Chia, P.HZhong, F.LNiwa, SBonnard, CUtami, K.HZeng, RLee, HEskin, ANelson, S.FXie, W.HAl-Tawalbeh, SEl-Khateeb, MShboul, MPouladi, M.AAl-Raqad, MReversade, BMEDICINEPAEDIATRICS2020-10-202020-10-202018Chia, P.H, Zhong, F.L, Niwa, S, Bonnard, C, Utami, K.H, Zeng, R, Lee, H, Eskin, A, Nelson, S.F, Xie, W.H, Al-Tawalbeh, S, El-Khateeb, M, Shboul, M, Pouladi, M.A, Al-Raqad, M, Reversade, B (2018). A homozygous loss-of-function camk2a mutation causes growth delay, frequent seizures and severe intellectual disability. eLife 7 : e32451. ScholarBank@NUS Repository. https://doi.org/10.7554/eLife.324512050084Xhttps://scholarbank.nus.edu.sg/handle/10635/177855Calcium/calmodulin-dependent protein kinase II (CAMK2) plays fundamental roles in synaptic plasticity that underlies learning and memory. Here, we describe a new recessive neurodevelopmental syndrome with global developmental delay, seizures and intellectual disability. Using linkage analysis and exome sequencing, we found that this disease maps to chromosome 5q31.1-q34 and is caused by a biallelic germline mutation in CAMK2A. The missense mutation, p. His477Tyr is located in the CAMK2A association domain that is critical for its function and localization. Biochemically, the p.His477Tyr mutant is defective in self-oligomerization and unable to assemble into the multimeric holoenzyme.In vivo, CAMK2A H477Y failed to rescue neuronal defects in C. elegans lacking unc-43, the ortholog of human CAMK2A. In vitro, neurons derived from patient iPSCs displayed profound synaptic defects. Together, our data demonstrate that a recessive germline mutation in CAMK2A leads to neurodevelopmental defects in humans and suggest that dysfunctional CAMK2 paralogs may contribute to other neurological disorders. © Chia et al.Attribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/calcium calmodulin dependent protein kinase IIhistoneproteinprotein unc 43tyrosineunclassified drugcalcium calmodulin dependent protein kinase IICAMK2A protein, humananimal experimentanimal modelArticleCaenorhabditis eleganscase reportchromosome 5qclinical articleconsanguineous marriagecontrolled studyconvulsiondevelopmental delayfiring rategermline mutationgrowth disorderhomozygotehumanhuman cellinduced pluripotent stem cellintellectual impairmentloss of function mutationmissense mutationmyoclonus seizurenonhumanprotein functionprotein localizationseizuresynapsewhole exome sequencingchromosome 5consanguinitydevelopmental disorderDNA sequencefamily healthgenetic linkagegeneticsintellectual impairmentJordanseizureCalcium-Calmodulin-Dependent Protein Kinase Type 2Chromosomes, Human, Pair 5ConsanguinityDevelopmental DisabilitiesFamily HealthGenetic LinkageHomozygoteHumansIntellectual DisabilityJordanLoss of Function MutationMutation, MissenseSeizuresSequence Analysis, DNAArticle