48 results on '"Fatih, Jawid M."'
Search Results
2. Inverted triplications formed by iterative template switches generate structural variant diversity at genomic disorder loci
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Grochowski, Christopher M., Bengtsson, Jesse D., Du, Haowei, Gandhi, Mira, Lun, Ming Yin, Mehaffey, Michele G., Park, KyungHee, Höps, Wolfram, Benito, Eva, Hasenfeld, Patrick, Korbel, Jan O., Mahmoud, Medhat, Paulin, Luis F., Jhangiani, Shalini N., Hwang, James Paul, Bhamidipati, Sravya V., Muzny, Donna M., Fatih, Jawid M., Gibbs, Richard A., Pendleton, Matthew, Harrington, Eoghan, Juul, Sissel, Lindstrand, Anna, Sedlazeck, Fritz J., Pehlivan, Davut, Lupski, James R., and Carvalho, Claudia M.B.
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- 2024
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3. Monoallelic variation in DHX9, the gene encoding the DExH-box helicase DHX9, underlies neurodevelopment disorders and Charcot-Marie-Tooth disease
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Calame, Daniel G., Guo, Tianyu, Wang, Chen, Garrett, Lillian, Jolly, Angad, Dawood, Moez, Kurolap, Alina, Henig, Noa Zunz, Fatih, Jawid M., Herman, Isabella, Du, Haowei, Mitani, Tadahiro, Becker, Lore, Rathkolb, Birgit, Gerlini, Raffaele, Seisenberger, Claudia, Marschall, Susan, Hunter, Jill V., Gerard, Amanda, Heidlebaugh, Alexis, Challman, Thomas, Spillmann, Rebecca C., Jhangiani, Shalini N., Coban-Akdemir, Zeynep, Lalani, Seema, Liu, Lingxiao, Revah-Politi, Anya, Iglesias, Alejandro, Guzman, Edwin, Baugh, Evan, Boddaert, Nathalie, Rondeau, Sophie, Ormieres, Clothide, Barcia, Giulia, Tan, Queenie K.G., Thiffault, Isabelle, Pastinen, Tomi, Sheikh, Kazim, Biliciler, Suur, Mei, Davide, Melani, Federico, Shashi, Vandana, Yaron, Yuval, Steele, Mary, Wakeling, Emma, Østergaard, Elsebet, Nazaryan-Petersen, Lusine, Millan, Francisca, Santiago-Sim, Teresa, Thevenon, Julien, Bruel, Ange-Line, Thauvin-Robinet, Christel, Popp, Denny, Platzer, Konrad, Gawlinski, Pawel, Wiszniewski, Wojciech, Marafi, Dana, Pehlivan, Davut, Posey, Jennifer E., Gibbs, Richard A., Gailus-Durner, Valerie, Guerrini, Renzo, Fuchs, Helmut, Hrabě de Angelis, Martin, Hölter, Sabine M., Cheung, Hoi-Hung, Gu, Shen, and Lupski, James R.
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- 2023
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4. Rare variant enrichment analysis supports GREB1L as a contributory driver gene in the etiology of Mayer-Rokitansky-Küster-Hauser syndrome
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Jolly, Angad, Du, Haowei, Borel, Christelle, Chen, Na, Zhao, Sen, Grochowski, Christopher M., Duan, Ruizhi, Fatih, Jawid M., Dawood, Moez, Salvi, Sejal, Jhangiani, Shalini N., Muzny, Donna M., Koch, André, Rouskas, Konstantinos, Glentis, Stavros, Deligeoroglou, Efthymios, Bacopoulou, Flora, Wise, Carol A., Dietrich, Jennifer E., Van den Veyver, Ignatia B., Dimas, Antigone S., Brucker, Sara, Sutton, V. Reid, Gibbs, Richard A., Antonarakis, Stylianos E., Wu, Nan, Coban-Akdemir, Zeynep H., Zhu, Lan, Posey, Jennifer E., and Lupski, James R.
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- 2023
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5. The multiple de novo copy number variant (MdnCNV) phenomenon presents with peri-zygotic DNA mutational signatures and multilocus pathogenic variation
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Du, Haowei, Jolly, Angad, Grochowski, Christopher M., Yuan, Bo, Dawood, Moez, Jhangiani, Shalini N., Li, He, Muzny, Donna, Fatih, Jawid M., Coban-Akdemir, Zeynep, Carlin, Mary Esther, Scheuerle, Angela E., Witzl, Karin, Posey, Jennifer E., Pendleton, Matthew, Harrington, Eoghan, Juul, Sissel, Hastings, P. J., Bi, Weimin, Gibbs, Richard A., Sedlazeck, Fritz J., Lupski, James R., Carvalho, Claudia M. B., and Liu, Pengfei
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- 2022
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6. Biallelic loss-of-function variants in the splicing regulator NSRP1 cause a severe neurodevelopmental disorder with spastic cerebral palsy and epilepsy
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Calame, Daniel G., Bakhtiari, Somayeh, Logan, Rachel, Coban-Akdemir, Zeynep, Du, Haowei, Mitani, Tadahiro, Fatih, Jawid M., Hunter, Jill V., Herman, Isabella, Pehlivan, Davut, Jhangiani, Shalini N., Person, Richard, Schnur, Rhonda E., Jin, Sheng Chih, Bilguvar, Kaya, Posey, Jennifer E., Koh, Sookyong, Firouzabadi, Saghar G., Alehabib, Elham, Tafakhori, Abbas, Esmkhani, Sahra, Gibbs, Richard A., Noureldeen, Mahmoud M., Zaki, Maha S., Marafi, Dana, Darvish, Hossein, Kruer, Michael C., and Lupski, James R.
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- 2021
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7. Biallelic variation in the choline and ethanolamine transporter FLVCR1 underlies a pleiotropic disease spectrum from adult neurodegeneration to severe developmental disorders
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Calame, Daniel G, primary, Wong, Jovi Huixin, additional, Panda, Puravi, additional, Nguyen, Dat Tuan, additional, Leong, Nancy C.P., additional, Sangermano, Riccardo, additional, Patankar, Sohil G, additional, AlAbdi, Lama, additional, Safwat, Sylvia, additional, Flannery, Kyle, additional, Dardas, Zain, additional, Fatih, Jawid M, additional, Murali, Chaya, additional, Kannan, Varun, additional, Lotze, Timothy E, additional, Herman, Isabella, additional, Ammouri, Farrah, additional, Rezich, Brianna, additional, Efthymiou, Stephanie, additional, Alavi, Shahryar, additional, Murphy, David, additional, Firoozfar, Zahra, additional, Nasab, Mahya Ebrahimi, additional, Bahreini, Amir, additional, Ghasemi, Majid, additional, Haridy, Nourelhoda A, additional, Goldouzi, Hamid Reza, additional, Eghbal, Fatemeh, additional, Karimiani, Ehsan Ghayoor, additional, Srinivasan, Varunvenkat M, additional, Gowda, Vykuntaraju K, additional, Du, Haowei, additional, Jhangiani, Shalini N, additional, Coban-Akdemir, Zeynep, additional, Marafi, Dana, additional, Rodan, Lance, additional, Isikay, Sedat, additional, Rosenfeld, Jill A, additional, Ramanathan, Subhadra, additional, Staton, Michael, additional, Oberg, Kerby C, additional, Clark, Robin D, additional, Wenman, Catharina, additional, Loughlin, Sam, additional, Saad, Ramy, additional, Ashraf, Tazeen, additional, Male, Alison, additional, Tadros, Shereen, additional, Boostani, Reza, additional, Abdel-Salam, Ghada H.M., additional, Zaki, Maha, additional, Abdalla, Ebtesam, additional, Manzini, M Chiara, additional, Pehlivan, Davut, additional, Posey, Jennifer E, additional, Gibbs, Richard A, additional, Houlden, Henry, additional, Alkuraya, Fowzan S, additional, Bujakowska, Kinga, additional, Maroofian, Reza, additional, Lupski, James R, additional, and Nguyen, Long Nam, additional
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- 2024
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8. Biallelic and monoallelic variants in PLXNA1 are implicated in a novel neurodevelopmental disorder with variable cerebral and eye anomalies
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Dworschak, Gabriel C., Punetha, Jaya, Kalanithy, Jeshurun C., Mingardo, Enrico, Erdem, Haktan B., Akdemir, Zeynep C., Karaca, Ender, Mitani, Tadahiro, Marafi, Dana, Fatih, Jawid M., Jhangiani, Shalini N., Hunter, Jill V., Dakal, Tikam Chand, Dhabhai, Bhanupriya, Dabbagh, Omar, Alsaif, Hessa S., Alkuraya, Fowzan S., Maroofian, Reza, Houlden, Henry, Efthymiou, Stephanie, Dominik, Natalia, Salpietro, Vincenzo, Sultan, Tipu, Haider, Shahzad, Bibi, Farah, Thiele, Holger, Hoefele, Julia, Riedhammer, Korbinian M., Wagner, Matias, Guella, Ilaria, Demos, Michelle, Keren, Boris, Buratti, Julien, Charles, Perrine, Nava, Caroline, Héron, Delphine, Heide, Solveig, Valkanas, Elise, Waddell, Leigh B., Jones, Kristi J., Oates, Emily C., Cooper, Sandra T., MacArthur, Daniel, Syrbe, Steffen, Ziegler, Andreas, Platzer, Konrad, Okur, Volkan, Chung, Wendy K., O’Shea, Sarah A., Alcalay, Roy, Fahn, Stanley, Mark, Paul R., Guerrini, Renzo, Vetro, Annalisa, Hudson, Beth, Schnur, Rhonda E., Hoganson, George E., Burton, Jennifer E., McEntagart, Meriel, Lindenberg, Tobias, Yilmaz, Öznur, Odermatt, Benjamin, Pehlivan, Davut, Posey, Jennifer E., Lupski, James R., and Reutter, Heiko
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- 2021
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9. High prevalence of multilocus pathogenic variation in neurodevelopmental disorders in the Turkish population
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Mitani, Tadahiro, Isikay, Sedat, Gezdirici, Alper, Gulec, Elif Yilmaz, Punetha, Jaya, Fatih, Jawid M., Herman, Isabella, Akay, Gulsen, Du, Haowei, Calame, Daniel G., Ayaz, Akif, Tos, Tulay, Yesil, Gozde, Aydin, Hatip, Geckinli, Bilgen, Elcioglu, Nursel, Candan, Sukru, Sezer, Ozlem, Erdem, Haktan Bagis, Gul, Davut, Demiral, Emine, Elmas, Muhsin, Yesilbas, Osman, Kilic, Betul, Gungor, Serdal, Ceylan, Ahmet C., Bozdogan, Sevcan, Ozalp, Ozge, Cicek, Salih, Aslan, Huseyin, Yalcintepe, Sinem, Topcu, Vehap, Bayram, Yavuz, Grochowski, Christopher M., Jolly, Angad, Dawood, Moez, Duan, Ruizhi, Jhangiani, Shalini N., Doddapaneni, Harsha, Hu, Jianhong, Muzny, Donna M., Marafi, Dana, Akdemir, Zeynep Coban, Karaca, Ender, Carvalho, Claudia M.B., Gibbs, Richard A., Posey, Jennifer E., Lupski, James R., and Pehlivan, Davut
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- 2021
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10. HMZDupFinder: a robust computational approach for detecting intragenic homozygous duplications from exome sequencing data
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Du, Haowei, primary, Dardas, Zain, additional, Jolly, Angad, additional, Grochowski, Christopher M, additional, Jhangiani, Shalini N, additional, Li, He, additional, Muzny, Donna, additional, Fatih, Jawid M, additional, Yesil, Gozde, additional, Elçioglu, Nursel H, additional, Gezdirici, Alper, additional, Marafi, Dana, additional, Pehlivan, Davut, additional, Calame, Daniel G, additional, Carvalho, Claudia M B, additional, Posey, Jennifer E, additional, Gambin, Tomasz, additional, Coban-Akdemir, Zeynep, additional, and Lupski, James R, additional
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- 2023
