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25 results on '"Karimiani, Ehsan G."'

1. Loss of symmetric cell division of apical neural progenitors drives DENND5A-related developmental and epileptic encephalopathy

Author

Banks, Emily, Francis, Vincent, Lin, Sheng-Jia, Kharfallah, Fares, Fonov, Vladimir, Lévesque, Maxime, Han, Chanshuai, Kulasekaran, Gopinath, Tuznik, Marius, Bayati, Armin, Al-Khater, Reem, Alkuraya, Fowzan S., Argyriou, Loukas, Babaei, Meisam, Bahlo, Melanie, Bakhshoodeh, Behnoosh, Barr, Eileen, Bartik, Lauren, Bassiony, Mahmoud, Bertrand, Miriam, Braun, Dominique, Buchert, Rebecca, Budetta, Mauro, Cadieux-Dion, Maxime, Calame, Daniel G., Cope, Heidi, Cushing, Donna, Efthymiou, Stephanie, Elmaksoud, Marwa Abd, El Said, Huda G., Froukh, Tawfiq, Gill, Harinder K., Gleeson, Joseph G., Gogoll, Laura, Goh, Elaine S.-Y., Gowda, Vykuntaraju K., Haack, Tobias B., Hashem, Mais O., Hauser, Stefan, Hoffman, Trevor L., Hogue, Jacob S., Hosokawa, Akimoto, Houlden, Henry, Huang, Kevin, Huynh, Stephanie, Karimiani, Ehsan G., Kaulfuß, Silke, Korenke, G. Christoph, Kritzer, Amy, Lee, Hane, Lupski, James R., Marco, Elysa J., McWalter, Kirsty, Minassian, Arakel, Minassian, Berge A., Murphy, David, Neira-Fresneda, Juanita, Northrup, Hope, Nyaga, Denis M., Oehl-Jaschkowitz, Barbara, Osmond, Matthew, Person, Richard, Pehlivan, Davut, Petree, Cassidy, Sadleir, Lynette G., Saunders, Carol, Schoels, Ludger, Shashi, Vandana, Spillmann, Rebecca C., Srinivasan, Varunvenkat M., Torbati, Paria N., Tos, Tulay, Zaki, Maha S., Zhou, Dihong, Zweier, Christiane, Trempe, Jean-François, Durcan, Thomas M., Gan-Or, Ziv, Avoli, Massimo, Alves, Cesar, Varshney, Gaurav K., Maroofian, Reza, Rudko, David A., and McPherson, Peter S.

Published
2024
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2. Elucidating the clinical and genetic spectrum of inositol polyphosphate phosphatase INPP4A-related neurodevelopmental disorder

Author

Rawlins, Lettie E., Maroofian, Reza, Cannon, Stuart J., Daana, Muhannad, Zamani, Mina, Ghani, Shamsul, Leslie, Joseph S., Ubeyratna, Nishanka, Khan, Nasar, Khan, Hamid, Scardamaglia, Annarita, Cloarec, Robin, Khan, Shujaat Ali, Umair, Muhammad, Sadeghian, Saeid, Galehdari, Hamid, Al-Maawali, Almundher, Al-Kindi, Adila, Azizimalamiri, Reza, Shariati, Gholamreza, Ahmad, Faraz, Al-Futaisi, Amna, Rodriguez Cruz, Pedro M., Salazar-Villacorta, Ainara, Ndiaye, Moustapha, Diop, Amadou G., Sedaghat, Alireza, Saberi, Alihossein, Hamid, Mohammad, Zaki, Maha S., Vona, Barbara, Owrang, Daniel, Alhashem, Abdullah M., Obeid, Makram, Khan, Amjad, Beydoun, Ahmad, Najjar, Marwan, Tajsharghi, Homa, Zifarelli, Giovanni, Bauer, Peter, Hakami, Wejdan S., Al Hashem, Amal M., Boustany, Rose-Mary N., Burglen, Lydie, Alavi, Shahryar, Gunning, Adam C., Owens, Martina, Karimiani, Ehsan G., Gleeson, Joseph G., Milh, Mathieu, Salah, Somaya, Khan, Jahangir, Haucke, Volker, Wright, Caroline F., McGavin, Lucy, Elpeleg, Orly, Shabbir, Muhammad I., Houlden, Henry, Ebner, Michael, Baple, Emma L., and Crosby, Andrew H.

Published
2024
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3. Biallelic loss of LDB3 leads to a lethal pediatric dilated cardiomyopathy

Author

Koopmann, Tamara T., Jamshidi, Yalda, Naghibi-Sistani, Mohammad, van der Klift, Heleen M., Birjandi, Hassan, Al-Hassnan, Zuhair, Alwadai, Abdullah, Zifarelli, Giovanni, Karimiani, Ehsan G., Sedighzadeh, Sahar, Bahreini, Amir, Nouri, Nayereh, Peter, Merlene, Watanabe, Kyoko, van Duyvenvoorde, Hermine A., Ruivenkamp, Claudia A. L., Teunissen, Aalbertine K. K., Ten Harkel, Arend D. J., van Duinen, Sjoerd G., Haak, Monique C., Prada, Carlos E., Santen, Gijs W. E., and Maroofian, Reza

Published
2023
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4. Genotype-phenotype correlations in RHOBTB2-associated neurodevelopmental disorders

Author

Langhammer, Franziska, Maroofian, Reza, Badar, Rueda, Gregor, Anne, Rochman, Michelle, Ratliff, Jeffrey B., Koopmans, Marije, Herget, Theresia, Hempel, Maja, Kortüm, Fanny, Heron, Delphine, Mignot, Cyril, Keren, Boris, Brooks, Susan, Botti, Christina, Ben-Zeev, Bruria, Argilli, Emanuela, Sherr, Elliot H., Gowda, Vykuntaraju K., Srinivasan, Varunvenkat M., Bakhtiari, Somayeh, Kruer, Michael C., Salih, Mustafa A., Kuechler, Alma, Muller, Eric A., Blocker, Karli, Kuismin, Outi, Park, Kristen L., Kochhar, Aaina, Brown, Kathleen, Ramanathan, Subhadra, Clark, Robin D., Elgizouli, Magdeldin, Melikishvili, Gia, Tabatadze, Nazhi, Stark, Zornitza, Mirzaa, Ghayda M., Ong, Jinfon, Grasshoff, Ute, Bevot, Andrea, von Wintzingerode, Lydia, Jamra, Rami A., Hennig, Yvonne, Goldenberg, Paula, Al Alam, Chadi, Charif, Majida, Boulouiz, Redouane, Bellaoui, Mohammed, Amrani, Rim, Al Mutairi, Fuad, Tamim, Abdullah M., Abdulwahab, Firdous, Alkuraya, Fowzan S., Khouj, Ebtissal M., Alvi, Javeria R., Sultan, Tipu, Hashemi, Narges, Karimiani, Ehsan G., Ashrafzadeh, Farah, Imannezhad, Shima, Efthymiou, Stephanie, Houlden, Henry, Sticht, Heinrich, and Zweier, Christiane

Published
2023
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5. Loss of TNR causes a nonprogressive neurodevelopmental disorder with spasticity and transient opisthotonus

Author

Wagner, Matias, Lévy, Jonathan, Jung-Klawitter, Sabine, Bakhtiari, Somayeh, Monteiro, Fabiola, Maroofian, Reza, Bierhals, Tatjana, Hempel, Maja, Elmaleh-Bergès, Monique, Kitajima, Joao P., Kim, Chong A., Salomao, Julia G., Amor, David J., Cooper, Monica S., Perrin, Laurence, Pipiras, Eva, Neu, Axel, Doosti, Mohammad, Karimiani, Ehsan G., Toosi, Mehran B., Houlden, Henry, Jin, Sheng Chih, Si, Yue C., Rodan, Lance H., Venselaar, Hanka, Kruer, Michael C., Kok, Fernando, Hoffmann, Georg F., Strom, Tim M., Wortmann, Saskia B., Tabet, Anne-Claude, and Opladen, Thomas

Published
2020
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6. Neuroinflammation and Lysosomal Abnormalities Characterise the Essential Role for Oxidation Resistance 1 in the Developing and Adult Cerebellum.

Author

Bucknor, Eboni M. V., Johnson, Errin, Efthymiou, Stephanie, Alvi, Javeria R., Sultan, Tipu, Houlden, Henry, Maroofian, Reza, Karimiani, Ehsan G., Finelli, Mattéa J., and Oliver, Peter L.

