCNMA1 (c.2026dupT; p. (Tyr676 Leufs
7)) in both children. Our report defines a novel autosomal recessive KCNMA1-related epileptic phenotype that encompasses cerebellar atrophy without paroxysmal dyskinesia, and highlights the sensitivity of the developing brain to both increased and decreased activity of the KCNMA1-encoded channels.