Macrocephaly and developmental delay caused by missense variants in RAB5C
Author:
Koop Klaas1ORCID, Yuan Weimin23, Tessadori Federico4ORCID, Rodriguez-Polanco Wilmer R56, Grubbs Jeremy7, Zhang Bo23, Osmond Matt8, Graham Gail8, Sawyer Sarah9, Conboy Erin10, Vetrini Francesco10, Treat Kayla10, Płoski Rafal11ORCID, Pienkowski Victor Murcia1112, Kłosowska Anna1314, Fieg Elizabeth1516, Krier Joel1516, Mallebranche Coralie17, Alban Ziegler18, Aldinger Kimberly A192021ORCID, Ritter Deborah2223, Macnamara Ellen2425, Sullivan Bonnie2627, Herriges John28, Alaimo Joseph T28, Helbig Catherine2930, Ellis Colin A31, van Eyk Clare3233, Gecz Jozef3233, Farrugia Daniel34, Osei-Owusu Ikeoluwa35, Adès Lesley36, van den Boogaard Marie-Jose3738, Fuchs Sabine1, Bakker Jeroen4, Duran Karen4, Dawson Zachary D23, Lindsey Anika23, Huang Huiyan23, Baldridge Dustin23, Silverman Gary A23, Grant Barth D56, Raizen David7, 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 Gijs3738, Pak Stephen C23, Rehmann Holger39, Schedl Tim23, van Hasselt Peter1,
Affiliation:
1. Department of Pediatrics, University Medical Center Utrecht , Utrecht, 3584 EA , The Netherlands 2. Departments of Pediatrics and Genetics , C. elegans Model Organism Screening Center, , St Louis, MO 63110 , USA 3. Washington University in St Louis School of Medicine , C. elegans Model Organism Screening Center, , St Louis, MO 63110 , USA 4. Hubrecht Institute-KNAW and University Medical Center Utrecht , Utrecht, 3584 CT , The Netherlands 5. Department of Molecular Biology and Biochemistry , Rutgers, , Piscataway, NJ, 08854 , USA 6. The State University of New Jersey , Rutgers, , Piscataway, NJ, 08854 , USA 7. Department of Neurology and the Chronobiology and Sleep Institute, University of Pennsylvania , Philadelphia, PA, 19104 , USA 8. Children's Hospital of Eastern Ontario Research Institute, University of Ottawa , Ottawa, Ontario, K1H 8L1 , Canada 9. Department of Pediatrics, Children's Hospital of Eastern Ontario, University of Ottawa , Ottawa, Ontario, K1H 8L1 , Canada 10. Department of Medical and Molecular Genetics, Indiana University School of Medicine , Indianapolis, IN, 46202 , USA 11. Department of Medical Genetics, Medical University of Warsaw , Warsaw, 02-106 , Poland 12. Marseille Medical Genetics U1251, Aix Marseille University , Marseille, 13005 , France 13. Department of Pediatrics , Hematology and Oncology, , Gdańsk, 80-210 , Poland 14. Medical University of Gdańsk , Hematology and Oncology, , Gdańsk, 80-210 , Poland 15. Brigham and Women's Hospital , Boston, MA, 02115 , USA 16. Harvard Medical School , Boston, MA, 02115 , USA 17. Unité d'Onco-Hémato-Immunologie pédiatrique, CHU d’Angers , Angers, 49933 , France 18. Service de génétique, CHU d’Angers , Angers, 49933 , France 19. Center for Integrative Brain Research, Seattle Children's Research Institute , Seattle, WA, 98195 , USA 20. Division of Genetic Medicine , Department of Pediatrics, , Seattle, WA, 98195 , USA 21. University of Washington , Department of Pediatrics, , Seattle, WA, 98195 , USA 22. Department of Pediatrics , Oncology Section, , Houston, TX, 77030 , USA 23. Baylor College of Medicine , Oncology Section, , Houston, TX, 77030 , USA 24. Undiagnosed Diseases Program Translational Laboratory , NHGRI, , Bethesda, MD, 20892 , USA 25. National Institutes of Health , NHGRI, , Bethesda, MD, 20892 , USA 26. Division of Clinical Genetics , Department of Pediatrics, , Kansas City, MO, 64108 , USA 27. Children's Mercy-Kansas City , Department of Pediatrics, , Kansas City, MO, 64108 , USA 28. Department of Pathology and Laboratory Medicine, Children's Mercy-Kansas City , Kansas City, MO, 64108 , USA 29. The Epilepsy Neurogenetics Initiative , Division of Neurology, Department of Pediatrics, , Philadelphia, PA, 19104 , USA 30. The Children's Hospital of Philadelphia , Division of Neurology, Department of Pediatrics, , Philadelphia, PA, 19104 , USA 31. Department of Neurology, University of Pennsylvania Perelman School of Medicine , Philadelphia PA, 19104 , USA 32. Robinson Research Institute , Faculty of Health and Medical Sciences, , Adelaide, SA, 5006 , Australia 33. University of Adelaide , Faculty of Health and Medical Sciences, , Adelaide, SA, 5006 , Australia 34. Haematology, Mater Dei Hospital , Msida, MSD2090 , Malta 35. Program in Medical and Population Genetics, Broad Institute of MIT and Harvard , Cambridge, MA, 02142 , USA 36. Department of Clinical Genetics, The Children’s Hospital at Westmead Clinical School, Faculty of Medicine and Health, University of Sydney , Sydney, 2145 , Australia 37. Department of Genetics , Center for Molecular Medicine, , Utrecht, 3584EA , The Netherlands 38. University Medical Center Utrecht, Utrecht University , Center for Molecular Medicine, , Utrecht, 3584EA , The Netherlands 39. Department of Energy and Biotechnology, Flensburg University of Applied Sciences , 24943, Flensburg , Germany
Abstract
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.
Funder
National Institutes of Health St. Louis Children's Hospital Caenorhabditis Genetics Center Ontario Genomics Institute Canadian Institutes of Health Research Ontario Research Fund Genome Alberta Genome British Columbia Children's Hospital of Eastern Ontario Foundation
Publisher
Oxford University Press (OUP)
Subject
Genetics (clinical),Genetics,Molecular Biology,General Medicine
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