Subjects
NEUROINFLAMMATION, CEREBELLUM, GENE expression, HUMAN abnormalities, CEREBELLAR ataxia, CEREBELLAR cortex, OXIDATIVE stress
Abstract

Loss-of-function mutations in the TLDc family of proteins cause a range of severe childhood-onset neurological disorders with common clinical features that include cerebellar neurodegeneration, ataxia and epilepsy. Of these proteins, oxidation resistance 1 (OXR1) has been implicated in multiple cellular pathways related to antioxidant function, transcriptional regulation and cellular survival; yet how this relates to the specific neuropathological features in disease remains unclear. Here, we investigate a range of loss-of-function mouse model systems and reveal that constitutive deletion of Oxr1 leads to a rapid and striking neuroinflammatory response prior to neurodegeneration that is associated with lysosomal pathology. We go on to show that neuroinflammation and cell death in Oxr1 knockouts can be completely rescued by the neuronal expression of Oxr1, suggesting that the phenotype is driven by the cell-intrinsic defects of neuronal cells lacking the gene. Next, we generate a ubiquitous, adult inducible knockout of Oxr1 that surprisingly displays rapid-onset ataxia and cerebellar neurodegeneration, establishing for the first time that the distinctive pathology associated with the loss of Oxr1 occurs irrespective of developmental stage. Finally, we describe two new homozygous human pathogenic variants in OXR1 that cause neurodevelopmental delay, including a novel stop-gain mutation. We also compare functionally two missense human pathogenic mutations in OXR1, including one newly described here, that cause different clinical phenotypes but demonstrate partially retained neuroprotective activity against oxidative stress. Together, these data highlight the essential role of Oxr1 in modulating neuroinflammatory and lysosomal pathways in the mammalian brain and support the hypothesis that OXR1 protein dosage may be critical for pathological outcomes in disease. [ABSTRACT FROM AUTHOR]

Published
2024
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7. Bi-allelic genetic variants in the translational GTPases GTPBP1 and GTPBP2 cause a distinct identical neurodevelopmental syndrome

Author

Hannah, Michael G., Bugiardini, Enrico, Bertini, Enrico, Kriouile, Yamna, El-Khorassani, Mohamed, Aguennouz, Mhammed, Groppa, Stanislav, Karashova, Blagovesta M., Goraya, Jatinder S., Sultan, Tipu, Avdjieva, Daniela, Kathom, Hadil, Tincheva, Radka, Banu, Selina, Veggiotti, Pierangelo, Verrotti, Alberto, Lanari, Marcello, Savasta, Salvatore, Macaya, Alfons, Garavaglia, Barbara, Borgione, Eugenia, Papacostas, Savvas, Vikelis, Michail, Chelban, Viorica, Kaiyrzhanov, Rauan, Cortese, Andrea, Sullivan, Roisin, Papanicolaou, Eleni Z., Dardiotis, Efthymios, Maqbool, Shazia, Ibrahim, Shahnaz, Kirmani, Salman, Rana, Nuzhat N., Atawneh, Osama, Lim, Shen-Yang, Zuccotti, Gian V., Marseglia, Gian L., Esposito, Susanna, Shaikh, Farooq, Cogo, Paola, Corsello, Giovanni, Mangano, Salvatore, Nardello, Rosaria, Mangano, Donato, Scardamaglia, Annarita, Koutsis, George, Scuderi, Carmela, Ferrara, Pietro, Morello, Giovanna, Zollo, Massimo, Berni-Canani, Roberto, Terracciano, Luigi M., Sisto, Antonio, Di Fabio, Sandra, Strano, Federica, Scorrano, Giovanna, Di Bella, Saverio, Di Francesco, Ludovica, Manizha, Ganieva, Isrofilov, Maksud, Guliyeva, Ulviyya, Salayev, Kamran, Khachatryan, Samson, Xiromerisiou, Georgia, Spanaki, Cleanthe, Fiorillo, Chiara, Iacomino, Michele, Gaudio, Eugenio, Munell, Francina, Gagliano, Antonella, Jan, Farida, Chimenz, Roberto, Gitto, Eloisa, Iughetti, Lorenzo, Di Rosa, Gabriella, Maghnie, Mohamad, Pettoello-Mantovani, Massimo, Gupta, Neerja, Kabra, Madhulika, Benrhouma, Hanene, Tazir, Meriem, Bottone, Gabriella, Farello, Giovanni, Delvecchio, Maurizio, Di-Donato, Giulio, Obeid, Makram, Bakhtadze, Sophia, Saadi, Nebal W., Miraglia-Del-Giudice, Michele, Maccarone, Rita, Zaki, Maha S., Triki, Chahnez C., Kara, Majdi, Karimiani, Ehsan G., Salih, Ahmed M., Ramenghi, Luca A., Seri, Marco, Di-Falco, Giovanna, Mandarà, Luana, Barrano, Giuseppe, Elisa, Maurizio, Cherubini, Enrico, Operto, Francesca F., Valenzise, Mariella, Cattaneo, Antonino, Zazzeroni, Francesca, Alesse, Edoardo, Matricardi, Sara, Zafar, Faisal, Ullah, Ehsan, Afzal, Erum, Rahman, Fatima, Ahmed, Muhammad M., Parisi, Pasquale, Spalice, Alberto, De Filippo, Maria, Licari, Amelia, Trebbi, Edoardo, Romano, Ferdinando, Heimer, Gali, Al-Khawaja, Issam, Al-Mutairi, Fuad, Alkuraya, Fowzan S., Rizig, Mie, Shashkin, Chingiz, Zharkynbekova, Nazira, Koneyev, Kairgali, Salpietro, Vincenzo, Maroofian, Reza, Wangen, Jamie, Ciolfi, Andrea, Barresi, Sabina, Efthymiou, Stephanie, Lamaze, Angelique, Aughey, Gabriel N., Al Mutairi, Fuad, Rad, Aboulfazl, Rocca, Clarissa, Calì, Elisa, Accogli, Andrea, Zara, Federico, Striano, Pasquale, Mojarrad, Majid, Tariq, Huma, Giacopuzzi, Edoardo, Taylor, Jenny C., Oprea, Gabriela, Skrahina, Volha, Rehman, Khalil Ur, Abd Elmaksoud, Marwa, Bassiony, Mahmoud, El Said, Huda G., Abdel-Hamid, Mohamed S., Al Shalan, Maha, Seo, Gohun, Kim, Sohyun, Lee, Hane, Khang, Rin, Issa, Mahmoud Y., Elbendary, Hasnaa M., Rafat, Karima, Marinakis, Nikolaos M., Traeger-Synodinos, Joanne, Ververi, Athina, Sourmpi, Mara, Eslahi, Atieh, Khadivi Zand, Farhad, Beiraghi Toosi, Mehran, Babaei, Meisam, Jackson, Adam, Bertoli-Avella, Aida, Pagnamenta, Alistair T., Niceta, Marcello, Battini, Roberta, Corsello, Antonio, Leoni, Chiara, Chiarelli, Francesco, Dallapiccola, Bruno, Faqeih, Eissa Ali, Tallur, Krishnaraya K., Alfadhel, Majid, Alobeid, Eman, Maddirevula, Sateesh, Mankad, Kshitij, Banka, Siddharth, Ghayoor-Karimiani, Ehsan, Tartaglia, Marco, Chung, Wendy K., Green, Rachel, Jepson, James E.C., and Houlden, Henry

Published
2024
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8. Biallelic loss of LDB3 leads to a lethal pediatric dilated cardiomyopathy

Author

Koopmann, Tamara T., primary, Jamshidi, Yalda, additional, Naghibi-Sistani, Mohammad, additional, van der Klift, Heleen M., additional, Birjandi, Hassan, additional, Al-Hassnan, Zuhair, additional, Alwadai, Abdullah, additional, Zifarelli, Giovanni, additional, Karimiani, Ehsan G., additional, Sedighzadeh, Sahar, additional, Bahreini, Amir, additional, Nouri, Nayereh, additional, Peter, Merlene, additional, Watanabe, Kyoko, additional, van Duyvenvoorde, Hermine A., additional, Ruivenkamp, Claudia A. L., additional, Teunissen, Aalbertine K. K., additional, Ten Harkel, Arend D. J., additional, van Duinen, Sjoerd G., additional, Haak, Monique C., additional, Prada, Carlos E., additional, Santen, Gijs W. E., additional, and Maroofian, Reza, additional

Published
2022
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9. HIDEA syndrome is caused by biallelic, pathogenic, rare or founder P4HTM variants impacting the active site or the overall stability of the P4H‐TM protein

Author

Kraatari‐Tiri, Minna, primary, Soikkonen, Leila, additional, Myllykoski, Matti, additional, Jamshidi, Yalda, additional, Karimiani, Ehsan G., additional, Komulainen‐Ebrahim, Jonna, additional, Kallankari, Hanna, additional, Mignot, Cyril, additional, Depienne, Christel, additional, Keren, Boris, additional, Nougues, Marie‐Christine, additional, Alsahlawi, Zahra, additional, Romito, Antonio, additional, Martini, Javier, additional, Toosi, Mehran B., additional, Carroll, Christopher J., additional, Tripolszki, Kornelia, additional, Bauer, Peter, additional, Uusimaa, Johanna, additional, Bertoli‐Avella, Aida M., additional, Koivunen, Peppi, additional, and Rahikkala, Elisa, additional

Published
2022
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10. Variable skeletal phenotypes associated with biallelic variants in PRKG2

Author

Pagnamenta, Alistair T., Diaz-Gonzalez, Francisca, Banos-Pinero, Benito, Ferla, Matteo P., Toosi, Mehran B., Calder, Alistair D., Karimiani, Ehsan G., Doosti, Mohammad, Wainwright, Andrew, Wordsworth, Paul, Bailey, Kathryn, Ejeskär, Katarina, Lester, Tracy, Maroofian, Reza, Heath, Karen E., Tajsharghi, Homa, Shears, Deborah, Taylor, Jenny C., Pagnamenta, Alistair T., Diaz-Gonzalez, Francisca, Banos-Pinero, Benito, Ferla, Matteo P., Toosi, Mehran B., Calder, Alistair D., Karimiani, Ehsan G., Doosti, Mohammad, Wainwright, Andrew, Wordsworth, Paul, Bailey, Kathryn, Ejeskär, Katarina, Lester, Tracy, Maroofian, Reza, Heath, Karen E., Tajsharghi, Homa, Shears, Deborah, and Taylor, Jenny C.

