Whole exome sequencing was performed through a commercial testing laboratory to elucidate the underlying etiology for the child's presentation. A <em>de novoem> mutation was hypothesized. In attempt to establish pathogenicity of our candidate variant, cellular electrophysiologic functional analysis of the putative <em>de novoem> mutation was performed using patch-clamp technology.
Whole exome sequencing revealed a p.P1353L variant in the <em>CACNA1Aem> gene, which encodes for the α1-subunit of the brain-specific P/Q-type calcium channel (CaV2.1). This presynaptic high-voltage-gated channel couples neuronal excitation to the vesicular release of neurotransmitter and is implicated in several neurologic disorders. DNA Sanger sequencing confirmed that the <em>de novoem> mutation was absent in both parents and present in the child only. Electrophysiologic analysis of P1353L-CACNA1A demonstrated near complete loss of function, with a 95% reduction in peak current density.
Whole exome sequencing coupled with cellular electrophysiologic functional analysis of a <em>de novoem><em>CACNA1Aem> missense mutation has elucidated the probable underlying pathophysiologic mechanism responsible for the child's phenotype. Genetic testing of <em>CACNA1Aem> in patients with congenital hypotonia and developmental delay may be warranted.