Biallelic MADD variants cause a phenotypic spectrum ranging from developmental delay to a multisystem disorder

作者：Pauline E. Schneeberger, Fanny Kortüm, Georg Christoph Korenke, Malik Alawi, René Santer, Mathias Woidy, Daniela Buhaş, Stephanie J. Fox, Jane Juusola, Majid Alfadhel, Bryn D. Webb, Emanuele G. Coci, Rami Abou Jamra, Manuela Siekmeyer, Saskia Biskup, Corina Heller, Esther M. Maier, Poupak Javaher-Haghighi, Maria Francesca Bedeschi, Paola Francesca Ajmone, Maria Rosaria Iascone, Hilde Peeters, Katleen Ballon, Jaak Jaeken, Aroa Rodríguez Alonso, María Palomares‐Bralo, Fernando Santos‐Simarro, Marije E. C. Meuwissen, Diane Beysen, R. Frank Kooy, Henry Houlden, David P. Murphy, Mohammad Doosti, Ehsan Ghayoor Karimiani, Majid Mojarrad, Reza Maroofian, Lenka Nosková, Stanislav Kmoch, Tomáš Honzík, Heidi Cope, Amarilis Sanchez‐Valle, Undiagnosed Diseases Network, Maria T. Acosta, Margaret P Adam, David R. Adams, Pankaj B. Agrawal, Mercedes E. Alejandro, Justin C. Alvey, Laura M. Amendola, Ashley Andrews, Euan A. Ashley, Mahshid Sababi Azamian, Carlos A. Bacino, Güney Bademci, Eva H. Baker, Ashok Balasubramanyam, Dustin Baldridge, Jim Bale, Michael Bamshad, Deborah Barbouth, Gabriel F. Batzli, Pinar Bayrak‐Toydemir, Anita E. Beck, Alan H. Beggs, Edward M. Behrens, Gill Bejerano, Jimmy Bennet, Beverly Berg-Rood, Raphael Bernier, Jonathan Adam Bernstein, Gerard T. Berry, Anna Bican, Stephanie Bivona, Elizabeth Blue, John Peyton Bohnsack, Carsten Bonnenmann, Devon E. Bonner, Lorenzo D. Botto, Brenna M. Boyd, Lauren C. Briere, Elly Brokamp, Gabrielle Brown, Elizabeth A. Burke, Lindsay Catherine Burrage, Manish J. Butte, Peter H. Byers, William E. Byrd, John C. Carey, Olveen Carrasquillo, Ta Chen Chang, Sirisak Chanprasert, Hsiao‐Tuan Chao, Gary Clark, Terra R. Coakley, Laurel A. Cobban, Joy D Cogan, Francis Sessions Cole, Heather A. Colley, Cynthia M. Cooper, Heidi Cope, William James Craigen, Andrew B. Crouse, Michael L. Cunningham, Precilla D’Souza, Hongzheng Dai, Surendra Dasari, Mariska Davids, Jyoti G. Dayal, Matthew A. Deardorff, Esteban C. Dell’Angelica, Shweta U. Dhar, Katrina M. Dipple, Daniel Doherty, Naghmeh Dorrani, Emilie D. Douine, David D. Draper, Laura Duncan, Dawn Earl, David J. Eckstein, Lisa Emrick, Christine M. Eng, Cecilia Esteves, Tyra Estwick, Marni J. Falk, Liliana Fernández, Carlos Gil Ferreira, Elizabeth L. Fieg, Paul Graham Fisher, Brent L. Fogel, Irman Forghani, Laure Frésard, William Allen Gahl, Ian A. Glass, Rena A. Godfrey, Katie L. Golden‐Grant, Alica M. Goldman, David B. Goldstein, Alana L. Grajewski, Catherine A. Groden, Andrea Lynne Gropman, Irma Gutierrez, Sihoun Hahn, Rizwan Hamid, Neil A. Hanchard, Kelly Hassey, Nichole Hayes, Frances A. High, Anne V Hing, Fuki Marie Hisama, Ingrid A. Holm, Jason Hom, Martha J. Horike-Pyne, Alden Huang, Yong Huang, Rosario M. Isasi, Fariha Jamal, Gail Pairitz Jarvik, Jeffrey G. Jarvik, Suman Jayadev, Jean M. Johnston, Lefkothea P. Karaviti, Emily G. Kelley, J. Phillip Kennedy, Dana Kiley, Isaac S. Kohane, Jennefer N. Kohler, Deborah Krakow, Donna M. Krasnewich, Elijah Kravets, Susan Korrick, Mary E. Koziura, Joel B. Krier, Seema R. Lalani, Byron Lam, Christina T. Lam, Brendan C. Lanpher, Ian R. Lanza, C. Christopher Lau, Kimberly LeBlanc, Brendan Lee, Hane Lee, Roy C. Levitt, Richard Alan Lewis, Sharyn A. Lincoln, Pengfei Liu, Xue Zhong Liu, Nicola Longo, Sandra K. Loo, Joseph Loscalzo, Richard L. Maas, Ellen F. Macnamara, Calum A. MacRae, Valerie V. Braden Maduro, Marta M. Majcherska, May Christine V. Malicdan, Laura A. Mamounas, Teri A. Manolio, Rong Mao, Kenneth R. Maravilla, Thomas C. Markello, Ronit Marom, Gábor Marth, Beth A. Martin, Martín G. Martín, Julián A. Martínez-Agosto, Shruti Marwaha, Jacob L. McCauley, Allyn