ABCC9-related Intellectual disability Myopathy Syndrome is a KATP channelopathy with loss-of-function mutations in ABCC9

<jats:title>Abstract</jats:title><jats:p>Mutations in genes encoding K<jats:sub>ATP</jats:sub>channel subunits have been reported for pancreatic disorders and Cantú syndrome. Here, we report a syndrome in six patients from two families with a consistent phenotype of mild intellectual disability, similar facies, myopathy, and cerebral white matter hyperintensities, with cardiac systolic dysfunction present in the two oldest patients. Patients are homozygous for a splice-site mutation in<jats:italic>ABCC9</jats:italic>(c.1320 + 1 G > A), which encodes the sulfonylurea receptor 2 (SUR2) subunit of K<jats:sub>ATP</jats:sub>channels. This mutation results in an in-frame deletion of exon 8, which results in non-functional K<jats:sub>ATP</jats:sub>channels in recombinant assays. SUR2 loss-of-function causes fatigability and cardiac dysfunction in mice, and reduced activity, cardiac dysfunction and ventricular enlargement in zebrafish. We term this channelopathy resulting from loss-of-function of SUR2-containing K<jats:sub>ATP</jats:sub>channels<jats:italic>ABCC9</jats:italic>-related Intellectual disability Myopathy Syndrome (AIMS). The phenotype differs from Cantú syndrome, which is caused by gain-of-function<jats:italic>ABCC9</jats:italic>mutations, reflecting the opposing consequences of K<jats:sub>ATP</jats:sub>loss- versus gain-of-function.</jats:p>