Abstract

CC BY 4.0Published Online First: 15 November 2021Brief communicationThe Genomics England Research ConsortiumCorrespondence to Dr Deborah Shears; debbie.shears@ouh.nhs.uk Dr Jenny C Taylor; jenny@well.ox.ac.uk

Published
2022
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11. Biallelic ADAM22 pathogenic variants cause progressive encephalopathy and infantile-onset refractory epilepsy

Author

Van Der Knoop, Marieke M., Maroofian, Reza, Fukata, Yuko, Van Ierland, Yvette, Karimiani, Ehsan G., Lehesjoki, Anna Elina, Muona, Mikko, Paetau, Anders, Miyazaki, Yuri, Hirano, Yoko, Selim, Laila, De França, Marina, Fock, Rodrigo Ambrosio, Beetz, Christian, Ruivenkamp, Claudia A.L., Eaton, Alison J., Morneau-Jacob, Francois D., Sagi-Dain, Lena, Shemer-Meiri, Lilach, Peleg, Amir, Haddad-Halloun, Jumana, Kamphuis, Daan J., Peeters-Scholte, Cacha M.P.C.D., Kurul, Semra Hiz, Horvath, Rita, Lochmöller, Hanns, Murphy, David, Waldmöller, Stephan, Spranger, Stephanie, Overberg, David, Muir, Alison M., Rad, Aboulfazl, Vona, Barbara, Abdulwahad, Firdous, Maddirevula, Sateesh, Povolotskaya, Inna S., Voinova, Victoria Y., Gowda, Vykuntaraju K., Srinivasan, Varunvenkat M., Alkuraya, Fowzan S., Mefford, Heather C., Alfadhel, Majid, Haack, Tobias B., Striano, Pasquale, Severino, Mariasavina, Fukata, Masaki, Hilhorst-Hofstee, Yvonne, Houlden, Henry, Van Der Knoop, Marieke M., Maroofian, Reza, Fukata, Yuko, Van Ierland, Yvette, Karimiani, Ehsan G., Lehesjoki, Anna Elina, Muona, Mikko, Paetau, Anders, Miyazaki, Yuri, Hirano, Yoko, Selim, Laila, De França, Marina, Fock, Rodrigo Ambrosio, Beetz, Christian, Ruivenkamp, Claudia A.L., Eaton, Alison J., Morneau-Jacob, Francois D., Sagi-Dain, Lena, Shemer-Meiri, Lilach, Peleg, Amir, Haddad-Halloun, Jumana, Kamphuis, Daan J., Peeters-Scholte, Cacha M.P.C.D., Kurul, Semra Hiz, Horvath, Rita, Lochmöller, Hanns, Murphy, David, Waldmöller, Stephan, Spranger, Stephanie, Overberg, David, Muir, Alison M., Rad, Aboulfazl, Vona, Barbara, Abdulwahad, Firdous, Maddirevula, Sateesh, Povolotskaya, Inna S., Voinova, Victoria Y., Gowda, Vykuntaraju K., Srinivasan, Varunvenkat M., Alkuraya, Fowzan S., Mefford, Heather C., Alfadhel, Majid, Haack, Tobias B., Striano, Pasquale, Severino, Mariasavina, Fukata, Masaki, Hilhorst-Hofstee, Yvonne, and Houlden, Henry

Abstract

Pathogenic variants in A Disintegrin And Metalloproteinase (ADAM) 22, the postsynaptic cell membrane receptor for the glycoprotein leucine-rich repeat glioma-inactivated protein 1 (LGI1), have been recently associated with recessive developmental and epileptic encephalopathy. However, so far, only two affected individuals have been described and many features of this disorder are unknown. We refine the phenotype and report 19 additional individuals harbouring compound heterozygous or homozygous inactivating ADAM22 variants, of whom 18 had clinical data available. Additionally, we provide follow-up data from two previously reported cases. All affected individuals exhibited infantile-onset, treatment-resistant epilepsy. Additional clinical features included moderate to profound global developmental delay/intellectual disability (20/20), hypotonia (12/20) and delayed motor development (19/20). Brain MRI findings included cerebral atrophy (13/20), supported by post-mortem histological examination in patient-derived brain tissue, cerebellar vermis atrophy (5/20), and callosal hypoplasia (4/20). Functional studies in transfected cell lines confirmed the deleteriousness of all identified variants and indicated at least three distinct pathological mechanisms: (i) defective cell membrane expression; (ii) impaired LGI1-binding; and/or (iii) impaired interaction with the postsynaptic density protein PSD-95. We reveal novel clinical and molecular hallmarks of ADAM22 deficiency and provide knowledge that might inform clinical management and early diagnostics.

Published
2022

12. Clinico-radiological features, molecular spectrum, and identification of prognostic factors in developmental and epileptic encephalopathy due to inosine triphosphate pyrophosphatase (ITPase) deficiency

Author

Scala, Marcello, Wortmann, Saskia B., Kaya, Namik, Stellingwerff, Menno D., Pistorio, Angela, Glamuzina, Emma, van Karnebeek, Clara D., Skrypnyk, Cristina, Iwanicka-Pronicka, Katarzyna, Piekutowska-Abramczuk, Dorota, Ciara, Elżbieta, Tort, Frederic, Sheidley, Beth, Poduri, Annapurna, Jayakar, Parul, Jayakar, Anuj, Upadia, Jariya, Walano, Nicolette, Haack, Tobias B., Prokisch, Holger, Aldhalaan, Hesham, Karimiani, Ehsan G., Yildiz, Yilmaz, Ceylan, Ahmet C., Santiago-Sim, Teresa, Dameron, Amy, Yang, Hui, Toosi, Mehran B., Ashrafzadeh, Farah, Akhondian, Javad, Imannezhad, Shima, Mirzadeh, Hanieh S., Maqbool, Shazia, Farid, Aisha, Al-Muhaizea, Mohamed A., Alshwameen, Meznah O., Aldowsari, Lama, Alsagob, Maysoon, Alyousef, Ashwaq, AlMass, Rawan, AlHargan, Aljouhra, Alwadei, Ali H., AlRasheed, Maha M., Colak, Dilek, Alqudairy, Hanan, Khan, Sameena, Lines, Matthew A., García Cazorla, M. Ángeles, Ribes, Antonia, Morava, Eva, Bibi, Farah, Haider, Shahzad, Ferla, Matteo P., Taylor, Jenny C., Alsaif, Hessa S., Firdous, Abdulwahab, Hashem, Mais, Shashkin, Chingiz, Koneev, Kairgali, Kaiyrzhanov, Rauan, Efthymiou, Stephanie, Genomics, Queen Square, Schmitt-Mechelke, Thomas, Ziegler, Andreas, Issa, Mahmoud Y., Elbendary, Hasnaa M., Striano, Pasquale, Alkuraya, Fowzan S., Zaki, Maha S., Gleeson, Joseph G., Barakat, Tahsin Stefan, Bierau, Jorgen, van der Knaap, Marjo S., Maroofian, Reza, Houlden, Henry, Scala, Marcello, Wortmann, Saskia B., Kaya, Namik, Stellingwerff, Menno D., Pistorio, Angela, Glamuzina, Emma, van Karnebeek, Clara D., Skrypnyk, Cristina, Iwanicka-Pronicka, Katarzyna, Piekutowska-Abramczuk, Dorota, Ciara, Elżbieta, Tort, Frederic, Sheidley, Beth, Poduri, Annapurna, Jayakar, Parul, Jayakar, Anuj, Upadia, Jariya, Walano, Nicolette, Haack, Tobias B., Prokisch, Holger, Aldhalaan, Hesham, Karimiani, Ehsan G., Yildiz, Yilmaz, Ceylan, Ahmet C., Santiago-Sim, Teresa, Dameron, Amy, Yang, Hui, Toosi, Mehran B., Ashrafzadeh, Farah, Akhondian, Javad, Imannezhad, Shima, Mirzadeh, Hanieh S., Maqbool, Shazia, Farid, Aisha, Al-Muhaizea, Mohamed A., Alshwameen, Meznah O., Aldowsari, Lama, Alsagob, Maysoon, Alyousef, Ashwaq, AlMass, Rawan, AlHargan, Aljouhra, Alwadei, Ali H., AlRasheed, Maha M., Colak, Dilek, Alqudairy, Hanan, Khan, Sameena, Lines, Matthew A., García Cazorla, M. Ángeles, Ribes, Antonia, Morava, Eva, Bibi, Farah, Haider, Shahzad, Ferla, Matteo P., Taylor, Jenny C., Alsaif, Hessa S., Firdous, Abdulwahab, Hashem, Mais, Shashkin, Chingiz, Koneev, Kairgali, Kaiyrzhanov, Rauan, Efthymiou, Stephanie, Genomics, Queen Square, Schmitt-Mechelke, Thomas, Ziegler, Andreas, Issa, Mahmoud Y., Elbendary, Hasnaa M., Striano, Pasquale, Alkuraya, Fowzan S., Zaki, Maha S., Gleeson, Joseph G., Barakat, Tahsin Stefan, Bierau, Jorgen, van der Knaap, Marjo S., Maroofian, Reza, and Houlden, Henry

Abstract

Developmental and epileptic encephalopathy 35 (DEE 35) is a severe neurological condition caused by biallelic variants in ITPA, encoding inosine triphosphate pyrophosphatase, an essential enzyme in purine metabolism. We delineate the genotypic and phenotypic spectrum of DEE 35, analyzing possible predictors for adverse clinical outcomes. We investigated a cohort of 28 new patients and reviewed previously described cases, providing a comprehensive characterization of 40 subjects. Exome sequencing was performed to identify underlying ITPA pathogenic variants. Brain MRI (magnetic resonance imaging) scans were systematically analyzed to delineate the neuroradiological spectrum. Survival curves according to the Kaplan–Meier method and log-rank test were used to investigate outcome predictors in different subgroups of patients. We identified 18 distinct ITPA pathogenic variants, including 14 novel variants, and two deletions. All subjects showed profound developmental delay, microcephaly, and refractory epilepsy followed by neurodevelopmental regression. Brain MRI revision revealed a recurrent pattern of delayed myelination and restricted diffusion of early myelinating structures. Congenital microcephaly and cardiac involvement were statistically significant novel clinical predictors of adverse outcomes. We refined the molecular, clinical, and neuroradiological characterization of ITPase deficiency, and identified new clinical predictors which may have a potentially important impact on diagnosis, counseling, and follow-up of affected individuals.

