@article{752dc7252cbc48ce8e1619299453252d,
title = "Immunological and hematological findings as major features in a patient with a new germline pathogenic CBL variant",
abstract = "Casitas B-lineage lymphoma (CBL) encodes an adaptor protein with E3-ligase activity negatively controlling intracellular signaling downstream of receptor tyrosine kinases. Somatic CBL mutations play a driver role in a variety of cancers, particularly myeloid malignancies, whereas germline defects in the same gene underlie a RASopathy having clinical overlap with Noonan syndrome (NS) and predisposing to juvenile myelomonocytic leukemia and vasculitis. Other features of the disorder include cardiac defects, postnatal growth delay, cryptorchidism, facial dysmorphisms, and predisposition to develop autoimmune disorders. Here we report a novel CBL variant (c.1202G>T; p.Cys401Phe) occurring de novo in a subject with caf{\'e}-au-lait macules, feeding difficulties, mild dysmorphic features, psychomotor delay, autism spectrum disorder, thrombocytopenia, hepatosplenomegaly, and recurrent hypertransaminasemia. The identified variant affects an evolutionarily conserved residue located in the RING finger domain, a known mutational hot spot of both germline and somatic mutations. Functional studies documented enhanced EGF-induced ERK phosphorylation in transiently transfected COS1 cells. The present findings further support the association of pathogenic CBL variants with immunological and hematological manifestations in the context of a presentation with only minor findings reminiscent of NS or a clinically related RASopathy.",
keywords = "CBL, CBL syndrome, Noonan syndrome, RAS signaling, phenotypic spectrum",
author = "{Undiagnosed Diseases Network} and Emilia Stellacci and Carter, {Jennefer N.} and Luca Pannone and David Stevenson and Dorsa Moslehi and Serenella Venanzi and Acosta, {Maria T.} and Adams, {David R.} and Ben Afzali and Ali Al-Beshri and Eric Allenspach and Aimee Allworth and Alvarez, {Raquel L.} and Justin Alvey and Ashley Andrews and Ashley, {Euan A.} and Bacino, {Carlos A.} and Guney Bademci and Ashok Balasubramanyam and Dustin Baldridge and Erin Baldwin and Jim Bale and Michael Bamshad and Deborah Barbouth and Pinar Bayrak-Toydemir and Anita Beck and Beggs, {Alan H.} and Edward Behrens and Gill Bejerano and Bellen, {Hugo J.} and Jimmy Bennett and Bernstein, {Jonathan A.} and Berry,, {Gerard T.} and Anna Bican and Stephanie Bivona and Elizabeth Blue and John Bohnsack and Devon Bonner and Nicholas Borja and Lorenzo Botto and Briere, {Lauren C.} and Burke, {Elizabeth A.} and Burrage, {Lindsay C.} and Butte, {Manish J.} and Peter Byers and Byrd, {William E.} and Kaitlin Callaway and John Carey and George Carvalho and Thomas Cassini and Sirisak Chanprasert and Chao, {Hsiao Tuan} and Ivan Chinn and Clark, {Gary D.} and Coakley, {Terra R.} and Cobban, {Laurel A.} and Cogan, {Joy D.} and Matthew Coggins and Cole, {F. Sessions} and Brian Corner and Corona, {Rosario I.} and Craigen, {William J.} and Crouse, {Andrew B.} and Vishnu Cuddapah and Precilla D'Souza and Hongzheng Dai and Kahlen Darr and Surendra Dasari and Joie Davis and Margaret Delgado and Dell'Angelica, {Esteban C.} and Katrina Dipple and Daniel Doherty and Naghmeh Dorrani and Jessica Douglas and Douine, {Emilie D.} and Dawn Earl and Emrick, {Lisa T.} and Eng, {Christine M.} and Cecilia Esteves and Kimberly Ezell and Fieg, {Elizabeth L.} and Fisher, {Paul G.} and Fogel, {Brent L.} and Jiayu Fu and Gahl, {William A.} and Rebecca Ganetzky and Emily Glanton and Ian Glass and Goddard, {Page C.} and Gonzalez, {Joanna M.} and Andrea Gropman and Halley, {Meghan C.} and Rizwan Hamid and Neal Hanchard and Kelly Hassey and Nichole Hayes and Frances High and Anne Hing and Hisama, {Fuki M.} and Holm, {Ingrid A.} and Jason Hom and Martha Horike-Pyne and Alden Huang and Yan Huang and Anna Hurst and Wendy Introne and Jarvik, {Gail P.} and Suman Jayadev and Orpa Jean-Marie and Vaidehi Jobanputra and Oguz Kanca and Yigit Karasozen and Shamika Ketkar and Dana Kiley and Gonench Kilich and Eric Klee and Kobren, {Shilpa N.} and Kohane, {Isaac S.} and Carter, {Jennefer N.} and Bruce Korf and Susan Korrick and Deborah Krakow and Elijah Kravets and Lalani, {Seema R.} and Christina Lam and Lanpher, {Brendan C.} and Lanza, {Ian R.} and Kumarie Latchman and Kimberly LeBlanc and Lee, {Brendan H.} and Leppig, {Kathleen A.} and Lewis, {Richard A.} and Pengfei Liu and Nicola Longo and Joseph Loscalzo and Maas, {Richard L.} and Macnamara, {Ellen F.} and MacRae, {Calum A.} and Maduro, {Valerie V.} and Maghiro, {Audrey Stephannie} and Rachel Mahoney and Malicdan, {May Christine V.} and Rong Mao and Ronit Marom and Gabor Marth and Martin, {Beth A.} and Martin, {Martin G.} and Mart{\'i}nez-Agosto, {Julian A.} and Shruti Marwaha and Allyn McConkie-Rosell and Ashley McMinn and Matthew Might and Mohamad Mikati and Danny Miller and Ghayda Mirzaa and Breanna Mitchell and Paolo Moretti and Marie Morimoto and Mulvihill, {John J.} and Lindsay Mulvihill and Mariko Nakano-Okuno and Nelson, {Stanley F.} and Serena Neumann and Dargie Nitsuh and Donna Novacic and Devin Oglesbee and Orengo, {James P.} and Laura Pace and Stephen Pak and Pallais, {J. Carl} and Parker, {Neil H.} and L{\'e}Shon Peart and Leoyklang Petcharet and Phillips, {John A.} and Vairo, {Filippo Pintoe} and Posey, {Jennifer E.} and Lorraine Potocki and Swerdzewski, {Barbara N.Pusey} and Aaron Quinlan and Rader, {Daniel J.} and Ramakrishnan Rajagopalan and Rao, {Deepak A.} and Anna Raper and Wendy Raskind and Adriana Rebelo and Reuter, {Chloe M.} and Lynette Rives and Rodan, {Lance H.} and Martin Rodriguez and Rosenfeld, {Jill A.} and Elizabeth Rosenthal and Francis Rossignol and Maura Ruzhnikov and Marla Sabaii and Sampson, {Jacinda B.} and Timothy Schedl and Jimann Shin and Lilianna Solnica-Krezel and Jennifer Wambach",
note = "Publisher Copyright: {\textcopyright} 2024 The Author(s). American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.",
year = "2024",
month = aug,
doi = "10.1002/ajmg.a.63627",
language = "English",
volume = "194",
journal = "American Journal of Medical Genetics, Part A",
issn = "1552-4825",
number = "8",
}