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11. Break-induced replication underlies formation of inverted triplications and generates unexpected diversity in haplotype structures
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Grochowski, Christopher M., primary, Bengtsson, Jesse D., additional, Du, Haowei, additional, Gandhi, Mira, additional, Lun, Ming Yin, additional, Mehaffey, Michele G., additional, Park, KyungHee, additional, Höps, Wolfram, additional, Benito-Garagorri, Eva, additional, Hasenfeld, Patrick, additional, Korbel, Jan O., additional, Mahmoud, Medhat, additional, Paulin, Luis F., additional, Jhangiani, Shalini N., additional, Muzny, Donna M., additional, Fatih, Jawid M., additional, Gibbs, Richard A., additional, Pendleton, Matthew, additional, Harrington, Eoghan, additional, Juul, Sissel, additional, Lindstrand, Anna, additional, Sedlazeck, Fritz J., additional, Pehlivan, Davut, additional, Lupski, James R., additional, and Carvalho, Claudia M.B., additional
- Published
- 2023
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12. Biallelic missense variants in COG3 cause a congenital disorder of glycosylation with impairment of retrograde vesicular trafficking
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Duan, Ruizhi, primary, Marafi, Dana, additional, Xia, Zhi‐Jie, additional, Ng, Bobby G., additional, Maroofian, Reza, additional, Sumya, Farhana Taher, additional, Saad, Ahmed K., additional, Du, Haowei, additional, Fatih, Jawid M., additional, Hunter, Jill V., additional, Elbendary, Hasnaa M., additional, Baig, Shahid M., additional, Abdullah, Uzma, additional, Ali, Zafar, additional, Efthymiou, Stephanie, additional, Murphy, David, additional, Mitani, Tadahiro, additional, Withers, Marjorie A., additional, Jhangiani, Shalini N., additional, Coban‐Akdemir, Zeynep, additional, Calame, Daniel G., additional, Pehlivan, Davut, additional, Gibbs, Richard A., additional, Posey, Jennifer E., additional, Houlden, Henry, additional, Lupashin, Vladimir V., additional, Zaki, Maha S., additional, Freeze, Hudson H., additional, and Lupski, James R., additional
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- 2023
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13. A biallelic frameshift indel in PPP1R35 as a cause of primary microcephaly
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Dawood, Moez, primary, Akay, Gulsen, additional, Mitani, Tadahiro, additional, Marafi, Dana, additional, Fatih, Jawid M., additional, Gezdirici, Alper, additional, Najmabadi, Hossein, additional, Kahrizi, Kimia, additional, Punetha, Jaya, additional, Grochowski, Christopher M., additional, Du, Haowei, additional, Jolly, Angad, additional, Li, He, additional, Coban‐Akdemir, Zeynep, additional, Sedlazeck, Fritz J., additional, Hunter, Jill V., additional, Jhangiani, Shalini N., additional, Muzny, Donna, additional, Pehlivan, Davut, additional, Posey, Jennifer E., additional, Carvalho, Claudia M. B., additional, Gibbs, Richard A., additional, and Lupski, James R., additional
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- 2023
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14. TCEAL1 loss-of-function results in an X-linked dominant neurodevelopmental syndrome and drives the neurological disease trait in Xq22.2 deletions
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Hijazi, Hadia, primary, Reis, Linda M., additional, Pehlivan, Davut, additional, Bernstein, Jonathan A., additional, Muriello, Michael, additional, Syverson, Erin, additional, Bonner, Devon, additional, Estiar, Mehrdad A., additional, Gan-Or, Ziv, additional, Rouleau, Guy A., additional, Lyulcheva, Ekaterina, additional, Greenhalgh, Lynn, additional, Tessarech, Marine, additional, Colin, Estelle, additional, Guichet, Agnès, additional, Bonneau, Dominique, additional, van Jaarsveld, R.H., additional, Lachmeijer, A.M.A., additional, Ruaud, Lyse, additional, Levy, Jonathan, additional, Tabet, Anne-Claude, additional, Ploski, Rafal, additional, Rydzanicz, Małgorzata, additional, Kępczyński, Łukasz, additional, Połatyńska, Katarzyna, additional, Li, Yidan, additional, Fatih, Jawid M., additional, Marafi, Dana, additional, Rosenfeld, Jill A., additional, Coban-Akdemir, Zeynep, additional, Bi, Weimin, additional, Gibbs, Richard A., additional, Hobson, Grace M., additional, Hunter, Jill V., additional, Carvalho, Claudia M.B., additional, Posey, Jennifer E., additional, Semina, Elena V., additional, and Lupski, James R., additional
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- 2022
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15. Developmental genomics of limb malformations: Allelic series in association with gene dosage effects contribute to the clinical variability
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Duan, Ruizhi, primary, Hijazi, Hadia, additional, Gulec, Elif Yilmaz, additional, Eker, Hatice Koçak, additional, Costa, Silvia R., additional, Sahin, Yavuz, additional, Ocak, Zeynep, additional, Isikay, Sedat, additional, Ozalp, Ozge, additional, Bozdogan, Sevcan, additional, Aslan, Huseyin, additional, Elcioglu, Nursel, additional, Bertola, Débora R., additional, Gezdirici, Alper, additional, Du, Haowei, additional, Fatih, Jawid M., additional, Grochowski, Christopher M., additional, Akay, Gulsen, additional, Jhangiani, Shalini N., additional, Karaca, Ender, additional, Gu, Shen, additional, Coban-Akdemir, Zeynep, additional, Posey, Jennifer E., additional, Bayram, Yavuz, additional, Sutton, V. Reid, additional, Carvalho, Claudia M.B., additional, Pehlivan, Davut, additional, Gibbs, Richard A., additional, and Lupski, James R., additional
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- 2022
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16. A reverse genetics and genomics approach to gene paralog function and disease: Myokymia and the juxtaparanode
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Marafi, Dana, primary, Kozar, Nina, additional, Duan, Ruizhi, additional, Bradley, Stephen, additional, Yokochi, Kenji, additional, Al Mutairi, Fuad, additional, Saadi, Nebal Waill, additional, Whalen, Sandra, additional, Brunet, Theresa, additional, Kotzaeridou, Urania, additional, Choukair, Daniela, additional, Keren, Boris, additional, Nava, Caroline, additional, Kato, Mitsuhiro, additional, Arai, Hiroshi, additional, Froukh, Tawfiq, additional, Faqeih, Eissa Ali, additional, AlAsmari, Ali M., additional, Saleh, Mohammed M., additional, Pinto e Vairo, Filippo, additional, Pichurin, Pavel N., additional, Klee, Eric W., additional, Schmitz, Christopher T., additional, Grochowski, Christopher M., additional, Mitani, Tadahiro, additional, Herman, Isabella, additional, Calame, Daniel G., additional, Fatih, Jawid M., additional, Du, Haowei, additional, Coban-Akdemir, Zeynep, additional, Pehlivan, Davut, additional, Jhangiani, Shalini N., additional, Gibbs, Richard A., additional, Miyatake, Satoko, additional, Matsumoto, Naomichi, additional, Wagstaff, Laura J., additional, Posey, Jennifer E., additional, Lupski, James R., additional, Meijer, Dies, additional, and Wagner, Matias, additional
- Published
- 2022
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17. Biallelic Variants in the Ectonucleotidase ENTPD1 Cause a Complex Neurodevelopmental Disorder with Intellectual Disability, Distinct White Matter Abnormalities, and Spastic Paraplegia
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Calame, Daniel G., primary, Herman, Isabella, additional, Maroofian, Reza, additional, Marshall, Aren E., additional, Donis, Karina Carvalho, additional, Fatih, Jawid M., additional, Mitani, Tadahiro, additional, Du, Haowei, additional, Grochowski, Christopher M., additional, Sousa, Sergio B., additional, Gijavanekar, Charul, additional, Bakhtiari, Somayeh, additional, Ito, Yoko A., additional, Rocca, Clarissa, additional, Hunter, Jill V., additional, Sutton, V. Reid, additional, Emrick, Lisa T., additional, Boycott, Kym M., additional, Lossos, Alexander, additional, Fellig, Yakov, additional, Prus, Eugenia, additional, Kalish, Yosef, additional, Meiner, Vardiella, additional, Suerink, Manon, additional, Ruivenkamp, Claudia, additional, Muirhead, Kayla, additional, Saadi, Nebal W., additional, Zaki, Maha S., additional, Bouman, Arjan, additional, Barakat, Tahsin Stefan, additional, Skidmore, David L., additional, Osmond, Matthew, additional, Silva, Thiago Oliveira, additional, Murphy, David, additional, Karimiani, Ehsan Ghayoor, additional, Jamshidi, Yalda, additional, Jaddoa, Asaad Ghanim, additional, Tajsharghi, Homa, additional, Jin, Sheng Chih, additional, Abbaszadegan, Mohammad Reza, additional, Ebrahimzadeh‐Vesal, Reza, additional, Hosseini, Susan, additional, Alavi, Shahryar, additional, Bahreini, Amir, additional, Zarean, Elahe, additional, Salehi, Mohammad Mehdi, additional, Al‐Sannaa, Nouriya Abbas, additional, Zifarelli, Giovanni, additional, Bauer, Peter, additional, Robson, Simon C., additional, Coban‐Akdemir, Zeynep, additional, Travaglini, Lorena, additional, Nicita, Francesco, additional, Jhangiani, Shalini N., additional, Gibbs, Richard A., additional, Posey, Jennifer E., additional, Kruer, Michael C., additional, Kernohan, Kristin D., additional, Morales Saute, Jonas A., additional, Houlden, Henry, additional, Vanderver, Adeline, additional, Elsea, Sarah H., additional, Pehlivan, Davut, additional, Marafi, Dana, additional, and Lupski, James R., additional
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- 2022
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18. Additional file 1 of The multiple de novo copy number variant (MdnCNV) phenomenon presents with peri-zygotic DNA mutational signatures and multilocus pathogenic variation
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Du, Haowei, Jolly, Angad, Grochowski, Christopher M., Yuan, Bo, Dawood, Moez, Jhangiani, Shalini N., Li, He, Muzny, Donna, Fatih, Jawid M., Coban-Akdemir, Zeynep, Carlin, Mary Esther, Scheuerle, Angela E., Witzl, Karin, Posey, Jennifer E., Pendleton, Matthew, Harrington, Eoghan, Juul, Sissel, Hastings, P. J., Bi, Weimin, Gibbs, Richard A., Sedlazeck, Fritz J., Lupski, James R., Carvalho, Claudia M. B., and Liu, Pengfei
- Abstract
Additional file 1. Supplementary methods, clinical description of BAB9637, BAB3097, and BAB9484, Table S1, S3, S5, S6, Figure S1-S9.