Published
2022

13. Biallelic ADAM22 pathogenic variants cause progressive encephalopathy and infantile-onset refractory epilepsy

Author

van der Knoop, Marieke M, primary, Maroofian, Reza, additional, Fukata, Yuko, additional, van Ierland, Yvette, additional, Karimiani, Ehsan G, additional, Lehesjoki, Anna Elina, additional, Muona, Mikko, additional, Paetau, Anders, additional, Miyazaki, Yuri, additional, Hirano, Yoko, additional, Selim, Laila, additional, de França, Marina, additional, Fock, Rodrigo Ambrosio, additional, Beetz, Christian, additional, Ruivenkamp, Claudia A L, additional, Eaton, Alison J, additional, Morneau-Jacob, Francois D, additional, Sagi-Dain, Lena, additional, Shemer-Meiri, Lilach, additional, Peleg, Amir, additional, Haddad-Halloun, Jumana, additional, Kamphuis, Daan J, additional, Peeters-Scholte, Cacha M P C D, additional, Kurul, Semra Hiz, additional, Horvath, Rita, additional, Lochmüller, Hanns, additional, Murphy, David, additional, Waldmüller, Stephan, additional, Spranger, Stephanie, additional, Overberg, David, additional, Muir, Alison M, additional, Rad, Aboulfazl, additional, Vona, Barbara, additional, Abdulwahad, Firdous, additional, Maddirevula, Sateesh, additional, Povolotskaya, Inna S, additional, Voinova, Victoria Y, additional, Gowda, Vykuntaraju K, additional, Srinivasan, Varunvenkat M, additional, Alkuraya, Fowzan S, additional, Mefford, Heather C, additional, Alfadhel, Majid, additional, Haack, Tobias B, additional, Striano, Pasquale, additional, Severino, Mariasavina, additional, Fukata, Masaki, additional, Hilhorst-Hofstee, Yvonne, additional, and Houlden, Henry, additional

Published
2022
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14. Clinico‐radiological features, molecular spectrum, and identification of prognostic factors in developmental and epileptic encephalopathy due to inosine triphosphate pyrophosphatase (ITPase) deficiency

Author

Scala, Marcello, primary, Wortmann, Saskia B., additional, Kaya, Namik, additional, Stellingwerff, Menno D., additional, Pistorio, Angela, additional, Glamuzina, Emma, additional, Karnebeek, Clara D., additional, Skrypnyk, Cristina, additional, Iwanicka‐Pronicka, Katarzyna, additional, Piekutowska‐Abramczuk, Dorota, additional, Ciara, Elżbieta, additional, Tort, Frederic, additional, Sheidley, Beth, additional, Poduri, Annapurna, additional, Jayakar, Parul, additional, Jayakar, Anuj, additional, Upadia, Jariya, additional, Walano, Nicolette, additional, Haack, Tobias B., additional, Prokisch, Holger, additional, Aldhalaan, Hesham, additional, Karimiani, Ehsan G., additional, Yildiz, Yilmaz, additional, Ceylan, Ahmet C., additional, Santiago‐Sim, Teresa, additional, Dameron, Amy, additional, Yang, Hui, additional, Toosi, Mehran B., additional, Ashrafzadeh, Farah, additional, Akhondian, Javad, additional, Imannezhad, Shima, additional, Mirzadeh, Hanieh S., additional, Maqbool, Shazia, additional, Farid, Aisha, additional, Al‐Muhaizea, Mohamed A., additional, Alshwameen, Meznah O., additional, Aldowsari, Lama, additional, Alsagob, Maysoon, additional, Alyousef, Ashwaq, additional, AlMass, Rawan, additional, AlHargan, Aljouhra, additional, Alwadei, Ali H., additional, AlRasheed, Maha M., additional, Colak, Dilek, additional, Alqudairy, Hanan, additional, Khan, Sameena, additional, Lines, Matthew A., additional, García Cazorla, M. Ángeles, additional, Ribes, Antonia, additional, Morava, Eva, additional, Bibi, Farah, additional, Haider, Shahzad, additional, Ferla, Matteo P., additional, Taylor, Jenny C., additional, Alsaif, Hessa S., additional, Firdous, Abdulwahab, additional, Hashem, Mais, additional, Shashkin, Chingiz, additional, Koneev, Kairgali, additional, Kaiyrzhanov, Rauan, additional, Efthymiou, Stephanie, additional, Genomics, Queen Square, additional, Schmitt‐Mechelke, Thomas, additional, Ziegler, Andreas, additional, Issa, Mahmoud Y., additional, Elbendary, Hasnaa M., additional, Striano, Pasquale, additional, Alkuraya, Fowzan S., additional, Zaki, Maha S., additional, Gleeson, Joseph G., additional, Barakat, Tahsin Stefan, additional, Bierau, Jorgen, additional, Knaap, Marjo S., additional, Maroofian, Reza, additional, and Houlden, Henry, additional

Published
2022
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15. Variable skeletal phenotypes associated with biallelic variants in PRKG2

Author

Pagnamenta, Alistair T, primary, Diaz-Gonzalez, Francisca, additional, Banos-Pinero, Benito, additional, Ferla, Matteo P, additional, Toosi, Mehran B, additional, Calder, Alistair D, additional, Karimiani, Ehsan G, additional, Doosti, Mohammad, additional, Wainwright, Andrew, additional, Wordsworth, Paul, additional, Bailey, Kathryn, additional, Ejeskär, Katarina, additional, Lester, Tracy, additional, Maroofian, Reza, additional, Heath, Karen E, additional, Tajsharghi, Homa, additional, Shears, Deborah, additional, and Taylor, Jenny C, additional

Published
2021
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16. Biallelic ADAM22 pathogenic variants cause progressive encephalopathy and infantile-onset refractory epilepsy.

Author

Knoop, Marieke M van der, Maroofian, Reza, Fukata, Yuko, Ierland, Yvette van, Karimiani, Ehsan G, Lehesjoki, Anna Elina, Muona, Mikko, Paetau, Anders, Miyazaki, Yuri, Hirano, Yoko, Selim, Laila, França, Marina de, Fock, Rodrigo Ambrosio, Beetz, Christian, Ruivenkamp, Claudia A L, Eaton, Alison J, Morneau-Jacob, Francois D, Sagi-Dain, Lena, Shemer-Meiri, Lilach, and Peleg, Amir

Subjects
RESEARCH, NERVE tissue proteins, BRAIN diseases, RESEARCH methodology, SIGNAL peptides, EVALUATION research, ATROPHY, COMPARATIVE studies, GLYCOPROTEINS, RESEARCH funding
Abstract

Pathogenic variants in A Disintegrin And Metalloproteinase (ADAM) 22, the postsynaptic cell membrane receptor for the glycoprotein leucine-rich repeat glioma-inactivated protein 1 (LGI1), have been recently associated with recessive developmental and epileptic encephalopathy. However, so far, only two affected individuals have been described and many features of this disorder are unknown. We refine the phenotype and report 19 additional individuals harbouring compound heterozygous or homozygous inactivating ADAM22 variants, of whom 18 had clinical data available. Additionally, we provide follow-up data from two previously reported cases. All affected individuals exhibited infantile-onset, treatment-resistant epilepsy. Additional clinical features included moderate to profound global developmental delay/intellectual disability (20/20), hypotonia (12/20) and delayed motor development (19/20). Brain MRI findings included cerebral atrophy (13/20), supported by post-mortem histological examination in patient-derived brain tissue, cerebellar vermis atrophy (5/20), and callosal hypoplasia (4/20). Functional studies in transfected cell lines confirmed the deleteriousness of all identified variants and indicated at least three distinct pathological mechanisms: (i) defective cell membrane expression; (ii) impaired LGI1-binding; and/or (iii) impaired interaction with the postsynaptic density protein PSD-95. We reveal novel clinical and molecular hallmarks of ADAM22 deficiency and provide knowledge that might inform clinical management and early diagnostics. [ABSTRACT FROM AUTHOR]

Published
2022
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18. A homozygous MED11 C-terminal variant causes a lethal neurodegenerative disease

