C12ORF57 is a conserved protein essential for neuronal development and synaptic homeostasis, primarily characterized by its role in corpus callosum morphogenesis and excitatory neuronal regulation. 1 Loss-of-function mutations in C12ORF57 cause Temtamy syndrome, an autosomal recessive neurodevelopmental disorder characterized by intellectual disability, epilepsy, and corpus callosum dysgenesis. 2 The syndrome presents with variable phenotypic expressivity; among 56 patients, 73.2% exhibited epilepsy, 63% had corpus callosal abnormalities, and additional features included congenital heart disease (51.4%) and white matter abnormalities (38%). 2 Mechanistically, C12ORF57 (also termed GRCC10) functions as a principal regulator of synaptic AMPA receptor homeostatic downscaling in response to elevated neuronal activity. 3 The protein modulates calcium/calmodulin-dependent kinase 4 (CAMK4) activity, thereby regulating CREB and ARC expression to control AMPA receptor levels. 3 Loss of C12ORF57 function disrupts this homeostatic mechanism, resulting in elevated AMPA receptor expression and increased miniature excitatory postsynaptic current amplitudes, leading to enhanced seizure susceptibility. 3 C12ORF57 variants should be considered in developmental delay/intellectual disability etiology, particularly in consanguineous populations where founder mutations exist. 2