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- 2022
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19. Novel RETREG1 (FAM134B)founder allele is linked to HSAN2B and renal disease in a Turkish family
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Taşdelen, Elifcan, primary, Calame, Daniel G., additional, Akay, Gulsen, additional, Mitani, Tadahiro, additional, Fatih, Jawid M., additional, Herman, Isabella, additional, Du, Haowei, additional, Coban‐Akdemir, Zeynep, additional, Marafi, Dana, additional, Jhangiani, Shalini N., additional, Posey, Jennifer E., additional, Gibbs, Richard A., additional, Altıparmak, Taylan, additional, Kutlay, Nüket Yürür, additional, Lupski, James R., additional, and Pehlivan, Davut, additional
- Published
- 2022
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20. Niacin therapy improves outcome and normalizes metabolic abnormalities in an NAXD-deficient patient
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Manor, Joshua, primary, Calame, Daniel G., additional, Gijavanekar, Charul, additional, Tran, Alyssa, additional, Fatih, Jawid M., additional, Lalani, Seema R., additional, Mizerik, Elizabeth, additional, Parnes, Mered, additional, Mehta, Vidya P., additional, Adesina, Adekunle M., additional, Lupski, James R., additional, Scaglia, Fernando, additional, and Elsea, Sarah H., additional
- Published
- 2022
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21. Quantitative dissection of multilocus pathogenic variation in an Egyptian infant with severe neurodevelopmental disorder resulting from multiple molecular diagnoses
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Herman, Isabella, primary, Jolly, Angad, additional, Du, Haowei, additional, Dawood, Moez, additional, Abdel‐Salam, Ghada M. H., additional, Marafi, Dana, additional, Mitani, Tadahiro, additional, Calame, Daniel G., additional, Coban‐Akdemir, Zeynep, additional, Fatih, Jawid M., additional, Hegazy, Ibrahim, additional, Jhangiani, Shalini N., additional, Gibbs, Richard A., additional, Pehlivan, Davut, additional, Posey, Jennifer E., additional, and Lupski, James R., additional
- Published
- 2021
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22. Biallelic variants in SLC38A3 encoding a glutamine transporter cause epileptic encephalopathy
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Marafi, Dana, primary, Fatih, Jawid M, additional, Kaiyrzhanov, Rauan, additional, Ferla, Matteo P, additional, Gijavanekar, Charul, additional, Al-Maraghi, Aljazi, additional, Liu, Ning, additional, Sites, Emily, additional, Alsaif, Hessa S, additional, Al-Owain, Mohammad, additional, Zakkariah, Mohamed, additional, El-Anany, Ehab, additional, Guliyeva, Ulviyya, additional, Guliyeva, Sughra, additional, Gaba, Colette, additional, Haseeb, Ateeq, additional, Alhashem, Amal M, additional, Danish, Enam, additional, Karageorgou, Vasiliki, additional, Beetz, Christian, additional, Subhi, Alaa A, additional, Mullegama, Sureni V, additional, Torti, Erin, additional, Sebastin, Monisha, additional, Breilyn, Margo Sheck, additional, Duberstein, Susan, additional, Abdel-Hamid, Mohamed S, additional, Mitani, Tadahiro, additional, Du, Haowei, additional, Rosenfeld, Jill A, additional, Jhangiani, Shalini N, additional, Coban Akdemir, Zeynep, additional, Gibbs, Richard A, additional, Taylor, Jenny C, additional, Fakhro, Khalid A, additional, Hunter, Jill V, additional, Pehlivan, Davut, additional, Zaki, Maha S, additional, Gleeson, Joseph G, additional, Maroofian, Reza, additional, Houlden, Henry, additional, Posey, Jennifer E, additional, Sutton, V Reid, additional, Alkuraya, Fowzan S, additional, Elsea, Sarah H, additional, and Lupski, James R, additional
- Published
- 2021
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23. Deep clinicopathological phenotyping identifies a previously unrecognized pathogenic EMD splice variant
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Calame, Daniel G., primary, Fatih, Jawid M., additional, Herman, Isabella, additional, Coban‐Akdemir, Zeynep, additional, Du, Haowei, additional, Mitani, Tadahiro, additional, Jhangiani, Shalini N., additional, Marafi, Dana, additional, Gibbs, Richard A., additional, Posey, Jennifer E., additional, Mehta, Vidya P., additional, Mohila, Carrie A., additional, Abid, Farida, additional, Lotze, Timothy E., additional, Pehlivan, Davut, additional, Adesina, Adekunle M., additional, and Lupski, James R., additional
- Published
- 2021
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24. Novel RETREG1 (FAM134B) founder allele is linked to HSAN2B and renal disease in a Turkish family.
- Author
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Taşdelen, Elifcan, Calame, Daniel G., Akay, Gulsen, Mitani, Tadahiro, Fatih, Jawid M., Herman, Isabella, Du, Haowei, Coban‐Akdemir, Zeynep, Marafi, Dana, Jhangiani, Shalini N., Posey, Jennifer E., Gibbs, Richard A., Altıparmak, Taylan, Kutlay, Nüket Yürür, Lupski, James R., and Pehlivan, Davut
- Abstract
Hereditary sensory and autonomic neuropathy type 2B (HSAN2B) is a rare autosomal recessive peripheral neuropathy caused by biallelic variants in RETREG1 (formerly FAM134B). HSAN2B is characterized by sensory impairment resulting in skin ulcerations, amputations, and osteomyelitis as well as variable weakness, spasticity, and autonomic dysfunction. Here, we report four affected individuals with recurrent osteomyelitis, ulceration, and amputation of hands and feet, sensory neuropathy, hyperhidrosis, urinary incontinence, and renal failure from a family without any known shared parental ancestry. Due to the history of chronic recurrent multifocal osteomyelitis and microcytic anemia, a diagnosis of Majeed syndrome was considered; however, sequencing of LPIN2 was negative. Family‐based exome sequencing (ES) revealed a novel homozygous ultrarare RETREG1 variant NM_001034850.2:c.321G>A;p.Trp107Ter. Electrophysiological studies of the proband demonstrated axonal sensorimotor neuropathy predominantly in the lower extremities. Consistent with the lack of shared ancestry, the coefficient of inbreeding calculated from ES data was low (F = 0.002), but absence of heterozygosity (AOH) analysis demonstrated a 7.2 Mb AOH block surrounding the variant consistent with a founder allele. Two of the four affected individuals had unexplained renal failure which has not been reported in HSAN2B cases to date. Therefore, this report describes a novel RETREG1 founder allele and suggests renal failure may be an unrecognized feature of the RETREG1‐disease spectrum. [ABSTRACT FROM AUTHOR]
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- 2022
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25. Risk of sudden cardiac death in EXOSC5‐related disease
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Calame, Daniel G., primary, Herman, Isabella, additional, Fatih, Jawid M., additional, Du, Haowei, additional, Akay, Gulsen, additional, Jhangiani, Shalini N., additional, Coban‐Akdemir, Zeynep, additional, Milewicz, Dianna M., additional, Gibbs, Richard A., additional, Posey, Jennifer E., additional, Marafi, Dana, additional, Hunter, Jill V., additional, Fan, Yuxin, additional, Lupski, James R., additional, and Miyake, Christina Y., additional
- Published
- 2021
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26. A novel homozygousSLC13A5whole‐gene deletion generated byAlu/Alu‐mediated rearrangement in an Iraqi family with epileptic encephalopathy
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Duan, Ruizhi, primary, Saadi, Nebal Waill, additional, Grochowski, Christopher M., additional, Bhadila, Ghalia, additional, Faridoun, Afnan, additional, Mitani, Tadahiro, additional, Du, Haowei, additional, Fatih, Jawid M., additional, Jhangiani, Shalini N., additional, Akdemir, Zeynep C., additional, Gibbs, Richard A., additional, Pehlivan, Davut, additional, Posey, Jennifer E., additional, Marafi, Dana, additional, and Lupski, James R., additional
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- 2021
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27. Biallelic variants in SLC38A3 encoding a glutamine transporter cause epileptic encephalopathy.