Author

Calì, Elisa, Lin, Sheng-Jia, Rocca, Clarissa, Sahin, Yavuz, Al Shamsi, Aisha, El Chehadeh, Salima, Chaabouni, Myriam, Mankad, Kshitij, Galanaki, Evangelia, Efthymiou, Stephanie, Sudhakar, Sniya, Athanasiou-Fragkouli, Alkyoni, Çelik, Tamer, Narlı, Nejat, Bianca, Sebastiano, Murphy, David, De Carvalho Moreira, Francisco Martins, Hannah, Michael G., Bugiardini, Enrico, Kriouile, Yamna, El Khorassani, Mohamed, Aguennouz, Mhammed, Groppa, Stanislav, Karashova, Blagovesta Marinova, Di Rosa, Gabriella, Goraya, Jatinder S., Sultan, Tipu, Avdjieva, Daniela, Kathom, Hadil, Tincheva, Radka, Banu, Selina, Veggiotti, Pierangelo, Verrotti, Alberto, Savasta, Salvatore, Ruiz, Alfons Macaya, Garavaglia, Barbara, Borgione, Eugenia, Papacostas, Savvas, Compagnoni, Chiara, Piccirilli, Alessandra, Vikelis, Michail, Chelban, Viorica, Kaiyrzhanov, Rauan, Cortese, Andrea, Sullivan, Roisin, Papanicolaou, Eleni Zamba, Dardiotis, Efthymios, Maqbool, Shazia, Ibrahim, Shahnaz, Kirmani, Salman, Rana, Nuzhat Noureen, Atawneh, Osama, Lim, Shen-Yang, Shaikh, Farooq, Scardamaglia, Annarita, Koutsis, George, Mangano, Salvatore, Scuderi, Carmela, Borgione, Eugenia, Morello, Giovanna, Zollo, Massimo, Heimer, Gali, Striano, Pasquale, Al-Khawaja, Issam, Al-Mutairi, Fuad, Alkuraya, Fowzan S., Rizig, Mie, Shashkin, Chingiz, Zharkynbekova, Nazira, Koneyev, Kairgali, Manizha, Ganieva, Isrofilov, Maksud, Guliyeva, Ulviyya, Salayev, Kamran, Khachatryan, Samson, Xiromerisiou, Georgia, Spanaki, Cleanthe, Tucci, Arianna, Fiorillo, Chiara, Rissotto, Federico, Munell, Francina, Gagliano, Antonella, Jan, Farida, Chimenz, Roberto, Gitto, Eloisa, Cuppari, Caterina, Romeo, Carmelo, Magrinelli, Francesca, Gupta, Neerja, Kabra, Madhulika, Benrhouma, Hanene, Tazir, Meriem, Zagaroli, Luca, Caloisi, Claudia, Fabiano, Cecilia, Bottone, Gabriella, Farello, Giovanni, Di Fabio, Sandra, Obeid, Makram, Bakhtadze, Sophia, Saadi, Nebal W., Zaki, Maha S., Triki, Chahnez C., Kara, Majdi, Belcastro, Vincenzo, Specchio, Nicola, Karimiani, Ehsan G., Salih, Ahmed M., Ramenghi, Luca A., David, Emanuele, Curró, Riccardo, Iezzi, Maria Laura, Iapadre, Giulia, Nanni, Giuliana, Scorrano, Giovanna, Fiorile, Maria F., Brancati, Francesco, Di Falco, Giovanna, Mandarà, Luana, Barrano, Giuseppe, Elia, Maurizio, Terrone, Gaetano, Operto, Francesca F., Valenzise, Mariella, Della Rocca, Ylenia, Zazzeroni, Francesca, Alesse, Edoardo, Manti, Filippo, Galosi, Serena, Nardecchia, Francesca, Leuzzi, Vincenzo, Pironti, Erica, Amore, Greta, Ceravolo, Giorgia, Zafar, Faisal, Ullah, Ehsan, Afzal, Erum, Javed, Iram, Rahman, Fatima, Ahmed, Muhammad Mehboob, Parisi, Pasquale, Borgia, Paola, Mangano, Giuseppe D., Chiarelli, Francesco, Genomics, Queen Square, Accogli, Andrea, Petree, Cassidy, Huang, Kevin, Monastiri, Kamel, Edizadeh, Masoud, Nardello, Rosaria, Ognibene, Marzia, De Marco, Patrizia, Ruggieri, Martino, Zara, Federico, Striano, Pasquale, Şahin, Yavuz, Al-Gazali, Lihadh, Abi Warde, Marie Therese, Gerard, Benedicte, Zifarelli, Giovanni, Beetz, Christian, Fortuna, Sara, Soler, Miguel, Valente, Enza Maria, Varshney, Gaurav, Maroofian, Reza, Salpietro, Vincenzo, and Houlden, Henry

Abstract

The mediator (MED) multisubunit-complex modulates the activity of the transcriptional machinery, and genetic defects in different MED subunits (17, 20, 27) have been implicated in neurologic diseases. In this study, we identified a recurrent homozygous variant in MED11(c.325C>T; p.Arg109Ter) in 7 affected individuals from 5 unrelated families.

Published
2022
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19. Novel mutation identification and copy number variant detection via exome sequencing in congenital muscular dystrophy

Author

Cauley, Edmund S., primary, Pittman, Alan, additional, Mummidivarpu, Swati, additional, Karimiani, Ehsan G., additional, Martinez, Samantha, additional, Moroni, Isabella, additional, Boostani, Reza, additional, Podini, Daniele, additional, Mora, Marina, additional, Jamshidi, Yalda, additional, Hoffman, Eric P., additional, and Manzini, M. Chiara, additional

Published
2020
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20. AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders

