Mechanism of KMT5B haploinsufficiency in neurodevelopment in humans and mice
Authors: Sheppard Sarah E. , Bryant Laura , Wickramasekara Rochelle N. , Vaccaro Courtney , Robertson Brynn , Hallgren Jodi , Hulen Jason , Watson Cynthia J. , Faundes Victor , Duffourd Yannis , Lee Pearl , Simon M. Celeste , de la Cruz Xavier , Padilla Natália , Flores-Mendez Marco , Akizu Naiara , Smiler Jacqueline , Pellegrino Da Silva Renata , Li Dong , March Michael , Diaz-Rosado Abdias , Peixoto de Barcelos Isabella , Choa Zhao Xiang , Lim Chin Yan , Dubourg Christèle , Journel Hubert , Demurger Florence , Mulhern Maureen , Akman Cigdem , Lippa Natalie , Andrews Marisa , Baldridge Dustin , Constantino John , van Haeringen Arie , Snoeck-Streef Irina , Chow Penny , Hing Anne , Graham John M. , Au Margaret , Faivre Laurence , Shen Wei , Mao Rong , Palumbos Janice , Viskochil David , Gahl William , Tifft Cynthia , Macnamara Ellen , Hauser Natalie , Miller Rebecca , Maffeo Jessica , Afenjar Alexandra , Doummar Diane , Keren Boris , Arn Pamela , Macklin-Mantia Sarah , Meerschaut Ilse , Callewaert Bert , Reis André , Zweier Christiane , Brewer Carole , Saggar Anand , Smeland Marie F. , Kumar Ajith , Elmslie Frances , Deshpande Charu , Nizon Mathilde , Cogne Benjamin , van Ierland Yvette , Wilke Martina , van Slegtenhorst Marjon , Koudijs Suzanne , Chen Jin Yun , Dredge David , Pier Danielle , Wortmann Saskia , Kamsteeg Erik-Jan , Koch Johannes , Haynes Devon , Pollack Lynda , Titheradge Hannah , Ranguin Kara , Denommé-Pichon Anne-Sophie , Weber Sacha , Pérez de la Fuente Rubén , Sánchez del Pozo Jaime , Lezana Rosales Jose Miguel , Joset Pascal , Steindl Katharina , Rauch Anita , Mei Davide , Mari Francesco , Guerrini Renzo , Lespinasse James , Tran Mau-Them Frédéric , Philippe Christophe , Dauriat Benjamin , Raymond Laure , Moutton Sébastien , Cueto-González Anna M. , Tan Tiong Yang , Mignot Cyril , Grotto Sarah , Renaldo Florence , Drivas Theodore G. , Hennessy Laura , Raper Anna , Parenti Ilaria , Kaiser Frank J. , Kuechler Alma , Busk Øyvind L. , Islam Lily , Siedlik Jacob A. , Henderson Lindsay B. , Juusola Jane , Person Richard , Schnur Rhonda E. , Vitobello Antonio , Banka Siddharth , Bhoj Elizabeth J. , Stessman Holly A. F. 
Published: April 2023

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.