- Author
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Marafi, Dana, Fatih, Jawid M, Kaiyrzhanov, Rauan, Ferla, Matteo P, Gijavanekar, Charul, Al-Maraghi, Aljazi, Liu, Ning, Sites, Emily, Alsaif, Hessa S, Al-Owain, Mohammad, Zakkariah, Mohamed, El-Anany, Ehab, Guliyeva, Ulviyya, Guliyeva, Sughra, Gaba, Colette, Haseeb, Ateeq, Alhashem, Amal M, Danish, Enam, Karageorgou, Vasiliki, and Beetz, Christian
- Abstract
The solute carrier (SLC) superfamily encompasses >400 transmembrane transporters involved in the exchange of amino acids, nutrients, ions, metals, neurotransmitters and metabolites across biological membranes. SLCs are highly expressed in the mammalian brain; defects in nearly 100 unique SLC-encoding genes (OMIM: https://www.omim.org) are associated with rare Mendelian disorders including developmental and epileptic encephalopathy and severe neurodevelopmental disorders. Exome sequencing and family-based rare variant analyses on a cohort with neurodevelopmental disorders identified two siblings with developmental and epileptic encephalopathy and a shared deleterious homozygous splicing variant in SLC38A3. The gene encodes SNAT3, a sodium-coupled neutral amino acid transporter and a principal transporter of the amino acids asparagine, histidine, and glutamine, the latter being the precursor for the neurotransmitters GABA and glutamate. Additional subjects with a similar developmental and epileptic encephalopathy phenotype and biallelic predicted-damaging SLC38A3 variants were ascertained through GeneMatcher and collaborations with research and clinical molecular diagnostic laboratories. Untargeted metabolomic analysis was performed to identify novel metabolic biomarkers. Ten individuals from seven unrelated families from six different countries with deleterious biallelic variants in SLC38A3 were identified. Global developmental delay, intellectual disability, hypotonia, and absent speech were common features while microcephaly, epilepsy, and visual impairment were present in the majority. Epilepsy was drug-resistant in half. Metabolomic analysis revealed perturbations of glutamate, histidine, and nitrogen metabolism in plasma, urine, and CSF of selected subjects, potentially representing biomarkers of disease. Our data support the contention that SLC38A3 is a novel disease gene for developmental and epileptic encephalopathy and illuminate the likely pathophysiology of the disease as perturbations in glutamine homeostasis. [ABSTRACT FROM AUTHOR]
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- 2022
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28. Quantitative dissection of multilocus pathogenic variation in an Egyptian infant with severe neurodevelopmental disorder resulting from multiple molecular diagnoses.
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Herman, Isabella, Jolly, Angad, Du, Haowei, Dawood, Moez, Abdel‐Salam, Ghada M. H., Marafi, Dana, Mitani, Tadahiro, Calame, Daniel G., Coban‐Akdemir, Zeynep, Fatih, Jawid M., Hegazy, Ibrahim, Jhangiani, Shalini N., Gibbs, Richard A., Pehlivan, Davut, Posey, Jennifer E., and Lupski, James R.
- Abstract
Genomic sequencing and clinical genomics have demonstrated that substantial subsets of atypical and/or severe disease presentations result from multilocus pathogenic variation (MPV) causing blended phenotypes. In an infant with a severe neurodevelopmental disorder, four distinct molecular diagnoses were found by exome sequencing (ES). The blended phenotype that includes brain malformation, dysmorphism, and hypotonia was dissected using the Human Phenotype Ontology (HPO). ES revealed variants in CAPN3 (c.259C > G:p.L87V), MUSK (c.1781C > T:p.A594V), NAV2 (c.1996G > A:p.G666R), and ZC4H2 (c.595A > C:p.N199H). CAPN3, MUSK, and ZC4H2 are established disease genes linked to limb‐girdle muscular dystrophy (OMIM# 253600), congenital myasthenia (OMIM# 616325), and Wieacker–Wolff syndrome (WWS; OMIM# 314580), respectively. NAV2 is a retinoic‐acid responsive novel disease gene candidate with biological roles in neurite outgrowth and cerebellar dysgenesis in mouse models. Using semantic similarity, we show that no gene identified by ES individually explains the proband phenotype, but rather the totality of the clinically observed disease is explained by the combination of disease‐contributing effects of the identified genes. These data reveal that multilocus pathogenic variation can result in a blended phenotype with each gene affecting a different part of the nervous system and nervous system‐muscle connection. We provide evidence from this n = 1 study that in patients with MPV and complex blended phenotypes resulting from multiple molecular diagnoses, quantitative HPO analysis can allow for dissection of phenotypic contribution of both established disease genes and novel disease gene candidates not yet proven to cause human disease. [ABSTRACT FROM AUTHOR]
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- 2022
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29. BiallelicGRM7variants cause epilepsy, microcephaly, and cerebral atrophy
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Marafi, Dana, primary, Mitani, Tadahiro, additional, Isikay, Sedat, additional, Hertecant, Jozef, additional, Almannai, Mohammed, additional, Manickam, Kandamurugu, additional, Abou Jamra, Rami, additional, El‐Hattab, Ayman W., additional, Rajah, Jaishen, additional, Fatih, Jawid M., additional, Du, Haowei, additional, Karaca, Ender, additional, Bayram, Yavuz, additional, Punetha, Jaya, additional, Rosenfeld, Jill A., additional, Jhangiani, Shalini N., additional, Boerwinkle, Eric, additional, Akdemir, Zeynep C., additional, Erdin, Serkan, additional, Hunter, Jill V., additional, Gibbs, Richard A., additional, Pehlivan, Davut, additional, Posey, Jennifer E., additional, and Lupski, James R., additional
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- 2020
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30. Deficiencies in vesicular transport mediated by TRAPPC4 are associated with severe syndromic intellectual disability
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Van Bergen, Nicole J, primary, Guo, Yiran, additional, Al-Deri, Noraldin, additional, Lipatova, Zhanna, additional, Stanga, Daniela, additional, Zhao, Sarah, additional, Murtazina, Rakhilya, additional, Gyurkovska, Valeriya, additional, Pehlivan, Davut, additional, Mitani, Tadahiro, additional, Gezdirici, Alper, additional, Antony, Jayne, additional, Collins, Felicity, additional, Willis, Mary J H, additional, Coban Akdemir, Zeynep H, additional, Liu, Pengfei, additional, Punetha, Jaya, additional, Hunter, Jill V, additional, Jhangiani, Shalini N, additional, Fatih, Jawid M, additional, Rosenfeld, Jill A, additional, Posey, Jennifer E, additional, Gibbs, Richard A, additional, Karaca, Ender, additional, Massey, Sean, additional, Ranasinghe, Thisara G, additional, Sleiman, Patrick, additional, Troedson, Chris, additional, Lupski, James R, additional, Sacher, Michael, additional, Segev, Nava, additional, Hakonarson, Hakon, additional, and Christodoulou, John, additional
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- 2019
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31. Bi-allelic Pathogenic Variants in TUBGCP2 Cause Microcephaly and Lissencephaly Spectrum Disorders
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Mitani, Tadahiro, primary, Punetha, Jaya, additional, Akalin, Ibrahim, additional, Pehlivan, Davut, additional, Dawidziuk, Mateusz, additional, Coban Akdemir, Zeynep, additional, Yilmaz, Sarenur, additional, Aslan, Ezgi, additional, Hunter, Jill V., additional, Hijazi, Hadia, additional, Grochowski, Christopher M., additional, Jhangiani, Shalini N., additional, Karaca, Ender, additional, Fatih, Jawid M., additional, Iwanowski, Piotr, additional, Gambin, Tomasz, additional, Wlasienko, Pawel, additional, Goszczanska-Ciuchta, Alicja, additional, Bekiesinska-Figatowska, Monika, additional, Hosseini, Masoumeh, additional, Arzhangi, Sanaz, additional, Najmabadi, Hossein, additional, Rosenfeld, Jill A., additional, Du, Haowei, additional, Marafi, Dana, additional, Blaser, Susan, additional, Teitelbaum, Ronni, additional, Silver, Rachel, additional, Posey, Jennifer E., additional, Ropers, Hans-Hilger, additional, Gibbs, Richard A., additional, Wiszniewski, Wojciech, additional, Lupski, James R., additional, Chitayat, David, additional, Kahrizi, Kimia, additional, and Gawlinski, Pawel, additional
- Published
- 2019
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32. The Genomics Of Arthrogryposis, A Complex Trait: Candidate Genes And Further Evidence For Oligogenic Inheritance
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Pehlivan, Davut, Bayram, Yavuz, Gunes, Nilay, Akdemir, Zeynep Coban, Shukla, Anju, Bierhals, Tatjana, Tabakci, Burcu, Sahin, Yavuz, Gezdirici, Alper, Fatih, Jawid M., Gulec, Elif Yilmaz, Yesil, Gozde, Punetha, Jaya, Ocak, Zeynep, Grochowski, Christopher M., Karaca, Ender, Albayrak, Hatice Mutlu, Radhakrishnan, Periyasamy, Erdem, Haktan Bagis, and Sahin, Ibrahim
- Abstract
Arthrogryposis is a clinical finding that is present either as a feature of a neuromuscular condition or as part of a systemic disease in over 400 Mendelian conditions. The underlying molecular etiology remains largely unknown because of genetic and phenotypic heterogeneity. We applied exome sequencing (ES) in a cohort of 89 families with the clinical sign of arthrogryposis. Additional molecular techniques including array comparative genomic hybridization (aCGH) and Droplet Digital PCR (ddPCR) were performed on individuals who were found to have pathogenic copy number variants (CNVs) and mosaicism, respectively. A molecular diagnosis was established in 65.2% (58/89) of families. Eleven out of 58 families (19.0%) showed evidence for potential involvement of pathogenic variation at more than one locus, probably driven by absence of heterozygosity (AOH) burden due to identity-by-descent (IBD). RYR3, MYOM2, ERGIC1, SPTBN4, and ABCA7 represent genes, identified in two or more families, for which mutations are probably causative for arthrogryposis. We also provide evidence for the involvement of CNVs in the etiology of arthrogryposis and for the idea that both mono-allelic and bi-allelic variants in the same gene cause either similar or distinct syndromes. We were able to identify the molecular etiology in nine out of 20 families who underwent reanalysis. In summary, our data from family-based ES further delineate the molecular etiology of arthrogryposis, yielded several candidate disease-associated genes, and provide evidence for mutational burden in a biological pathway or network. Our study also highlights the importance of reanalysis of individuals with unsolved diagnoses in conjunction with sequencing extended family members.