Author

Salpietro Vincenzo, Dixon Christine L., Guo Hui, Bello Oscar D., Vandrovcova Jana, Efthymiou Stephanie, Maroofian Reza, Heimer Gali, Burglen Lydie, Valence Stephanie, Torti Erin, Hacke Moritz, Rankin Julia, Tariq Huma, Colin Estelle, Procaccio Vincent, Striano Pasquale, Mankad Kshitij, Lieb Andreas, Chen Sharon, Pisani Laura, Bettencourt Conceicao, Mannikko Roope, Manole Andreea, Brusco Alfredo, Grosso Enrico, Ferrero Giovanni Battista, Armstrong-Moron Judith, Gueden Sophie, Bar-Yosef Omer, Tzadok Michal, Monaghan Kristin G., Santiago-Sim Teresa, Person Richard E., Cho Megan T., Willaert Rebecca, Yoo Yongjin, Chae Jong-Hee, Quan Yingting, Wu Huidan, Wang Tianyun, Bernier Raphael A., Xia Kun, Blesson Alyssa, Jain Mahim, Motazacker Mohammad M., Jaeger Bregje, Schneider Amy L., Boysen Katja, Muir Alison M., Myers Candace T., Gavrilova Ralitza H., Gunderson Lauren, Schultz-Rogers Laura, Klee Eric W., Dyment David, Osmond Matthew, Parellada Mara, Llorente Cloe, Gonzalez-Penas Javier, Carracedo Angel, Van Haeringen Arie, Ruivenkamp Claudia, Nava Caroline, Heron Delphine, Nardello Rosaria, Iacomino Michele, Minetti Carlo, Skabar Aldo, Fabretto Antonella, Chez Michael, Tsai Anne, Fassi Emily, Shinawi Marwan, Constantino John N., De Zorzi Rita, Fortuna Sara, Kok Fernando, Keren Boris, Bonneau Dominique, Choi Murim, Benzeev Bruria, Zara Federico, Mefford Heather C., Scheffer Ingrid E., Clayton-Smith Jill, Macaya Alfons, Rothman James E., Eichler Evan E., Kullmann Dimitri M., Houlden Henry, Raspall-Chaure Miquel, Hanna Michael G., Bugiardini Enrico, Hostettler Isabel, O'Callaghan Benjamin, Khan Alaa, Cortese Andrea, O'Connor Emer, Yau Wai Y., Bourinaris Thomas, Kaiyrzhanov Rauan, Chelban Viorica, Madej Monika, Diana Maria C., Vari Maria S., Pedemonte Marina, Bruno Claudio, Balagura Ganna, Scala Marcello, Fiorillo Chiara, Nobili Lino, Malintan Nancy T., Zanetti Maria N., Krishnakumar Shyam S., Lignani Gabriele, Jepson James E. C., Broda Paolo, Baldassari Simona, Rossi Pia, Fruscione Floriana, Madia Francesca, Traverso Monica, De-Marco Patrizia, Perez-Duenas Belen, Munell Francina, Kriouile Yamna, El-Khorassani Mohamed, Karashova Blagovesta, Avdjieva Daniela, Kathom Hadil, Tincheva Radka, Van-Maldergem Lionel, Nachbauer Wolfgang, Boesch Sylvia, Gagliano Antonella, Amadori Elisabetta, Goraya Jatinder S., Sultan Tipu, Kirmani Salman, Ibrahim Shahnaz, Jan Farida, Mine, Jun, Banu Selina, Veggiotti Pierangelo, Zuccotti Gian V, Ferrari Michel D., Van Den Maagdenberg Arn M. J., Verrotti Alberto, Marseglia Gian L., Savasta Salvatore, Soler Miguel A., Scuderi Carmela, Borgione Eugenia, Chimenz Roberto, Gitto Eloisa, Dipasquale Valeria, Sallemi Alessia, Fusco Monica, Cuppari Caterina, Cutrupi Maria C., Ruggieri Martino, Cama Armando, Capra Valeria, Mencacci Niccolo E., Boles Richard, Gupta Neerja, Kabra Madhulika, Papacostas Savvas, Zamba-Papanicolaou Eleni, Dardiotis Efthymios, Maqbool Shazia, Rana Nuzhat, Atawneh Osama, Lim Shen Y., Shaikh Farooq, Koutsis George, Breza Marianthi, Coviello Domenico A., Dauvilliers Yves A., AlKhawaja Issam, AlKhawaja Mariam, Al-Mutairi Fuad, Stojkovic Tanya, Ferrucci Veronica, Zollo Massimo, Alkuraya Fowzan S., Kinali Maria, Sherifa Hamed, Benrhouma Hanene, Turki Ilhem B. Y., Tazir Meriem, Obeid Makram, Bakhtadze Sophia, Saadi Nebal W., Zaki Maha S., Triki Chahnez C., Benfenati Fabio, Gustincich Stefano, Kara Majdi, Belcastro Vincenzo, Specchio Nicola, Capovilla Giuseppe, Karimiani Ehsan G., Salih Ahmed M., Okubadejo Njideka U., Ojo Oluwadamilola O., Oshinaike Olajumoke O., Oguntunde Olapeju, Wahab Kolawole, Bello Abiodun H., Abubakar Sanni, Obiabo Yahaya, Nwazor Ernest, Ekenze Oluchi, Williams Uduak, Iyagba Alagoma, Taiwo Lolade, Komolafe Morenikeji, Senkevich Konstantin, Shashkin Chingiz, Zharkynbekova Nazira, Koneyev Kairgali, Manizha Ganieva, Isrofilov Maksud, Guliyeva Ulviyya, Salayev Kamran, Khachatryan Samson, Rossi Salvatore, Silvestri Gabriella, Haridy Nourelhoda, Ramenghi Luca A., Xiromerisiou Georgia, David Emanuele, Aguennouz Mhammed, Fidani Liana, Spanaki Cleanthe, Tucci Arianna, Salpietro Vincenzo, Dixon Christine L., Guo Hui, Bello Oscar D., Vandrovcova Jana, Efthymiou Stephanie, Maroofian Reza, Heimer Gali, Burglen Lydie, Valence Stephanie, Torti Erin, Hacke Moritz, Rankin Julia, Tariq Huma, Colin Estelle, Procaccio Vincent, Striano Pasquale, Mankad Kshitij, Lieb Andreas, Chen Sharon, Pisani Laura, Bettencourt Conceicao, Mannikko Roope, Manole Andreea, Brusco Alfredo, Grosso Enrico, Ferrero Giovanni Battista, Armstrong-Moron Judith, Gueden Sophie, Bar-Yosef Omer, Tzadok Michal, Monaghan Kristin G., Santiago-Sim Teresa, Person Richard E., Cho Megan T., Willaert Rebecca, Yoo Yongjin, Chae Jong-Hee, Quan Yingting, Wu Huidan, Wang Tianyun, Bernier Raphael A., Xia Kun, Blesson Alyssa, Jain Mahim, Motazacker Mohammad M., Jaeger Bregje, Schneider Amy L., Boysen Katja, Muir Alison M., Myers Candace T., Gavrilova Ralitza H., Gunderson Lauren, Schultz-Rogers Laura, Klee Eric W., Dyment David, Osmond Matthew, Parellada Mara, Llorente Cloe, Gonzalez-Penas Javier, Carracedo Angel, Van Haeringen Arie, Ruivenkamp Claudia, Nava Caroline, Heron Delphine, Nardello Rosaria, Iacomino Michele, Minetti Carlo, Skabar Aldo, Fabretto Antonella, Chez Michael, Tsai Anne, Fassi Emily, Shinawi Marwan, Constantino John N., De Zorzi Rita, Fortuna Sara, Kok Fernando, Keren Boris, Bonneau Dominique, Choi Murim, Benzeev Bruria, Zara Federico, Mefford Heather C., Scheffer Ingrid E., Clayton-Smith Jill, Macaya Alfons, Rothman James E., Eichler Evan E., Kullmann Dimitri M., Houlden Henry, Raspall-Chaure Miquel, Hanna Michael G., Bugiardini Enrico, Hostettler Isabel, O'Callaghan Benjamin, Khan Alaa, Cortese Andrea, O'Connor Emer, Yau Wai Y., Bourinaris Thomas, Kaiyrzhanov Rauan, Chelban Viorica, Madej Monika, Diana Maria C., Vari Maria S., Pedemonte Marina, Bruno Claudio, Balagura Ganna, Scala Marcello, Fiorillo Chiara, Nobili Lino, Malintan Nancy T., Zanetti Maria N., Krishnakumar Shyam S., Lignani Gabriele, Jepson James E. C., Broda Paolo, Baldassari Simona, Rossi Pia, Fruscione Floriana, Madia Francesca, Traverso Monica, De-Marco Patrizia, Perez-Duenas Belen, Munell Francina, Kriouile Yamna, El-Khorassani Mohamed, Karashova Blagovesta, Avdjieva Daniela, Kathom Hadil, Tincheva Radka, Van-Maldergem Lionel, Nachbauer Wolfgang, Boesch Sylvia, Gagliano Antonella, Amadori Elisabetta, Goraya Jatinder S., Sultan Tipu, Kirmani Salman, Ibrahim Shahnaz, Jan Farida, Mine, Jun, Banu Selina, Veggiotti Pierangelo, Zuccotti Gian V, Ferrari Michel D., Van Den Maagdenberg Arn M. J., Verrotti Alberto, Marseglia Gian L., Savasta Salvatore, Soler Miguel A., Scuderi Carmela, Borgione Eugenia, Chimenz Roberto, Gitto Eloisa, Dipasquale Valeria, Sallemi Alessia, Fusco Monica, Cuppari Caterina, Cutrupi Maria C., Ruggieri Martino, Cama Armando, Capra Valeria, Mencacci Niccolo E., Boles Richard, Gupta Neerja, Kabra Madhulika, Papacostas Savvas, Zamba-Papanicolaou Eleni, Dardiotis Efthymios, Maqbool Shazia, Rana Nuzhat, Atawneh Osama, Lim Shen Y., Shaikh Farooq, Koutsis George, Breza Marianthi, Coviello Domenico A., Dauvilliers Yves A., AlKhawaja Issam, AlKhawaja Mariam, Al-Mutairi Fuad, Stojkovic Tanya, Ferrucci Veronica, Zollo Massimo, Alkuraya Fowzan S., Kinali Maria, Sherifa Hamed, Benrhouma Hanene, Turki Ilhem B. Y., Tazir Meriem, Obeid Makram, Bakhtadze Sophia, Saadi Nebal W., Zaki Maha S., Triki Chahnez C., Benfenati Fabio, Gustincich Stefano, Kara Majdi, Belcastro Vincenzo, Specchio Nicola, Capovilla Giuseppe, Karimiani Ehsan G., Salih Ahmed M., Okubadejo Njideka U., Ojo Oluwadamilola O., Oshinaike Olajumoke O., Oguntunde Olapeju, Wahab Kolawole, Bello Abiodun H., Abubakar Sanni, Obiabo Yahaya, Nwazor Ernest, Ekenze Oluchi, Williams Uduak, Iyagba Alagoma, Taiwo Lolade, Komolafe Morenikeji, Senkevich Konstantin, Shashkin Chingiz, Zharkynbekova Nazira, Koneyev Kairgali, Manizha Ganieva, Isrofilov Maksud, Guliyeva Ulviyya, Salayev Kamran, Khachatryan Samson, Rossi Salvatore, Silvestri Gabriella, Haridy Nourelhoda, Ramenghi Luca A., Xiromerisiou Georgia, David Emanuele, Aguennouz Mhammed, Fidani Liana, Spanaki Cleanthe, and Tucci Arianna

