Biallelic MADD variants cause a phenotypic spectrum ranging from developmental delay to a multisystem disorder
Authors: Schneeberger Pauline E , Kortüm Fanny , Korenke Georg Christoph , Alawi Malik , Santer René , Woidy Mathias , Buhas Daniela , Fox Stephanie , Juusola Jane , Alfadhel Majid , Webb Bryn D , Coci Emanuele G , Abou Jamra Rami , Siekmeyer Manuela , Biskup Saskia , Heller Corina , Maier Esther M , Javaher-Haghighi Poupak , Bedeschi Maria F , Ajmone Paola F , Iascone Maria , Peeters Hilde , Ballon Katleen , Jaeken Jaak , Rodríguez Alonso Aroa , Palomares-Bralo María , Santos-Simarro Fernando , Meuwissen Marije E C , Beysen Diane , Kooy R Frank , Houlden Henry , Murphy David , Doosti Mohammad , Karimiani Ehsan G , Mojarrad Majid , Maroofian Reza , Noskova Lenka , Kmoch Stanislav , Honzik Tomas , Cope Heidi , Sanchez-Valle Amarilis ,   Undiagnosed Diseases Network, Acosta Maria T , Adam Margaret , Adams David R , Agrawal Pankaj B , Alejandro Mercedes E , Alvey Justin , Amendola Laura , Andrews Ashley , Ashley Euan A , Azamian Mahshid S , Bacino Carlos A , Bademci Guney , Baker Eva , Balasubramanyam Ashok , Baldridge Dustin , Bale Jim , Bamshad Michael , Barbouth Deborah , Batzli Gabriel F , Bayrak-Toydemir Pinar , Beck Anita , Beggs Alan H , Behrens Edward , Bejerano Gill , Bennet Jimmy , Berg-Rood Beverly , Bernier Raphael , Bernstein Jonathan A , Berry Gerard T , Bican Anna , Bivona Stephanie , Blue Elizabeth , Bohnsack John , Bonnenmann Carsten , 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 , Chang Ta Chen Peter , Chanprasert Sirisak , Chao Hsiao-Tuan , Clark Gary D , Coakley Terra R , Cobban Laurel A , Cogan Joy D , Cole F Sessions , Colley Heather A , Cooper Cynthia M , Cope Heidi , Craigen William J , Crouse Andrew B , Cunningham Michael , D’Souza Precilla , Dai Hongzheng , Dasari Surendra , Davids Mariska , Dayal Jyoti G , Deardorff Matthew , Dell’Angelica Esteban C , Dhar Shweta U , Dipple Katrina , Doherty Daniel , Dorrani Naghmeh , Douine Emilie D , Draper David D , Duncan Laura , Earl Dawn , Eckstein David J , Emrick Lisa T , Eng Christine M , Esteves Cecilia , Estwick Tyra , Falk Marni , Fernandez Liliana , Ferreira Carlos , Fieg Elizabeth L , Fisher Paul G , Fogel Brent L , Forghani Irman , Fresard Laure , Gahl William A , Glass Ian , Godfrey Rena A , Golden-Grant Katie , Goldman Alica M , Goldstein David B , Grajewski Alana , Groden Catherine A , Gropman Andrea L , Gutierrez Irma , Hahn Sihoun , Hamid Rizwan , Hanchard Neil A , Hassey Kelly , Hayes Nichole , High Frances , Hing Anne , Hisama Fuki M , Holm Ingrid A , Hom Jason , Horike-Pyne Martha , Huang Alden , Huang Yong , Isasi Rosario , Jamal Fariha , Jarvik Gail P , Jarvik Jeffrey , Jayadev Suman , Johnston Jean M , Karaviti Lefkothea , Kelley Emily G , Kennedy Jennifer , Kiley Dana , Kohane Isaac S , Kohler Jennefer N , Krakow Deborah , Krasnewich Donna M , Kravets Elijah , Korrick Susan , Koziura Mary , Krier Joel B , Lalani Seema R , Lam Byron , Lam Christina , Lanpher Brendan C , Lanza Ian R , Christopher Lau C , LeBlanc Kimberly , Lee Brendan H , Lee Hane , Levitt Roy , Lewis Richard