- Published
- 2019
33. Two novel bi‐allelic KDELR2 missense variants cause osteogenesis imperfecta with neurodevelopmental features.
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Efthymiou, Stephanie, Herman, Isabella, Rahman, Fatima, Anwar, Najwa, Maroofian, Reza, Yip, Janice, Mitani, Tadahiro, Calame, Daniel G., Hunter, Jill V., Sutton, V. Reid, Gulec, Elif, Duan, Ruizhi, Fatih, Jawid M., Marafi, Dana, Pehlivan, Davut, Jhangiani, Shalini N., Gibbs, Richard A., Posey, Jennifer E., Maqbool, Shazia, and Lupski, James R.
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- 2021
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34. A novel homozygous SLC13A5 whole‐gene deletion generated by Alu/Alu‐mediated rearrangement in an Iraqi family with epileptic encephalopathy.
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Duan, Ruizhi, Saadi, Nebal Waill, Grochowski, Christopher M., Bhadila, Ghalia, Faridoun, Afnan, Mitani, Tadahiro, Du, Haowei, Fatih, Jawid M., Jhangiani, Shalini N., Akdemir, Zeynep C., Gibbs, Richard A., Pehlivan, Davut, Posey, Jennifer E., Marafi, Dana, and Lupski, James R.
- Abstract
Biallelic loss‐of‐function (LoF) of SLC13A5 (solute carrier family 13, member 5) induced deficiency in sodium/citrate transporter (NaCT) causes autosomal recessive developmental epileptic encephalopathy 25 with hypoplastic amelogenesis imperfecta (DEE25; MIM #615905). Many pathogenic SLC13A5 single nucleotide variants (SNVs) and small indels have been described; however, no cases with copy number variants (CNVs) have been sufficiently investigated. We describe a consanguineous Iraqi family harboring an 88.5 kb homozygous deletion including SLC13A5 in Chr17p13.1. The three affected male siblings exhibit neonatal‐onset epilepsy with fever‐sensitivity, recurrent status epilepticus, global developmental delay/intellectual disability (GDD/ID), and other variable neurological findings as shared phenotypical features of DEE25. Two of the three affected subjects exhibit hypoplastic amelogenesis imperfecta (AI), while the proband shows no evidence of dental abnormalities or AI at 2 years of age with apparently unaffected primary dentition. Characterization of the genomic architecture at this locus revealed evidence for genomic instability generated by an Alu/Alu‐mediated rearrangement; confirmed by break‐point junction Sanger sequencing. This multiplex family from a distinct population elucidates the phenotypic consequence of complete LoF of SLC13A5 and illustrates the importance of read‐depth‐based CNV detection in comprehensive exome sequencing analysis to solve cases that otherwise remain molecularly unsolved. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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35. Neurodevelopmental disorder in an Egyptian family with a biallelic ALKBH8 variant.
- Author
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Saad, Ahmed K., Maraf, Dana, Mitani, Tadahiro, Du, Haowei, Rafat, Karima, Fatih, Jawid M., Jhangiani, Shalini N., Coban-Akdemir, Zeynep, Gibbs, Richard A., Pehlivan, Davut, Hunter, Jill V., Posey, Jennifer E., Zaki, Maha S., and Lupski, James R.
- Abstract
Alkylated DNA repair protein AlkB homolog 8 (ALKBH8) is a member of the AlkB family of dioxygenases. ALKBH8 is a methyltransferase of the highly variable wobble nucleoside position in the anticodon loop of tRNA and thus plays a critical role in tRNA modification by preserving codon recognition and preventing errors in amino acid incorporation during translation. Moreover, its activity catalyzes uridine modifications that are proposed to be critical for accurate protein translation. Previously, two distinct homozygous truncating variants in the final exon of ALKBH8 were described in two unrelated large Saudi Arabian kindreds with intellectual developmental disorder and autosomal recessive 71 (MRT71) syndrome (MIM# 618504). Here, we report a third family—of Egyptian descent—harboring a novel homozygous frame‐shift variant in the last exon of ALKBH8. Two affected siblings in this family exhibit global developmental delay and intellectual disability as shared characteristic features of MRT71 syndrome, and we further characterize their observed dysmorphic features and brain MRI findings. This description of a third family with a truncating ALKBH8 variant from a distinct population broadens the phenotypic and genotypic spectrum of MRT71 syndrome, affirms that perturbations in tRNA biogenesis can contribute to neurogenetic disease traits, and firmly establishes ALKBH8 as a novel neurodevelopmental disease gene. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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36. HMZDupFinder: a robust computational approach for detecting intragenic homozygous duplications from exome sequencing data.
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Du, Haowei, Dardas, Zain, Jolly, Angad, Grochowski, Christopher M, Jhangiani, Shalini N, Li, He, Muzny, Donna, Fatih, Jawid M, Yesil, Gozde, Elçioglu, Nursel H, Gezdirici, Alper, Marafi, Dana, Pehlivan, Davut, Calame, Daniel G, Carvalho, Claudia M B, Posey, Jennifer E, Gambin, Tomasz, Coban-Akdemir, Zeynep, and Lupski, James R
- Published
- 2024
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37. Biallelic CACNA2D2 variants in epileptic encephalopathy and cerebellar atrophy
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Punetha, Jaya, primary, Karaca, Ender, additional, Gezdirici, Alper, additional, Lamont, Ryan E., additional, Pehlivan, Davut, additional, Marafi, Dana, additional, Appendino, Juan P., additional, Hunter, Jill V., additional, Akdemir, Zeynep C., additional, Fatih, Jawid M., additional, Jhangiani, Shalini N., additional, Gibbs, Richard A., additional, Innes, A. Micheil, additional, Posey, Jennifer E., additional, and Lupski, James R., additional
- Published
- 2019
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38. The Genomics of Arthrogryposis, a Complex Trait: Candidate Genes and Further Evidence for Oligogenic Inheritance
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Pehlivan, Davut, primary, Bayram, Yavuz, additional, Gunes, Nilay, additional, Coban Akdemir, Zeynep, additional, Shukla, Anju, additional, Bierhals, Tatjana, additional, Tabakci, Burcu, additional, Sahin, Yavuz, additional, Gezdirici, Alper, additional, Fatih, Jawid M., additional, Gulec, Elif Yilmaz, additional, Yesil, Gozde, additional, Punetha, Jaya, additional, Ocak, Zeynep, additional, Grochowski, Christopher M., additional, Karaca, Ender, additional, Albayrak, Hatice Mutlu, additional, Radhakrishnan, Periyasamy, additional, Erdem, Haktan Bagis, additional, Sahin, Ibrahim, additional, Yildirim, Timur, additional, Bayhan, Ilhan A., additional, Bursali, Aysegul, additional, Elmas, Muhsin, additional, Yuksel, Zafer, additional, Ozdemir, Ozturk, additional, Silan, Fatma, additional, Yildiz, Onur, additional, Yesilbas, Osman, additional, Isikay, Sedat, additional, Balta, Burhan, additional, Gu, Shen, additional, Jhangiani, Shalini N., additional, Doddapaneni, Harsha, additional, Hu, Jianhong, additional, Muzny, Donna M., additional, Boerwinkle, Eric, additional, Gibbs, Richard A., additional, Tsiakas, Konstantinos, additional, Hempel, Maja, additional, Girisha, Katta Mohan, additional, Gul, Davut, additional, Posey, Jennifer E., additional, Elcioglu, Nursel H., additional, Tuysuz, Beyhan, additional, and Lupski, James R., additional
- Published
- 2019
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39. Biallelic loss-of-function variants in the splicing regulator NSRP1cause a severe neurodevelopmental disorder with spastic cerebral palsy and epilepsy
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Calame, Daniel G., Bakhtiari, Somayeh, Logan, Rachel, Coban-Akdemir, Zeynep, Du, Haowei, Mitani, Tadahiro, Fatih, Jawid M., Hunter, Jill V., Herman, Isabella, Pehlivan, Davut, Jhangiani, Shalini N., Person, Richard, Schnur, Rhonda E., Jin, Sheng Chih, Bilguvar, Kaya, Posey, Jennifer E., Koh, Sookyong, Firouzabadi, Saghar G., Alehabib, Elham, Tafakhori, Abbas, Esmkhani, Sahra, Gibbs, Richard A., Noureldeen, Mahmoud M., Zaki, Maha S., Marafi, Dana, Darvish, Hossein, Kruer, Michael C., and Lupski, James R.
- Abstract
Alternative splicing plays a critical role in mouse neurodevelopment, regulating neurogenesis, cortical lamination, and synaptogenesis, yet few human neurodevelopmental disorders are known to result from pathogenic variation in splicing regulator genes. Nuclear Speckle Splicing Regulator Protein 1 (NSRP1) is a ubiquitously expressed splicing regulator not known to underlie a Mendelian disorder.
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- 2021
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40. Biallelic GRM7 variants cause epilepsy, microcephaly, and cerebral atrophy.
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Marafi, Dana, Mitani, Tadahiro, Isikay, Sedat, Hertecant, Jozef, Almannai, Mohammed, Manickam, Kandamurugu, Abou Jamra, Rami, El‐Hattab, Ayman W., Rajah, Jaishen, Fatih, Jawid M., Du, Haowei, Karaca, Ender, Bayram, Yavuz, Punetha, Jaya, Rosenfeld, Jill A., Jhangiani, Shalini N., Boerwinkle, Eric, Akdemir, Zeynep C., Erdin, Serkan, and Hunter, Jill V.
