Macrocephaly and developmental delay caused by missense variants in RAB5C
Authors: Koop Klaas , Yuan Weimin , Tessadori Federico , Rodriguez-Polanco Wilmer R , Grubbs Jeremy , Zhang Bo , Osmond Matt , Graham Gail , Sawyer Sarah , Conboy Erin , Vetrini Francesco , Treat Kayla , Płoski Rafal , Pienkowski Victor Murcia , Kłosowska Anna , Fieg Elizabeth , Krier Joel , Mallebranche Coralie , Alban Ziegler , Aldinger Kimberly A , Ritter Deborah , Macnamara Ellen , Sullivan Bonnie , Herriges John , Alaimo Joseph T , Helbig Catherine , Ellis Colin A , van Eyk Clare , Gecz Jozef , Farrugia Daniel , Osei-Owusu Ikeoluwa , Adès Lesley , van den Boogaard Marie-Jose , Fuchs Sabine , Bakker Jeroen , Duran Karen , Dawson Zachary D , Lindsey Anika , Huang Huiyan , Baldridge Dustin , Silverman Gary A , Grant Barth D , Raizen David ,   Undiagnosed Diseases Network, Acosta Maria T , Adam Margaret , Adams David R , Alvey Justin , Amendola Laura , Andrews Ashley , Ashley Euan A , Azamian Mahshid S , Bacino Carlos A , Bademci Guney , Balasubramanyam Ashok , Baldridge Dustin , Bale Jim , Bamshad Michael , Barbouth Deborah , Bayrak-Toydemir Pinar , Beck Anita , Beggs Alan H , Behrens Edward , Bejerano Gill , Bellen Hugo , Bennet Jimmy , Berg-Rood Beverly , Bernstein Jonathan A , Berry Gerard T , Bican Anna , Bivona Stephanie , Blue Elizabeth , Bohnsack John , Bonner Devon , Botto Lorenzo , Boyd Brenna , Briere Lauren C , Brokamp Elly , Brown Gabrielle , Burke Elizabeth A , Burrage Lindsay C , Butte Manish J , Byers Peter , Byrd William E , Carey John , Carrasquillo Olveen , Cassini Thomas , Peter Chang Ta Chen , Chanprasert Sirisak , Chao Hsiao-Tuan , Clark Gary D , Coakley Terra R , Cobban Laurel A , Cogan Joy D , Coggins Matthew , Sessions Cole F , Colley Heather A , Cooper Cynthia M , Cope Heidi , Craigen William J , Crouse Andrew B , Cunningham Michael , D’Souza Precilla , Dai Hongzheng , Dasari Surendra , Davis Joie , Dayal Jyoti G , Deardorff Matthew , Dell’Angelica Esteban C , Dipple Katrina , Doherty Daniel , Dorrani Naghmeh , Doss Argenia L , Douine Emilie D , Duncan Laura , Earl Dawn , Eckstein David J , Emrick Lisa T , Eng Christine M , Esteves Cecilia , Falk Marni , Fernandez Liliana , Fieg Elizabeth L , Findley Laurie C , Fisher Paul G , Fogel Brent L , Forghani Irman , Gahl William A , Glass Ian , Gochuico Bernadette , Godfrey Rena A , Golden-Grant Katie , Goldrich Madison P , Grajewski Alana , Gutierrez Irma , Hadley Don , Hahn Sihoun , Hamid Rizwan , Hassey Kelly , Hayes Nichole , High Frances , Hing Anne , Hisama Fuki M , Holm Ingrid A , Hom Jason , Horike-Pyne Martha , Huang Alden , Huang Yong , Introne Wendy , Isasi Rosario , Izumi Kosuke , Jamal Fariha , Jarvik Gail P , Jarvik Jeffrey , Jayadev Suman , Jean-Marie Orpa , Jobanputra Vaidehi , Karaviti Lefkothea , Kennedy Jennifer , Ketkar Shamika , Kiley Dana , Kilich Gonench , Kobren Shilpa N , Kohane Isaac S , Kohler Jennefer N , Krakow Deborah , Krasnewich Donna M , Kravets Elijah , Korrick Susan , Koziura Mary , Lalani Seema R , Lam Byron , Lam Christina , LaMoure Grace L , Lanpher Brendan C , Lanza Ian R , LeBlanc Kimberly , Lee Brendan H , Lee Hane , Levitt Roy , Lewis Richard A , Liu Pengfei , Liu Xue Zhong , Longo Nicola , Loo Sandra K , Loscalzo Joseph , Maas Richard L , Macnamara Ellen F , MacRae Calum A , Maduro Valerie V , Mahoney Rachel , Mak Bryan C , Malicdan May Christine V , Mamounas Laura A , Manolio Teri A , Mao Rong , Maravilla Kenneth , Marom Ronit , Marth Gabor , Martin Beth A , Martin Martin G , Martínez-Agosto Julian A , Marwaha Shruti , McCauley Jacob , McConkie-Rosell Allyn , McCray Alexa T , McGee Elisabeth , Mefford