Calcium/calmodulin-dependent protein kinases (CaMKs) are key mediators of calcium signaling and underpin neuronal health. Although widely studied, the contribution of CaMKs to Mendelian disease is rather enigmatic. Here, we describe an unusual neurodevelopmental phenotype, characterized by milestone delay, intellectual disability, autism, ataxia, and mixed hyperkinetic movement disorder including severe generalized dystonia, in a proband who remained etiologically undiagnosed despite exhaustive testing. We performed trio whole-exome sequencing to identify a de novo essential splice-site variant (c.981+1G>A) in CAMK4, encoding CaMKIV. Through in silico evaluation and cDNA analyses, we demonstrated that c.981+1G>A alters CAMK4 pre-mRNA processing and results in a stable mRNA transcript containing a 77-nt out-of-frame deletion and a premature termination codon within the last exon. The expected protein, p.Lys303Serfs*28, exhibits selective loss of the carboxy-terminal regulatory domain of CaMKIV and bears striking structural resemblance to previously reported synthetic mutants that confer constitutive CaMKIV activity. Biochemical studies in proband-derived cells confirmed an activating effect of c.981+1G>A and indicated that variant-induced excessive CaMKIV signaling is sensitive to pharmacological manipulation. Additionally, we found that variants predicted to cause selective depletion of CaMKIV's regulatory domain are unobserved in diverse catalogs of human variation, thus revealing that c.981+1G>A is a unique molecular event. We propose that our proband's phenotype is explainable by a dominant CAMK4 splice-disrupting mutation that acts through a gain-of-function mechanism. Our findings highlight the importance of CAMK4 in human neurodevelopment, provide a foundation for future clinical research of CAMK4, and suggest the CaMKIV signaling pathway as a potential drug target in neurological disease.

Department of Neurology and Center of Clinical Neuroscience 1st Faculty of Medicine Charles University and General Faculty Hospital Prague 120 00 Czech Republic

Institut für Humangenetik Helmholtz Zentrum München Munich 85764 Germany

Institut für Humangenetik Helmholtz Zentrum München Munich 85764 Germany Institut für Humangenetik Technische Universität München Munich 81675 Germany

Institut für Neurogenomik Helmholtz Zentrum München Munich 85764 Germany

Institut für Neurogenomik Helmholtz Zentrum München Munich 85764 Germany Institut für Humangenetik Technische Universität München Munich 81675 Germany Lehrstuhl für Neurogenetik Technische Universität München Munich 80333 Germany Munich Cluster for Systems Neurology SyNergy Munich 81377 Germany

Institut für Neurogenomik Helmholtz Zentrum München Munich 85764 Germany Klinik und Poliklinik für Neurologie Klinikum rechts der Isar Technische Universität München Munich 81675 Germany

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