- Subjects
CEREBRAL atrophy ,NEUROTRANSMITTER receptors ,GLUTAMATE receptors ,NEURAL transmission ,EPILEPSY ,LEUKODYSTROPHY ,NEUROCYSTICERCOSIS - Abstract
Objective: Defects in ion channels and neurotransmitter receptors are implicated in developmental and epileptic encephalopathy (DEE). Metabotropic glutamate receptor 7 (mGluR7), encoded by GRM7, is a presynaptic G‐protein‐coupled glutamate receptor critical for synaptic transmission. We previously proposed GRM7 as a candidate disease gene in two families with neurodevelopmental disorders (NDDs). One additional family has been published since. Here, we describe three additional families with GRM7 biallelic variants and deeply characterize the associated clinical neurological and electrophysiological phenotype and molecular data in 11 affected individuals from six unrelated families. Methods: Exome sequencing and family‐based rare variant analyses on a cohort of 220 consanguineous families with NDDs revealed three families with GRM7 biallelic variants; three additional families were identified through literature search and collaboration with a clinical molecular laboratory. Results: We compared the observed clinical features and variants of 11 affected individuals from the six unrelated families. Identified novel deleterious variants included two homozygous missense variants (c.2671G>A:p.Glu891Lys and c.1973G>A:p.Arg685Gln) and one homozygous stop‐gain variant (c.1975C>T:p.Arg659Ter). Developmental delay, neonatal‐ or infantile‐onset epilepsy, and microcephaly were universal. Three individuals had hypothalamic–pituitary–axis dysfunction without pituitary structural abnormality. Neuroimaging showed cerebral atrophy and hypomyelination in a majority of cases. Two siblings demonstrated progressive loss of myelination by 2 years in both and an acquired microcephaly pattern in one. Five individuals died in early or late childhood. Conclusion: Detailed clinical characterization of 11 individuals from six unrelated families demonstrates that rare biallelic GRM7 pathogenic variants can cause DEEs, microcephaly, hypomyelination, and cerebral atrophy. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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41. Deficiencies in vesicular transport mediated by TRAPPC4 are associated with severe syndromic intellectual disability.
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Bergen, Nicole J Van, Guo, Yiran, Al-Deri, Noraldin, Lipatova, Zhanna, Stanga, Daniela, Zhao, Sarah, Murtazina, Rakhilya, Gyurkovska, Valeriya, Pehlivan, Davut, Mitani, Tadahiro, Gezdirici, Alper, Antony, Jayne, Collins, Felicity, Willis, Mary J H, Akdemir, Zeynep H Coban, Liu, Pengfei, Punetha, Jaya, Hunter, Jill V, Jhangiani, Shalini N, and Fatih, Jawid M
- Subjects
GUANINE nucleotide exchange factors ,CHILDREN with developmental disabilities ,CHILDREN with intellectual disabilities ,INTELLECTUAL disabilities ,POLYACRYLAMIDE gel electrophoresis ,CARRIER proteins ,GEL permeation chromatography ,FAMILIAL spastic paraplegia - Abstract
The conserved transport protein particle (TRAPP) complexes regulate key trafficking events and are required for autophagy. TRAPPC4, like its yeast Trs23 orthologue, is a core component of the TRAPP complexes and one of the essential subunits for guanine nucleotide exchange factor activity for Rab1 GTPase. Pathogenic variants in specific TRAPP subunits are associated with neurological disorders. We undertook exome sequencing in three unrelated families of Caucasian, Turkish and French-Canadian ethnicities with seven affected children that showed features of early-onset seizures, developmental delay, microcephaly, sensorineural deafness, spastic quadriparesis and progressive cortical and cerebellar atrophy in an effort to determine the genetic aetiology underlying neurodevelopmental disorders. All seven affected subjects shared the same identical rare, homozygous, potentially pathogenic variant in a non-canonical, well-conserved splice site within TRAPPC4 (hg19:chr11:g.118890966A>G; TRAPPC4 : NM_016146.5; c.454+3A>G). Single nucleotide polymorphism array analysis revealed there was no haplotype shared between the tested Turkish and Caucasian families suggestive of a variant hotspot region rather than a founder effect. In silico analysis predicted the variant to cause aberrant splicing. Consistent with this, experimental evidence showed both a reduction in full-length transcript levels and an increase in levels of a shorter transcript missing exon 3, suggestive of an incompletely penetrant splice defect. TRAPPC4 protein levels were significantly reduced whilst levels of other TRAPP complex subunits remained unaffected. Native polyacrylamide gel electrophoresis and size exclusion chromatography demonstrated a defect in TRAPP complex assembly and/or stability. Intracellular trafficking through the Golgi using the marker protein VSVG-GFP-ts045 demonstrated significantly delayed entry into and exit from the Golgi in fibroblasts derived from one of the affected subjects. Lentiviral expression of wild-type TRAPPC4 in these fibroblasts restored trafficking, suggesting that the trafficking defect was due to reduced TRAPPC4 levels. Consistent with the recent association of the TRAPP complex with autophagy, we found that the fibroblasts had a basal autophagy defect and a delay in autophagic flux, possibly due to unsealed autophagosomes. These results were validated using a yeast trs23 temperature sensitive variant that exhibits constitutive and stress-induced autophagic defects at permissive temperature and a secretory defect at restrictive temperature. In summary we provide strong evidence for pathogenicity of this variant in a member of the core TRAPP subunit, TRAPPC4 that associates with vesicular trafficking and autophagy defects. This is the first report of a TRAPPC4 variant, and our findings add to the growing number of TRAPP-associated neurological disorders. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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42. Identifying Genes Whose Mutant Transcripts Cause Dominant Disease Traits by Potential Gain-of-Function Alleles
- Author
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Coban-Akdemir, Zeynep, primary, White, Janson J., additional, Song, Xiaofei, additional, Jhangiani, Shalini N., additional, Fatih, Jawid M., additional, Gambin, Tomasz, additional, Bayram, Yavuz, additional, Chinn, Ivan K., additional, Karaca, Ender, additional, Punetha, Jaya, additional, Poli, Cecilia, additional, Boerwinkle, Eric, additional, Shaw, Chad A., additional, Orange, Jordan S., additional, Gibbs, Richard A., additional, Lappalainen, Tuuli, additional, Lupski, James R., additional, and Carvalho, Claudia M.B., additional
- Published
- 2018
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43. Functional biology of the Steel syndrome founder allele and evidence for clan genomics derivation of COL27A1pathogenic alleles worldwide
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Gonzaga-Jauregui, Claudia, Yesil, Gozde, Nistala, Harikiran, Gezdirici, Alper, Bayram, Yavuz, Nannuru, Kalyan C., Pehlivan, Davut, Yuan, Bo, Jimenez, Johanna, Sahin, Yavuz, Paine, Ingrid S., Akdemir, Zeynep Coban, Rajamani, Saathyaki, Staples, Jeffrey, Dronzek, John, Howell, Kristen, Fatih, Jawid M., Smaldone, Silvia, Schlesinger, Alan E., Ramírez, Norman, Cornier, Alberto S., Kelly, Melissa A., Haber, Robert, Chim, Shek Man, Nieman, Kristy, Wu, Nan, Walls, Johnathon, Poueymirou, William, Siao, Chia-Jen, Sutton, V. Reid, Williams, Marc S., Posey, Jennifer E., Gibbs, Richard A., Carlo, Simon, Tegay, David H., Economides, Aris N., and Lupski, James R.
- Abstract
Previously we reported the identification of a homozygous COL27A1(c.2089G>C; p.Gly697Arg) missense variant and proposed it as a founder allele in Puerto Rico segregating with Steel syndrome (STLS, MIM #615155); a rare osteochondrodysplasia characterized by short stature, congenital bilateral hip dysplasia, carpal coalitions, and scoliosis. We now report segregation of this variant in five probands from the initial clinical report defining the syndrome and an additional family of Puerto Rican descent with multiple affected adult individuals. We modeled the orthologous variant in murine Col27a1and found it recapitulates some of the major Steel syndrome associated skeletal features including reduced body length, scoliosis, and a more rounded skull shape. Characterization of the in vivo murine model shows abnormal collagen deposition in the extracellular matrix and disorganization of the proliferative zone of the growth plate. We report additional COL27A1pathogenic variant alleles identified in unrelated consanguineous Turkish kindreds suggesting Clan Genomics and identity-by-descent homozygosity contributing to disease in this population. The hypothesis that carrier states for this autosomal recessive osteochondrodysplasia may contribute to common complex traits is further explored in a large clinical population cohort. Our findings augment our understanding of COL27A1biology and its role in skeletal development; and expand the functional allelic architecture in this gene underlying both rare and common disease phenotypes.