Heather , Lawrence Merritt J , Might Matthew , Mirzaa Ghayda , Morava Eva , Moretti Paolo M , Mulvihill John J , Nakano-Okuno Mariko , Nelson Stan F , Newman John H , Nicholas Sarah K , Nickerson Deborah , Nieves-Rodriguez Shirley , Novacic Donna , Oglesbee Devin , Orengo James P , Pace Laura , Pak Stephen C , Carl Pallais J , Palmer Christina G S , Papp Jeanette C , Parker Neil H , Phillips III John A , Posey Jennifer E , Potocki Lorraine , Pusey Barbara N , Quinlan Aaron , Raskind Wendy , Raja Archana N , Rao Deepak A , Raper Anna , Renteria Genecee , Reuter Chloe M , Rives Lynette , Robertson Amy K , Rodan Lance H , Rosenfeld Jill A , Rosenwasser Natalie , Rossignol Francis , Ruzhnikov Maura , Sacco Ralph , Sampson Jacinda B , Saporta Mario , Ron Scott C , Schaechter Judy , Schedl Timothy , Schoch Kelly , Scott Daryl A , Shashi Vandana , Shin Jimann , Signer Rebecca , Silverman Edwin K , Sinsheimer Janet S , Sisco Kathy , Smith Edward C , Smith Kevin S , Solem Emily , Solnica-Krezel Lilianna , Solomon Ben , Spillmann Rebecca C , Stoler Joan M , Sullivan Jennifer A , Sullivan Kathleen , Sun Angela , Sutton Shirley , Sweetser David A , Sybert Virginia , Tabor Holly K , Tan Amelia L M , Tan Queenie K-G , Tekin Mustafa , Telischi Fred , Thorson Willa , Tifft Cynthia J , Toro Camilo , Tran Alyssa A , Tucker Brianna M , Urv Tiina K , Vanderver Adeline , Velinder Matt , Viskochil Dave , Vogel Tiphanie P , Wahl Colleen E , Wallace Stephanie , Walley Nicole M , Walker Melissa , Wambach Jennifer , Wan Jijun , Wang Lee-kai , Wangler Michael F , Ward Patricia A , Wegner Daniel , Weisz-Hubshman Monika , Wener Mark , Wenger Tara , Wesseling Perry Katherine , Westerfield Monte , Wheeler Matthew T , Whitlock Jordan , Wolfe Lynne A , Woods Jeremy D , Worley Kim , Xiao Changrui , Yamamoto Shinya , Yang John , Zastrow Diane B , Zhang Zhe , Zhao Chunli , Zuchner Stephan , van Haaften Gijs , Pak Stephen C , Rehmann Holger , Schedl Tim , van Hasselt Peter 
Published: August 2023

Abstract
Rab GTPases are important regulators of intracellular vesicular trafficking. RAB5C is a member of the Rab GTPase family that plays an important role in the endocytic pathway, membrane protein recycling and signaling. Here we report on 12 individuals with nine different heterozygous de novo variants in RAB5C. All but one patient with missense variants (n = 9) exhibited macrocephaly, combined with mild-to-moderate developmental delay. Patients with loss of function variants (n = 2) had an apparently more severe clinical phenotype with refractory epilepsy and intellectual disability but a normal head circumference. Four missense variants were investigated experimentally. In vitro biochemical studies revealed that all four variants were damaging, resulting in increased nucleotide exchange rate, attenuated responsivity to guanine exchange factors and heterogeneous effects on interactions with effector proteins. Studies in C. elegans confirmed that all four variants were damaging in vivo and showed defects in endocytic pathway function. The variant heterozygotes displayed phenotypes that were not observed in null heterozygotes, with two shown to be through a dominant negative mechanism. Expression of the human RAB5C variants in zebrafish embryos resulted in defective development, further underscoring the damaging effects of the RAB5C variants. Our combined bioinformatic, in vitro and in vivo experimental studies and clinical data support the association of RAB5C missense variants with a neurodevelopmental disorder characterized by macrocephaly and mild-to-moderate developmental delay through disruption of the endocytic pathway.