Published
2019

21. AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders

Author

Vincenzo, Salpietro, Christine L, Dixon, Hui, Guo, Oscar D, Bello, Jana, Vandrovcova, Stephanie, Efthymiou, Reza, Maroofian, Gali, Heimer, Lydie, Burglen, Stephanie, Valence, Erin, Torti, Moritz, Hacke, Julia, Rankin, Huma, Tariq, Estelle, Colin, Vincent, Procaccio, Pasquale, Striano, Kshitij, Mankad, Andreas, Lieb, Sharon, Chen, Laura, Pisani, Conceicao, Bettencourt, Roope, Männikkö, Andreea, Manole, Alfredo, Brusco, Enrico, Grosso, Giovanni Battista, Ferrero, Judith, Armstrong-Moron, Sophie, Gueden, Omer, Bar-Yosef, Michal, Tzadok, Kristin G, Monaghan, Teresa, Santiago-Sim, Richard E, Person, Megan T, Cho, Rebecca, Willaert, Yongjin, Yoo, Jong-Hee, Chae, Yingting, Quan, Huidan, Wu, Tianyun, Wang, Raphael A, Bernier, Kun, Xia, Alyssa, Blesson, Mahim, Jain, Mohammad M, Motazacker, Bregje, Jaeger, Amy L, Schneider, Katja, Boysen, Alison M, Muir, Candace T, Myer, Ralitza H, Gavrilova, Lauren, Gunderson, Laura, Schultz-Roger, Eric W, Klee, David, Dyment, Matthew, Osmond, Mara, Parellada, Cloe, Llorente, Javier, Gonzalez-Peña, Angel, Carracedo, Arie, Van Haeringen, Claudia, Ruivenkamp, Caroline, Nava, Delphine, Heron, Rosaria, Nardello, Michele, Iacomino, Carlo, Minetti, Aldo, Skabar, Antonella, Fabretto, Hanna, Michael G., Bugiardini, Enrico, Hostettler, Isabel, O’Callaghan, Benjamin, Khan, Alaa, Cortese, Andrea, O’Connor, Emer, Yau, Wai Y., Bourinaris, Thoma, Kaiyrzhanov, Rauan, Chelban, Viorica, Madej, Monika, Diana, Maria C., Vari, Maria S., Pedemonte, Marina, Bruno, Claudio, Balagura, Ganna, Scala, Marcello, Fiorillo, Chiara, Nobili, Lino, Malintan, Nancy T., Zanetti, Maria N., Krishnakumar, Shyam S., Lignani, Gabriele, Jepson, James E. C., Broda, Paolo, Baldassari, Simona, Rossi, Pia, Fruscione, Floriana, Madia, Francesca, Traverso, Monica, De-Marco, Patrizia, Pérez-Dueñas, Belen, Munell, Francina, Kriouile, Yamna, El-Khorassani, Mohamed, Karashova, Blagovesta, Avdjieva, Daniela, Kathom, Hadil, Tincheva, Radka, Van-Maldergem, Lionel, Nachbauer, Wolfgang, Boesch, Sylvia, Gagliano, Antonella, Amadori, Elisabetta, Goraya, Jatinder S., Sultan, Tipu, Kirmani, Salman, Ibrahim, Shahnaz, Jan, Farida, Mine, Jun, Banu, Selina, Veggiotti, Pierangelo, Zuccotti, Gian V., Ferrari, Michel D., Van Den Maagdenberg, Arn M. J., Verrotti, Alberto, Marseglia, Gian L., Savasta, Salvatore, Soler, Miguel A., Scuderi, Carmela, Borgione, Eugenia, Chimenz, Roberto, Gitto, Eloisa, Dipasquale, Valeria, Sallemi, Alessia, Fusco, Monica, Cuppari, Caterina, Cutrupi, Maria C., Ruggieri, Martino, Cama, Armando, Capra, Valeria, Mencacci, Niccolò E., Boles, Richard, Gupta, Neerja, Kabra, Madhulika, Papacostas, Savva, Zamba-Papanicolaou, Eleni, Dardiotis, Efthymio, Maqbool, Shazia, Rana, Nuzhat, Atawneh, Osama, Lim, Shen Y., Shaikh, Farooq, Koutsis, George, Breza, Marianthi, Coviello, Domenico A., Dauvilliers, Yves A., Alkhawaja, Issam, Alkhawaja, Mariam, Al-Mutairi, Fuad, Stojkovic, Tanya, Ferrucci, Veronica, Zollo, Massimo, Alkuraya, Fowzan S., Kinali, Maria, Sherifa, Hamed, Benrhouma, Hanene, Turki, Ilhem B. Y., Tazir, Meriem, Obeid, Makram, Bakhtadze, Sophia, Saadi, Nebal W., Zaki, Maha S., Triki, Chahnez C., Benfenati, Fabio, Gustincich, Stefano, Kara, Majdi, Belcastro, Vincenzo, Specchio, Nicola, Capovilla, Giuseppe, Karimiani, Ehsan G., Salih, Ahmed M., Okubadejo, Njideka U., Ojo, Oluwadamilola O., Oshinaike, Olajumoke O., Oguntunde, Olapeju, Wahab, Kolawole, Bello, Abiodun H., Abubakar, Sanni, Obiabo, Yahaya, Nwazor, Ernest, Ekenze, Oluchi, Williams, Uduak, Iyagba, Alagoma, Taiwo, Lolade, Komolafe, Morenikeji, Senkevich, Konstantin, Shashkin, Chingiz, Zharkynbekova, Nazira, Koneyev, Kairgali, Manizha, Ganieva, Isrofilov, Maksud, Guliyeva, Ulviyya, Salayev, Kamran, Khachatryan, Samson, Rossi, Salvatore, Silvestri, Gabriella, Haridy, Nourelhoda, Ramenghi, Luca A., Xiromerisiou, Georgia, David, Emanuele, Aguennouz, Mhammed, Fidani, Liana, Spanaki &amp, Cleanthe, Tucci, Arianna, Miquel, Raspall-Chaure, Michael, Chez, Anne, Tsai, Emily, Fassi, Marwan, Shinawi, John N, Constantino, Rita, De Zorzi, Sara, Fortuna, Fernando, Kok, Boris, Keren, Dominique, Bonneau, Murim, Choi, Bruria, Benzeev, Federico, Zara, Heather C, Mefford, Ingrid E, Scheffer, Jill, Clayton-Smith, Alfons, Macaya, James E, Rothman, Evan E, Eichler, Dimitri M, Kullmann, Henry, Houlden, Salvatore Rossi, Gabriella Silvestri (ORCID:0000-0002-1950-1468), Vincenzo, Salpietro, Christine L, Dixon, Hui, Guo, Oscar D, Bello, Jana, Vandrovcova, Stephanie, Efthymiou, Reza, Maroofian, Gali, Heimer, Lydie, Burglen, Stephanie, Valence, Erin, Torti, Moritz, Hacke, Julia, Rankin, Huma, Tariq, Estelle, Colin, Vincent, Procaccio, Pasquale, Striano, Kshitij, Mankad, Andreas, Lieb, Sharon, Chen, Laura, Pisani, Conceicao, Bettencourt, Roope, Männikkö, Andreea, Manole, Alfredo, Brusco, Enrico, Grosso, Giovanni Battista, Ferrero, Judith, Armstrong-Moron, Sophie, Gueden, Omer, Bar-Yosef, Michal, Tzadok, Kristin G, Monaghan, Teresa, Santiago-Sim, Richard E, Person, Megan T, Cho, Rebecca, Willaert, Yongjin, Yoo, Jong-Hee, Chae, Yingting, Quan, Huidan, Wu, Tianyun, Wang, Raphael A, Bernier, Kun, Xia, Alyssa, Blesson, Mahim, Jain, Mohammad M, Motazacker, Bregje, Jaeger, Amy L, Schneider, Katja, Boysen, Alison M, Muir, Candace T, Myer, Ralitza H, Gavrilova, Lauren, Gunderson, Laura, Schultz-Roger, Eric W, Klee, David, Dyment, Matthew, Osmond, Mara, Parellada, Cloe, Llorente, Javier, Gonzalez-Peña, Angel, Carracedo, Arie, Van Haeringen, Claudia, Ruivenkamp, Caroline, Nava, Delphine, Heron, Rosaria, Nardello, Michele, Iacomino, Carlo, Minetti, Aldo, Skabar, Antonella, Fabretto, Hanna, Michael G., Bugiardini, Enrico, Hostettler, Isabel, O’Callaghan, Benjamin, Khan, Alaa, Cortese, Andrea, O’Connor, Emer, Yau, Wai Y., Bourinaris, Thoma, Kaiyrzhanov, Rauan, Chelban, Viorica, Madej, Monika, Diana, Maria C., Vari, Maria S., Pedemonte, Marina, Bruno, Claudio, Balagura, Ganna, Scala, Marcello, Fiorillo, Chiara, Nobili, Lino, Malintan, Nancy T., Zanetti, Maria N., Krishnakumar, Shyam S., Lignani, Gabriele, Jepson, James E. C., Broda, Paolo, Baldassari, Simona, Rossi, Pia, Fruscione, Floriana, Madia, Francesca, Traverso, Monica, De-Marco, Patrizia, Pérez-Dueñas, Belen, Munell, Francina, Kriouile, Yamna, El-Khorassani, Mohamed, Karashova, Blagovesta, Avdjieva, Daniela, Kathom, Hadil, Tincheva, Radka, Van-Maldergem, Lionel, Nachbauer, Wolfgang, Boesch, Sylvia, Gagliano, Antonella, Amadori, Elisabetta, Goraya, Jatinder S., Sultan, Tipu, Kirmani, Salman, Ibrahim, Shahnaz, Jan, Farida, Mine, Jun, Banu, Selina, Veggiotti, Pierangelo, Zuccotti, Gian V., Ferrari, Michel D., Van Den Maagdenberg, Arn M. J., Verrotti, Alberto, Marseglia, Gian L., Savasta, Salvatore, Soler, Miguel A., Scuderi, Carmela, Borgione, Eugenia, Chimenz, Roberto, Gitto, Eloisa, Dipasquale, Valeria, Sallemi, Alessia, Fusco, Monica, Cuppari, Caterina, Cutrupi, Maria C., Ruggieri, Martino, Cama, Armando, Capra, Valeria, Mencacci, Niccolò E., Boles, Richard, Gupta, Neerja, Kabra, Madhulika, Papacostas, Savva, Zamba-Papanicolaou, Eleni, Dardiotis, Efthymio, Maqbool, Shazia, Rana, Nuzhat, Atawneh, Osama, Lim, Shen Y., Shaikh, Farooq, Koutsis, George, Breza, Marianthi, Coviello, Domenico A., Dauvilliers, Yves A., Alkhawaja, Issam, Alkhawaja, Mariam, Al-Mutairi, Fuad, Stojkovic, Tanya, Ferrucci, Veronica, Zollo, Massimo, Alkuraya, Fowzan S., Kinali, Maria, Sherifa, Hamed, Benrhouma, Hanene, Turki, Ilhem B. Y., Tazir, Meriem, Obeid, Makram, Bakhtadze, Sophia, Saadi, Nebal W., Zaki, Maha S., Triki, Chahnez C., Benfenati, Fabio, Gustincich, Stefano, Kara, Majdi, Belcastro, Vincenzo, Specchio, Nicola, Capovilla, Giuseppe, Karimiani, Ehsan G., Salih, Ahmed M., Okubadejo, Njideka U., Ojo, Oluwadamilola O., Oshinaike, Olajumoke O., Oguntunde, Olapeju, Wahab, Kolawole, Bello, Abiodun H., Abubakar, Sanni, Obiabo, Yahaya, Nwazor, Ernest, Ekenze, Oluchi, Williams, Uduak, Iyagba, Alagoma, Taiwo, Lolade, Komolafe, Morenikeji, Senkevich, Konstantin, Shashkin, Chingiz, Zharkynbekova, Nazira, Koneyev, Kairgali, Manizha, Ganieva, Isrofilov, Maksud, Guliyeva, Ulviyya, Salayev, Kamran, Khachatryan, Samson, Rossi, Salvatore, Silvestri, Gabriella, Haridy, Nourelhoda, Ramenghi, Luca A., Xiromerisiou, Georgia, David, Emanuele, Aguennouz, Mhammed, Fidani, Liana, Spanaki &amp, Cleanthe, Tucci, Arianna, Miquel, Raspall-Chaure, Michael, Chez, Anne, Tsai, Emily, Fassi, Marwan, Shinawi, John N, Constantino, Rita, De Zorzi, Sara, Fortuna, Fernando, Kok, Boris, Keren, Dominique, Bonneau, Murim, Choi, Bruria, Benzeev, Federico, Zara, Heather C, Mefford, Ingrid E, Scheffer, Jill, Clayton-Smith, Alfons, Macaya, James E, Rothman, Evan E, Eichler, Dimitri M, Kullmann, Henry, Houlden, Salvatore Rossi, and Gabriella Silvestri (ORCID:0000-0002-1950-1468)