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- 2020
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44. The Genomics of Arthrogryposis, a Complex Trait: Candidate Genes and Further Evidence for Oligogenic Inheritance
- Author
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Maja Hempel, Jennifer E. Posey, Yavuz Bayram, Eric Boerwinkle, Katta M. Girisha, Ender Karaca, Timur Yildirim, Anju Shukla, Jaya Punetha, Ilhan A. Bayhan, Harsha Doddapaneni, Christopher M. Grochowski, Davut Gul, Aysegul Bursali, Davut Pehlivan, Elif Yilmaz Gulec, Richard A. Gibbs, Zeynep Ocak, Jawid M Fatih, Ibrahim Sahin, Gozde Yesil, Burhan Balta, Onur Yildiz, Alper Gezdirici, Tatjana Bierhals, James R. Lupski, Zafer Yüksel, Hatice Mutlu Albayrak, Donna M. Muzny, Jianhong Hu, Fatma Silan, Zeynep Coban Akdemir, Shen Gu, Öztürk Özdemir, Haktan Bağış Erdem, Periyasamy Radhakrishnan, Burcu Tabakci, Beyhan Tüysüz, Nilay Güneş, Shalini N. Jhangiani, Osman Yeşilbaş, Yavuz Sahin, Nursel Elcioglu, Muhsin Elmas, Konstantinos Tsiakas, Sedat Isikay, Pehlivan, Davut, Bayram, Yavuz, Gunes, Nilay, Akdemir, Zeynep Coban, Shukla, Anju, Bierhals, Tatjana, Tabakci, Burcu, Sahin, Yavuz, Gezdirici, Alper, Fatih, Jawid M., Gulec, Elif Yilmaz, Yesil, Gozde, Punetha, Jaya, Ocak, Zeynep, Grochowski, Christopher M., Karaca, Ender, Albayrak, Hatice Mutlu, Radhakrishnan, Periyasamy, Erdem, Haktan Bagis, Sahin, Ibrahim, Yildirim, Timur, Bayhan, Ilhan A., Bursali, Aysegul, Elmas, Muhsin, Yuksel, Zafer, Ozdemir, Ozturk, Silan, Fatma, Yildiz, Onur, Yesilbas, Osman, Isikay, Sedat, Balta, Burhan, Gu, Shen, Jhangiani, Shalini N., Doddapaneni, Harsha, Hu, Jianhong, Muzny, Donna M., Boerwinkle, Eric, Gibbs, Richard A., Tsiakas, Konstantinos, Hempel, Maja, Girisha, Katta Mohan, Gul, Davut, Posey, Jennifer E., Elcioglu, Nursel H., Tuysuz, Beyhan, Lupski, James R., HKÜ, Sağlık Bilimleri Fakültesi, Fizyoterapi ve Rehabilitasyon Bölümü, YEŞİL, Gözde, İÜC, Cerrahpaşa Tıp Fakültesi, Dahili Tıp Bilimleri Bölümü, and OMÜ
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Male ,0301 basic medicine ,Multifactorial Inheritance ,Candidate gene ,Vesicular Transport Proteins ,DE-NOVO ,DISEASE ,Cohort Studies ,MYOPATHY ,MULTIPLEX CONGENITA ,SKELETAL-MUSCLE ,MUTATIONS ,PATIENT ,FAT1 ,MECHANISMS ,DELETION ,0302 clinical medicine ,Candidate Genes and Further Evidence for Oligogenic Inheritance-, AMERICAN JOURNAL OF HUMAN GENETICS, cilt.105, ss.132-150, 2019 [Pehlivan D., Bayram Y., Gunes N., Akdemir Z. C. , Shukla A., Bierhals T., TABAKCI B., Sahin Y., Gezdirici A., Fatih J. M. , et al., -The Genomics of Arthrogryposis, a Complex Trait] ,Connectin ,Copy-number variation ,Child ,Genetics (clinical) ,Exome sequencing ,Arthrogryposis ,Genetics ,Mosaicism ,Oligogenic Inheritance ,Genomics ,Pedigree ,3. Good health ,Child, Preschool ,Female ,medicine.symptom ,Adult ,Genetic Markers ,Adolescent ,DNA Copy Number Variations ,Gestational Age ,Locus (genetics) ,Biology ,Article ,Young Adult ,03 medical and health sciences ,Exome Sequencing ,medicine ,Humans ,Genetic heterogeneity ,Infant, Newborn ,Infant ,Ryanodine Receptor Calcium Release Channel ,030104 developmental biology ,Mutation ,030217 neurology & neurosurgery ,Comparative genomic hybridization - Abstract
Erdem, Haktan Bagis/0000-0002-4391-1387; Albayrak, Hatice Mutlu/0000-0001-5624-3878; isikay, sedat/0000-0003-0103-9612; Grochowski, Christopher/0000-0002-3884-7720; Gezdirici, Alper/0000-0002-2432-9279; KM, Girisha/0000-0002-0139-8239; Gu, Shen/0000-0003-3107-1218; YESIL, GOZDE/0000-0003-1964-6306; Gezdirici, Alper/0000-0002-2432-9279; Tuysuz, Beyhan/0000-0002-9620-5021; Fatih, Jawid/0000-0002-3927-2711; YUKSEL, Zafer/0000-0002-2085-5773; Balta, Burhan/0000-0003-2672-2493; Posey, Jennifer/0000-0003-4814-6765; Bayhan, Ilhan/0000-0001-8308-1309; Punetha, Jaya/0000-0002-6774-4464; YILDIRIM, Timur/0000-0003-0291-7632 WOS:000473723000011 PubMed ID: 31230720 Arthrogryposis is a clinical finding that is present either as a feature of a neuromuscular condition or as part of a systemic disease in over 400 Mendelian conditions. The underlying molecular etiology remains largely unknown because of genetic and phenotypic heterogeneity. We applied exome sequencing (ES) in a cohort of 89 families with the clinical sign of arthrogryposis. Additional molecular techniques including array comparative genomic hybridization (aCGH) and Droplet Digital PCR (ddPCR) were performed on individuals who were found to have pathogenic copy number variants (CNVs) and mosaicism, respectively. A molecular diagnosis was established in 65.2% (58/89) of families. Eleven out of 58 families (19.0%) showed evidence for potential involvement of pathogenic variation at more than one locus, probably driven by absence of heterozygosity (AOH) burden due to identity-by-descent (IBD). RYR3, MYOM2, ERGIC1, SPTBN4, and ABCA7 represent genes, identified in two or more families, for which mutations are probably causative for arthrogryposis. We also provide evidence for the involvement of CNVs in the etiology of arthrogryposis and for the idea that both mono-allelic and bi-allelic variants in the same gene cause either similar or distinct syndromes. We were able to identify the molecular etiology in nine out of 20 families who underwent reanalysis. In summary, our data from family-based ES further delineate the molecular etiology of arthrogryposis, yielded several candidate disease-associated genes, and provide evidence for mutational burden in a biological pathway or network. Our study also highlights the importance of reanalysis of individuals with unsolved diagnoses in conjunction with sequencing extended family members. National Human Genome Research Institute (NHGRI)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Human Genome Research Institute (NHGRI) [UM1 HG006542]; National Heart, Lung, and Blood Institute (NHLBI)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Heart Lung & Blood Institute (NHLBI) [UM1 HG006542]; NHGRIUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Human Genome Research Institute (NHGRI) [K08 HG008986]; National Institutes of Health - Brain Disorders and Development Training Grant [T32 NS043124-17]; Clinical Research Training Scholarship in Neuromuscular Disease; Tubitak project, TurkeyTurkiye Bilimsel ve Teknolojik Arastirma Kurumu (TUBITAK) [217S675]; Indian Council of Medical Research, New Delhi, IndiaIndian Council of Medical Research (ICMR) [5/13/58/2015/NCD-III]; [R35 NS105078]; [512848]; NATIONAL HUMAN GENOME RESEARCH INSTITUTEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Human Genome Research Institute (NHGRI) [K08HG008986, UM1HG006542, K08HG008986, UM1HG006542, UM1HG006542, UM1HG006542, K08HG008986, UM1HG006542] Funding Source: NIH RePORTER; NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Neurological Disorders & Stroke (NINDS) [R35NS105078, T32NS043124, T32NS043124, T32NS043124, R35NS105078, T32NS043124, T32NS043124, R35NS105078, T32NS043124, T32NS043124, T32NS043124, R35NS105078] Funding Source: NIH RePORTER This work was supported in part by R35 NS105078 and MDA#512848 to J.R.L. and a jointly funded National Human Genome Research Institute (NHGRI) and National Heart, Lung, and Blood Institute (NHLBI) grant to the Baylor-Hopkins Center for Mendelian Genomics (UM1 HG006542). J.E.P. is supported by NHGRI K08 HG008986. D.P. is supported by the National Institutes of Health - Brain Disorders and Development Training Grant (T32 NS043124-17) and a Clinical Research Training Scholarship in Neuromuscular Disease partnered by the American Brain Foundation (ABF) and Muscle Study Group (MSG). This study is partly funded by Tubitak project number 217S675, Turkey to N.E. and B.T.. This study is partly funded by Indian Council of Medical Research, New Delhi, India with File no.: No. 5/13/58/2015/NCD-III to A.S.
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- 2019
45. Biallelic variation in the choline and ethanolamine transporter FLVCR1 underlies a pleiotropic disease spectrum from adult neurodegeneration to severe developmental disorders.
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Calame DG, Wong JH, Panda P, Nguyen DT, Leong NCP, Sangermano R, Patankar SG, Abdel-Hamid M, AlAbdi L, Safwat S, Flannery KP, Dardas Z, Fatih JM, Murali C, Kannan V, Lotze TE, Herman I, Ammouri F, Rezich B, Efthymiou S, Alavi S, Murphy D, Firoozfar Z, Nasab ME, Bahreini A, Ghasemi M, Haridy NA, Goldouzi HR, Eghbal F, Karimiani EG, Srinivasan VM, Gowda VK, Du H, Jhangiani SN, Coban-Akdemir Z, Marafi D, Rodan L, Isikay S, Rosenfeld JA, Ramanathan S, Staton M, Kerby C Oberg, Clark RD, Wenman C, Loughlin S, Saad R, Ashraf T, Male A, Tadros S, Boostani R, Abdel-Salam GMH, Zaki M, Abdalla E, Manzini MC, Pehlivan D, Posey JE, Gibbs RA, Houlden H, Alkuraya FS, Bujakowska K, Maroofian R, Lupski JR, and Nguyen LN
- Abstract
FLVCR1 encodes Feline leukemia virus subgroup C receptor 1 (FLVCR1), a solute carrier (SLC) transporter within the Major Facilitator Superfamily. FLVCR1 is a widely expressed transmembrane protein with plasma membrane and mitochondrial isoforms implicated in heme, choline, and ethanolamine transport. While Flvcr1 knockout mice die in utero with skeletal malformations and defective erythropoiesis reminiscent of Diamond-Blackfan anemia, rare biallelic pathogenic FLVCR1 variants are linked to childhood or adult-onset neurodegeneration of the retina, spinal cord, and peripheral nervous system. We ascertained from research and clinical exome sequencing 27 individuals from 20 unrelated families with biallelic ultra-rare missense and predicted loss-of-function (pLoF) FLVCR1 variant alleles. We characterize an expansive FLVCR1 phenotypic spectrum ranging from adult-onset retinitis pigmentosa to severe developmental disorders with microcephaly, reduced brain volume, epilepsy, spasticity, and premature death. The most severely affected individuals, including three individuals with homozygous pLoF variants, share traits with Flvcr1 knockout mice and Diamond-Blackfan anemia including macrocytic anemia and congenital skeletal malformations. Pathogenic FLVCR1 missense variants primarily lie within transmembrane domains and reduce choline and ethanolamine transport activity compared with wild-type FLVCR1 with minimal impact on FLVCR1 stability or subcellular localization. Several variants disrupt splicing in a mini-gene assay which may contribute to genotype-phenotype correlations. Taken together, these data support an allele-specific gene dosage model in which phenotypic severity reflects residual FLVCR1 activity. This study expands our understanding of Mendelian disorders of choline and ethanolamine transport and demonstrates the importance of choline and ethanolamine in neurodevelopment and neuronal homeostasis., Competing Interests: Potential Conflict of Interest J.R.L. has stock ownership in 23andMe, is a paid consultant for Genome International, and is a co-inventor on multiple United States and European patents related to molecular diagnostics for inherited neuropathies, eye diseases, genomic disorders, and bacterial genomic fingerprinting. The Department of Molecular and Human Genetics at Baylor College of Medicine receives revenue from clinical genetic testing conducted at Baylor Genetics (BG) Laboratories. Other authors have no potential conflicts to disclose.