McConkie‐Rosell, Colleen E. McCormack, Alexa T. McCray, Elisabeth McGee, Heather C. Mefford, J. Lawrence Merritt, Matthew Might, Ghayda Mirzaa, Eva Morava‐Kozicz, Paolo M. Moretti, Marie Morimoto, John Joseph Mulvihill, David R. Murdock, Mariko Nakano‐Okuno, Avi Nath, Stan F. Nelson, John H. Newman, Sarah Kogan Nicholas, Deborah A. Nickerson, Donna Novacic, Devin Oglesbee, James Peter Orengo, Laura Pace, Stephen Pak, J. Carl Pallais, Christina G.S. Palmer, Jeanette C. Papp, Neil H. Parker, John A Phillips, Jennifer Ellen Posey, Lorraine Potocki, Barbara N. Pusey, Aaron R. Quinlan, Wendy H. Raskind, Archana Natarajan Raja, Genecee Renteria, Chloe M. Reuter, Lynette C. Rives, Amy K. Robertson, Lance H. Rodan, Jill A. Rosenfeld, Natalie L. Rosenwasser, Robb K. Rowley, Maura R. Z. Ruzhnikov, Ralph L. Sacco, Jacinda B. Sampson, Susan Leanne Samson, Mario Saporta, C. Ron Scott, Judy L. Schaechter, Timothy Schedl, Kelly Schoch, Daryl A. Scott, Prashant Sharma, Vandana Shashi, Jimann Shin, Rebecca H. Signer, Catherine H. Sillari, Edwin K. Silverman, Janet S. Sinsheimer, Kathy Sisco, Edward C. Smith, Kevin S. Smith, Emily P. Solem, Lilianna Solnica‐Krezel, Rebecca C. Spillmann, Joan Marilyn Stoler, Nicholas Stong, Jennifer A. Sullivan, Kathleen E. Sullivan, Angela Sun, Shirley C. Sutton, David A. Sweetser, Virginia P. Sybert, Holly K. Tabor, Cecelia P. Tamburro, Queenie K.‐G. Tan, Mustafa Tekin, Fred Telischi, Willa L. Thorson, Cynthia J. Tifft, Camilo Toro, Alyssa A. Tran, Brianna M. Tucker, Tiina K. Urv, Adeline L. Vanderver, Matt Velinder, Dave Viskochil, Tiphanie P. Vogel, Colleen E. Wahl, Stephanie E Wallace, Nicole M Walley, Chris A. Walsh, Melissa Walker, Jennifer Wambach, Jijun Wan, Lee-kai Wang, Michael F. Wangler, Patricia A. Ward, Daniel Wegner, Mark H. Wener, Tara Lynn Wenger, Katherine Wesseling Perry, Monte Westerfield, Matthew T. Wheeler, Jordan Whitlock, Lynne A. Wolfe, Jeremy D. Woods, Shinya Yamamoto, John Jeongseok Yang, Guoyun Yu, Diane B. Zastrow, Chunli Zhao, Stephan L. Zuchner, Bruce D. Gelb, Ingo Kurth, Maja Hempel, Kerstin Kutsche · 发表于：Brain · 年份：2020 · DOI：10.1093/brain/awaa204 · 被引用次数：60 · 研究领域：Congenital heart defects research、Genomics and Rare Diseases、Genetics and Neurodevelopmental Disorders

In pleiotropic diseases, multiple organ systems are affected causing a variety of clinical manifestations. Here, we report a pleiotropic disorder with a unique constellation of neurological, endocrine, exocrine, and haematological findings that is caused by biallelic MADD variants. MADD, the mitogen-activated protein kinase (MAPK) activating death domain protein, regulates various cellular functions, such as vesicle trafficking, activity of the Rab3 and Rab27 small GTPases, tumour necrosis factor-α (TNF-α)-induced signalling and prevention of cell death. Through national collaboration and GeneMatcher, we collected 23 patients with 21 different pathogenic MADD variants identified by next-generation sequencing. We clinically evaluated the series of patients and categorized the phenotypes in two groups. Group 1 consists of 14 patients with severe developmental delay, endo- and exocrine dysfunction, impairment of the sensory and autonomic nervous system, and haematological anomalies. The clinical course during the first years of life can be potentially fatal. The nine patients in Group 2 have a predominant neurological phenotype comprising mild-to-severe developmental delay, hypotonia, speech impairment, and seizures. Analysis of mRNA revealed multiple aberrant MADD transcripts in two patient-derived fibroblast cell lines. Relative quantification of MADD mRNA and protein in fibroblasts of five affected individuals showed a drastic reduction or loss of MADD. We conducted functiona...