A , Lincoln Sharyn 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 , Majcherska Marta M , Malicdan May Christine V , Mamounas Laura A , Manolio Teri A , Mao Rong , Maravilla Kenneth , Markello Thomas C , Marom Ronit , Marth Gabor , Martin Beth A , Martin Martin G , Martínez-Agosto Julian A , Marwaha Shruti , McCauley Jacob , McConkie-Rosell Allyn , McCormack Colleen E , McCray Alexa T , McGee Elisabeth , Mefford Heather , Merritt J Lawrence , Might Matthew , Mirzaa Ghayda , Morava-Kozicz Eva , Moretti Paolo M , Morimoto Marie , Mulvihill John J , Murdock David R , Nakano-Okuno Mariko , Nath Avi , Nelson Stan F , Newman John H , Nicholas Sarah K , Nickerson Deborah , Novacic Donna , Oglesbee Devin , Orengo James P , Pace Laura , Pak Stephen , Carl Pallais J , Palmer Christina GS , Papp Jeanette C , Parker Neil H , Phillips John A , Posey Jennifer E , Potocki Lorraine , Pusey Barbara N , Quinlan Aaron , Raskind Wendy , Raja Archana N , Renteria Genecee , Reuter Chloe M , Rives Lynette , Robertson Amy K , Rodan Lance H , Rosenfeld Jill A , Rosenwasser Natalie , Rowley Robb K , Ruzhnikov Maura , Sacco Ralph , Sampson Jacinda B , Samson Susan L , Saporta Mario , Scott C Ron , Schaechter Judy , Schedl Timothy , Schoch Kelly , Scott Daryl A , Sharma Prashant , Shashi Vandana , Shin Jimann , Signer Rebecca , Sillari Catherine H , Silverman Edwin K , Sinsheimer Janet S , Sisco Kathy , Smith Edward C , Smith Kevin S , Solem Emily , Solnica-Krezel Lilianna , Spillmann Rebecca C , Stoler Joan M , Stong Nicholas , Sullivan Jennifer A , Sullivan Kathleen , Sun Angela , Sutton Shirley , Sweetser David A , Sybert Virginia , Tabor Holly K , Tamburro Cecelia P , 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 , Walsh Chris A , Walker Melissa , Wambach Jennifer , Wan Jijun , Wang Lee-kai , Wangler Michael F , Ward Patricia A , Wegner Daniel , Wener Mark , Wenger Tara , Perry Katherine Wesseling , Westerfield Monte , Wheeler Matthew T , Whitlock Jordan , Wolfe Lynne A , Woods Jeremy D , Yamamoto Shinya , Yang John , Yu Guoyun , Zastrow Diane B , Zhao Chunli , Zuchner Stephan , Gelb Bruce D , Kurth Ingo , Hempel Maja , Kutsche Kerstin 
Published: June 2020

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 functional tests to determine the impact of the variants on different pathways. Treatment of patient-derived fibroblasts with TNF-α resulted in reduced phosphorylation of the extracellular signal-regulated kinases 1 and 2, enhanced activation of the pro-apoptotic enzymes caspase-3 and -7 and increased apoptosis compared to control cells. We analysed internalization of epidermal growth factor in patient cells and identified a defect in endocytosis of epidermal growth factor. We conclude that MADD deficiency underlies multiple cellular defects that can be attributed to alterations of TNF-α-dependent signalling pathways and defects in vesicular trafficking. Our data highlight the multifaceted role of MADD as a signalling molecule in different organs and reveal its physiological role in regulating the function of the sensory and autonomic nervous system and endo- and exocrine glands.