De Novo Mutations in Protein Kinase Genes CAMK2A and CAMK2B Cause Intellectual Disability

Sébastien Küry, Geeske M. van Woerden, Thomas Besnard, Martina Proietti Onori, Xénia Latypova, Meghan C. Towne, Megan T. Cho, Trine E. Prescott, Melissa A. Ploeg, Stephan Sanders, Holly A.F. Stessman, Aurora Pujol, Ben Distel, Laurie A. Robak, Jonathan A. Bernstein, Anne-Sophie Denommé-Pichon, Gaëtan Lesca, Elizabeth A. Sellars, Jonathan Berg, Wilfrid Carré, Øyvind Løvold Busk, Bregje W.M. van Bon, Jeff L. Waugh, Matthew Deardorff, George E. Hoganson, Katherine B. Bosanko, Diana S. Johnson, Tabib Dabir, Øystein Lunde Holla, Ajoy Sarkar, Kristian Tveten, Julitta de Bellescize, Geir J. Braathen, Paulien A. Terhal, Dorothy K. Grange, Arie van Haeringen, Christina Lam, Ghayda Mirzaa, Jennifer Burton, Elizabeth J. Bhoj, Jessica Douglas, Avni B. Santani, Addie I. Nesbitt, Katherine L. Helbig, Marisa V. Andrews, Amber Begtrup, Sha Tang, Koen L.I. van Gassen, Jane Juusola, Kimberly Foss, Gregory M. Enns, Ute Moog, Katrin Hinderhofer, Nagarajan Paramasivam, Sharyn Lincoln, Brandon H. Kusako, Pierre Lindenbaum, Eric Charpentier, Catherine B. Nowak, Elouan Cherot, Thomas Simonet, Claudia A.L. Ruivenkamp, Sihoun Hahn, Catherine A. Brownstein, Fan Xia, Sébastien Schmitt, Wallid Deb, Dominique Bonneau, Mathilde Nizon, Delphine Quinquis, Jamel Chelly, Gabrielle Rudolf, Damien Sanlaville, Philippe Parent, Brigitte Gilbert-Dussardier, Annick Toutain, Vernon R. Sutton, Jenny Thies, Lisenka E.L.M. Peart-Vissers, Pierre Boisseau, Marie Vincent, Andreas M. Grabrucker, Christèle Dubourg, Undiagnosed Diseases Network, Wen-Hann Tan, Nienke E. Verbeek, Martin Granzow, Gijs W.E. Santen, Jay Shendure, Bertrand Isidor, Laurent Pasquier, Richard Redon, Yaping Yang, Matthew W. State, Tjitske Kleefstra, Benjamin Cogné, GEM HUGO, Deciphering Developmental Disorders Study, Slavé Petrovski, Kyle Retterer, Evan E. Eichler, Jill A. Rosenfeld, Pankaj B. Agrawal, Stéphane Bézieau, Sylvie Odent, Ype Elgersma, Sandra Mercier

Calcium/calmodulin-dependent protein kinase II (CAMK2) is one of the first proteins shown to be essential for normal learning and synaptic plasticity in mice, but its requirement for human brain development has not yet been established. Through a multi-center collaborative study based on a whole-exome sequencing approach, we identified 19 exceedingly rare de novo CAMK2A or CAMK2B variants in 24 unrelated individuals with intellectual disability. Variants were assessed for their effect on CAMK2 function and on neuronal migration. For both CAMK2A and CAMK2B, we identified mutations that decreased or increased CAMK2 auto-phosphorylation at Thr286/Thr287. We further found that all mutations affecting auto-phosphorylation also affected neuronal migration, highlighting the importance of tightly regulated CAMK2 auto-phosphorylation in neuronal function and neurodevelopment. Our data establish the importance of CAMK2A and CAMK2B and their auto-phosphorylation in human brain function and expand the phenotypic spectrum of the disorders caused by variants in key players of the glutamatergic signaling pathway.