Abstract

AMPA receptors (AMPARs) are tetrameric ligand-gated channels made up of combinations of GluA1-4 subunits encoded by GRIA1-4 genes. GluA2 has an especially important role because, following post-transcriptional editing at the Q607 site, it renders heteromultimeric AMPARs Ca2+-impermeable, with a linear relationship between current and trans-membrane voltage. Here, we report heterozygous de novo GRIA2 mutations in 28 unrelated patients with intellectual disability (ID) and neurodevelopmental abnormalities including autism spectrum disorder (ASD), Rett syndrome-like features, and seizures or developmental epileptic encephalopathy (DEE). In functional expression studies, mutations lead to a decrease in agonist-evoked current mediated by mutant subunits compared to wild-type channels. When GluA2 subunits are co-expressed with GluA1, most GRIA2 mutations cause a decreased current amplitude and some also affect voltage rectification. Our results show that de-novo variants in GRIA2 can cause neurodevelopmental disorders, complementing evidence that other genetic causes of ID, ASD and DEE also disrupt glutamatergic synaptic transmission.

Published
2019

22. Biallelic loss of LDB3leads to a lethal pediatric dilated cardiomyopathy

Author

Koopmann, Tamara T., Jamshidi, Yalda, Naghibi-Sistani, Mohammad, van der Klift, Heleen M., Birjandi, Hassan, Al-Hassnan, Zuhair, Alwadai, Abdullah, Zifarelli, Giovanni, Karimiani, Ehsan G., Sedighzadeh, Sahar, Bahreini, Amir, Nouri, Nayereh, Peter, Merlene, Watanabe, Kyoko, van Duyvenvoorde, Hermine A., Ruivenkamp, Claudia A. L., Teunissen, Aalbertine K. K., Ten Harkel, Arend D. J., van Duinen, Sjoerd G., Haak, Monique C., Prada, Carlos E., Santen, Gijs W. E., and Maroofian, Reza

Abstract

Autosomal dominant variants in LDB3(also known as ZASP), encoding the PDZ-LIM domain-binding factor, have been linked to a late onset phenotype of cardiomyopathy and myofibrillar myopathy in humans. However, despite knockout mice displaying a much more severe phenotype with premature death, bi-allelic variants in LDB3have not yet been reported. Here we identify biallelic loss-of-function variants in five unrelated cardiomyopathy families by next-generation sequencing. In the first family, we identified compound heterozygous LOF variants in LDB3in a fetus with bilateral talipes and mild left cardiac ventricular enlargement. Ultra-structural examination revealed highly irregular Z-disc formation, and RNA analysis demonstrated little/no expression of LDB3 protein with a functional C-terminal LIM domain in muscle tissue from the affected fetus. In a second family, a homozygous LDB3nonsense variant was identified in a young girl with severe early-onset dilated cardiomyopathy with left ventricular non-compaction; the same homozygous nonsense variant was identified in a third unrelated female infant with dilated cardiomyopathy. We further identified homozygous LDB3frameshift variants in two unrelated probands diagnosed with cardiomegaly and severely reduced left ventricular ejection fraction. Our findings demonstrate that recessive LDB3variants can lead to an early-onset severe human phenotype of cardiomyopathy and myopathy, reminiscent of the knockout mouse phenotype, and supporting a loss of function mechanism.

Published
2022
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23. Variable skeletal phenotypes associated with biallelic variants in PRKG2

Author

Pagnamenta, Alistair T, Diaz-Gonzalez, Francisca, Banos-Pinero, Benito, Ferla, Matteo P, Toosi, Mehran B, Calder, Alistair D, Karimiani, Ehsan G, Doosti, Mohammad, Wainwright, Andrew, Wordsworth, Paul, Bailey, Kathryn, Ejeska¨r, Katarina, Lester, Tracy, Maroofian, Reza, Heath, Karen E, Tajsharghi, Homa, Shears, Deborah, and Taylor, Jenny C

Published
2022
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24. Loss of symmetric cell division of apical neural progenitors drives DENND5A -related developmental and epileptic encephalopathy.

Author

Banks E, Francis V, Lin SJ, Kharfallah F, Fonov V, Levesque M, Han C, Kulasekaran G, Tuznik M, Bayati A, Al-Khater R, Alkuraya FS, Argyriou L, Babaei M, Bahlo M, Bakhshoodeh B, Barr E, Bartik L, Bassiony M, Bertrand M, Braun D, Buchert R, Budetta M, Cadieux-Dion M, Calame D, Cope H, Cushing D, Efthymiou S, Elmaksoud MA, El Said HG, Froukh T, Gill HK, Gleeson JG, Gogoll L, Goh ES, Gowda VK, Haack TB, Hashem MO, Hauser S, Hoffman TL, Hogue JS, Hosokawa A, Houlden H, Huang K, Huynh S, Karimiani EG, Kaulfuß S, Korenke GC, Kritzer A, Lee H, Lupski JR, Marco EJ, McWalter K, Minassian A, Minassian BA, Murphy D, Neira-Fresneda J, Northrup H, Nyaga D, Oehl-Jaschkowitz B, Osmond M, Person R, Pehlivan D, Petree C, Sadleir LG, Saunders C, Schoels L, Shashi V, Spillman RC, Srinivasan VM, Torbati PN, Tos T, Zaki MS, Zhou D, Zweier C, Trempe JF, Durcan TM, Gan-Or Z, Avoli M, Alves C, Varshney GK, Maroofian R, Rudko DA, and McPherson PS

Abstract

Developmental and epileptic encephalopathies (DEEs) are a heterogenous group of epilepsies in which altered brain development leads to developmental delay and seizures, with the epileptic activity further negatively impacting neurodevelopment. Identifying the underlying cause of DEEs is essential for progress toward precision therapies. Here we describe a group of individuals with biallelic variants in DENND5A and determine that variant type is correlated with disease severity. We demonstrate that DENND5A interacts with MUPP1 and PALS1, components of the Crumbs apical polarity complex, which is required for both neural progenitor cell identity and the ability of these stem cells to divide symmetrically. Induced pluripotent stem cells lacking DENND5A fail to undergo symmetric cell division during neural induction and have an inherent propensity to differentiate into neurons, and transgenic DENND5A mice, with phenotypes like the human syndrome, have an increased number of neurons in the adult subventricular zone. Disruption of symmetric cell division following loss of DENND5A results from misalignment of the mitotic spindle in apical neural progenitors. A subset of DENND5A is localized to centrosomes, which define the spindle poles during mitosis. Cells lacking DENND5A orient away from the proliferative apical domain surrounding the ventricles, biasing daughter cells towards a more fate-committed state and ultimately shortening the period of neurogenesis. This study provides a mechanism behind DENND5A -related DEE that may be generalizable to other developmental conditions and provides variant-specific clinical information for physicians and families., Competing Interests: Competing Interests KM and RP are employed by GeneDx, LLC. All other authors report no conflicts of interest.

Published
2024
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25. Biallelic MADD variants cause a phenotypic spectrum ranging from developmental delay to a multisystem disorder.

Author

Schneeberger PE, Kortüm F, Korenke GC, Alawi M, Santer R, Woidy M, Buhas D, Fox S, Juusola J, Alfadhel M, Webb BD, Coci EG, Abou Jamra R, Siekmeyer M, Biskup S, Heller C, Maier EM, Javaher-Haghighi P, Bedeschi MF, Ajmone PF, Iascone M, Peeters H, Ballon K, Jaeken J, Rodríguez Alonso A, Palomares-Bralo M, Santos-Simarro F, Meuwissen MEC, Beysen D, Kooy RF, Houlden H, Murphy D, Doosti M, Karimiani EG, Mojarrad M, Maroofian R, Noskova L, Kmoch S, Honzik T, Cope H, Sanchez-Valle A, Gelb BD, Kurth I, Hempel M, and Kutsche K

Subjects
Humans, Mutation, Phenotype, Protein Transport genetics, Signal Transduction genetics, Death Domain Receptor Signaling Adaptor Proteins genetics, Developmental Disabilities genetics, Guanine Nucleotide Exchange Factors genetics, Nervous System Diseases genetics
Abstract

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., (© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Published
2020
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