Mechanism of KMT5B haploinsufficiency in neurodevelopment in humans and mice
Sarah E. Sheppard, Laura Bryant, Rochelle N. Wickramasekara, Courtney Vaccaro, Brynn Robertson, Jodi Hallgren, Jason Hulen, Cynthia J. Watson, Víctor Faùndes, Yannis Duffourd, Pearl Lee, M. Celeste Simon, Xavier de la Cruz, Natàlia Padilla, Marco Flores‐Méndez, Naiara Akizu, Jacqueline Smiler, Renata Pellegrino da Silva, Dong Li, Michael March, Abdias Diaz‐Rosado, Isabella Peixoto de Barcelos, Zhao Xiang Choa, Chin Yan Lim, Christèle Dubourg, Hubert Journel, Florence Démurger, Maureen Mulhern, Cigdem I. Akman, Natalie Lippa, Marisa V. Andrews, Dustin Baldridge, John N. Constantino, Arie van Haeringen, Irina Snoeck-Streef, Penny Chow, Anne Hing, John M. Graham, Margaret Au, Laurence Faivre, Wei Shen, Rong Mao, Janice C. Palumbos, David Viskochil, William A. Gahl, Cynthia J. Tifft, Ellen F. Macnamara, Natalie Hauser, Rebecca L. Miller, Jessica Maffeo, Alexandra Afenjar, Diane Doummar, Boris Keren, Pamela Arn, Sarah K. Macklin‐Mantia, Ilse Meerschaut, Bert Callewaert, André Reis, Christiane Zweier, Carole Brewer, Anand Saggar, Marie Falkenberg Smeland, Ajith Kumar, Frances Elmslie, Charu Deshpande, Mathilde Nizon, Benjamin Cogné, Yvette van Ierland, Martina Wilke, Marjon van Slegtenhorst, Suzanne M. Koudijs, Jin Yun Chen, David Dredge, Danielle B. Pier, Saskia B. Wortmann, Erik‐Jan Kamsteeg, Johannes Koch, Devon Haynes, Lynda Pollack, Hannah Titheradge, Kara Ranguin, Anne‐Sophie Denommé‐Pichon, Sacha Weber, Rubén Pérez de la Fuente, Jaime Sánchez del Pozo, José Miguel Lezana Rosales, Pascal Joset, Katharina Steindl, Anita Rauch, Davide Mei, Francesco Mari, Renzo Guerrini, James Lespinasse, Frédéric Tran Mau‐Them, Christophe Philippe, Benjamin Dauriat, Laure Raymond, Sébastien Moutton, Anna M. Cueto‐González, Tiong Yang Tan
Abstract
Pathogenic variants in KMT5B , a lysine methyltransferase, are associated with global developmental delay, macrocephaly, autism, and congenital anomalies (OMIM # 617788). Given the relatively recent discovery of this disorder, it has not been fully characterized. Deep phenotyping of the largest ( n = 43) patient cohort to date identified that hypotonia and congenital heart defects are prominent features that were previously not associated with this syndrome. Both missense variants and putative loss-of-function variants resulted in slow growth in patient-derived cell lines. KMT5B homozygous knockout mice were smaller in size than their wild-type littermates but did not have significantly smaller brains, suggesting relative macrocephaly, also noted as a prominent clinical feature. RNA sequencing of patient lymphoblasts and Kmt5b haploinsufficient mouse brains identified differentially expressed pathways associated with nervous system development and function including axon guidance signaling. Overall, we identified additional pathogenic variants and clinical features in KMT5B -related neurodevelopmental disorder and provide insights into the molecular mechanisms of the disorder using multiple model systems.