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- 2024
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46. Break-induced replication underlies formation of inverted triplications and generates unexpected diversity in haplotype structures.
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Grochowski CM, Bengtsson JD, Du H, Gandhi M, Lun MY, Mehaffey MG, Park K, Höps W, Benito-Garagorri E, Hasenfeld P, Korbel JO, Mahmoud M, Paulin LF, Jhangiani SN, Muzny DM, Fatih JM, Gibbs RA, Pendleton M, Harrington E, Juul S, Lindstrand A, Sedlazeck FJ, Pehlivan D, Lupski JR, and Carvalho CMB
- Abstract
Background: The duplication-triplication/inverted-duplication (DUP-TRP/INV-DUP) structure is a type of complex genomic rearrangement (CGR) hypothesized to result from replicative repair of DNA due to replication fork collapse. It is often mediated by a pair of inverted low-copy repeats (LCR) followed by iterative template switches resulting in at least two breakpoint junctions in cis . Although it has been identified as an important mutation signature of pathogenicity for genomic disorders and cancer genomes, its architecture remains unresolved and is predicted to display at least four structural variation (SV) haplotypes., Results: Here we studied the genomic architecture of DUP-TRP/INV-DUP by investigating the genomic DNA of 24 patients with neurodevelopmental disorders identified by array comparative genomic hybridization (aCGH) on whom we found evidence for the existence of 4 out of 4 predicted SV haplotypes. Using a combination of short-read genome sequencing (GS), long- read GS, optical genome mapping and StrandSeq the haplotype structure was resolved in 18 samples. This approach refined the point of template switching between inverted LCRs in 4 samples revealing a DNA segment of ∼2.2-5.5 kb of 100% nucleotide similarity. A prediction model was developed to infer the LCR used to mediate the non-allelic homology repair., Conclusions: These data provide experimental evidence supporting the hypothesis that inverted LCRs act as a recombinant substrate in replication-based repair mechanisms. Such inverted repeats are particularly relevant for formation of copy-number associated inversions, including the DUP-TRP/INV-DUP structures. Moreover, this type of CGR can result in multiple conformers which contributes to generate diverse SV haplotypes in susceptible loci .
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- 2023
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47. Functional biology of the Steel syndrome founder allele and evidence for clan genomics derivation of COL27A1 pathogenic alleles worldwide.
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Gonzaga-Jauregui C, Yesil G, Nistala H, Gezdirici A, Bayram Y, Nannuru KC, Pehlivan D, Yuan B, Jimenez J, Sahin Y, Paine IS, Akdemir ZC, Rajamani S, Staples J, Dronzek J, Howell K, Fatih JM, Smaldone S, Schlesinger AE, Ramírez N, Cornier AS, Kelly MA, Haber R, Chim SM, Nieman K, Wu N, Walls J, Poueymirou W, Siao CJ, Sutton VR, Williams MS, Posey JE, Gibbs RA, Carlo S, Tegay DH, Economides AN, and Lupski JR
- Subjects
- Abnormalities, Multiple pathology, Adolescent, Animals, Bone Development, Child, Child, Preschool, Consanguinity, Extracellular Matrix metabolism, Extracellular Matrix pathology, Female, Fibrillar Collagens metabolism, Gene Frequency, Hip Dislocation pathology, Homozygote, Humans, Male, Mice, Mice, Inbred C57BL, Mutation, Pedigree, Scoliosis pathology, Syndrome, Abnormalities, Multiple genetics, Fibrillar Collagens genetics, Founder Effect, Hip Dislocation genetics, Scoliosis genetics
- Abstract
Previously we reported the identification of a homozygous COL27A1 (c.2089G>C; p.Gly697Arg) missense variant and proposed it as a founder allele in Puerto Rico segregating with Steel syndrome (STLS, MIM #615155); a rare osteochondrodysplasia characterized by short stature, congenital bilateral hip dysplasia, carpal coalitions, and scoliosis. We now report segregation of this variant in five probands from the initial clinical report defining the syndrome and an additional family of Puerto Rican descent with multiple affected adult individuals. We modeled the orthologous variant in murine Col27a1 and found it recapitulates some of the major Steel syndrome associated skeletal features including reduced body length, scoliosis, and a more rounded skull shape. Characterization of the in vivo murine model shows abnormal collagen deposition in the extracellular matrix and disorganization of the proliferative zone of the growth plate. We report additional COL27A1 pathogenic variant alleles identified in unrelated consanguineous Turkish kindreds suggesting Clan Genomics and identity-by-descent homozygosity contributing to disease in this population. The hypothesis that carrier states for this autosomal recessive osteochondrodysplasia may contribute to common complex traits is further explored in a large clinical population cohort. Our findings augment our understanding of COL27A1 biology and its role in skeletal development; and expand the functional allelic architecture in this gene underlying both rare and common disease phenotypes.
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- 2020
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48. Deficiencies in vesicular transport mediated by TRAPPC4 are associated with severe syndromic intellectual disability.
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Van Bergen NJ, Guo Y, Al-Deri N, Lipatova Z, Stanga D, Zhao S, Murtazina R, Gyurkovska V, Pehlivan D, Mitani T, Gezdirici A, Antony J, Collins F, Willis MJH, Coban Akdemir ZH, Liu P, Punetha J, Hunter JV, Jhangiani SN, Fatih JM, Rosenfeld JA, Posey JE, Gibbs RA, Karaca E, Massey S, Ranasinghe TG, Sleiman P, Troedson C, Lupski JR, Sacher M, Segev N, Hakonarson H, and Christodoulou J
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- Atrophy, Cerebellum diagnostic imaging, Cerebellum pathology, Cerebral Cortex diagnostic imaging, Cerebral Cortex pathology, Child, Child, Preschool, Craniofacial Abnormalities diagnostic imaging, Deafness genetics, Deafness physiopathology, Developmental Disabilities genetics, Developmental Disabilities physiopathology, Epilepsy genetics, Epilepsy physiopathology, Female, Hearing Loss, Sensorineural genetics, Hearing Loss, Sensorineural physiopathology, Humans, Infant, Infant, Newborn, Intellectual Disability genetics, Intellectual Disability physiopathology, Male, Microcephaly genetics, Microcephaly physiopathology, Microscopy, Fluorescence, Muscle Spasticity genetics, Muscle Spasticity physiopathology, Neurodevelopmental Disorders physiopathology, Pedigree, Quadriplegia genetics, Quadriplegia physiopathology, RNA Splice Sites genetics, Syndrome, Autophagy genetics, Craniofacial Abnormalities genetics, Fibroblasts metabolism, Nerve Tissue Proteins genetics, Neurodevelopmental Disorders genetics, Vesicular Transport Proteins genetics
- Abstract
The conserved transport protein particle (TRAPP) complexes regulate key trafficking events and are required for autophagy. TRAPPC4, like its yeast Trs23 orthologue, is a core component of the TRAPP complexes and one of the essential subunits for guanine nucleotide exchange factor activity for Rab1 GTPase. Pathogenic variants in specific TRAPP subunits are associated with neurological disorders. We undertook exome sequencing in three unrelated families of Caucasian, Turkish and French-Canadian ethnicities with seven affected children that showed features of early-onset seizures, developmental delay, microcephaly, sensorineural deafness, spastic quadriparesis and progressive cortical and cerebellar atrophy in an effort to determine the genetic aetiology underlying neurodevelopmental disorders. All seven affected subjects shared the same identical rare, homozygous, potentially pathogenic variant in a non-canonical, well-conserved splice site within TRAPPC4 (hg19:chr11:g.118890966A>G; TRAPPC4: NM_016146.5; c.454+3A>G). Single nucleotide polymorphism array analysis revealed there was no haplotype shared between the tested Turkish and Caucasian families suggestive of a variant hotspot region rather than a founder effect. In silico analysis predicted the variant to cause aberrant splicing. Consistent with this, experimental evidence showed both a reduction in full-length transcript levels and an increase in levels of a shorter transcript missing exon 3, suggestive of an incompletely penetrant splice defect. TRAPPC4 protein levels were significantly reduced whilst levels of other TRAPP complex subunits remained unaffected. Native polyacrylamide gel electrophoresis and size exclusion chromatography demonstrated a defect in TRAPP complex assembly and/or stability. Intracellular trafficking through the Golgi using the marker protein VSVG-GFP-ts045 demonstrated significantly delayed entry into and exit from the Golgi in fibroblasts derived from one of the affected subjects. Lentiviral expression of wild-type TRAPPC4 in these fibroblasts restored trafficking, suggesting that the trafficking defect was due to reduced TRAPPC4 levels. Consistent with the recent association of the TRAPP complex with autophagy, we found that the fibroblasts had a basal autophagy defect and a delay in autophagic flux, possibly due to unsealed autophagosomes. These results were validated using a yeast trs23 temperature sensitive variant that exhibits constitutive and stress-induced autophagic defects at permissive temperature and a secretory defect at restrictive temperature. In summary we provide strong evidence for pathogenicity of this variant in a member of the core TRAPP subunit, TRAPPC4 that associates with vesicular trafficking and autophagy defects. This is the first report of a TRAPPC4 variant, and our findings add to the growing number of TRAPP-associated neurological disorders., (© The Author(s) (2019). 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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