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139 results on '"Revah-Politi A"'

1. De novo variants in FRYL are associated with developmental delay, intellectual disability, and dysmorphic features

Author

Burrage, Lindsay C., Heaney, Jason D., Kim, Seon-Young, Lanza, Denise G., Liu, Zhandong, Mao, Dongxue, Milosavljevic, Aleksander, Nagamani, Sandesh C.S., Posey, Jennifer E., Ramamurthy, Uma, Ramanathan, Vivek, Rogers, Jeffrey, Rosenfeld, Jill A., Roth, Matthew, Zahedi Darshoori, Ramin, Pan, Xueyang, Tao, Alice M., Lu, Shenzhao, Ma, Mengqi, Hannan, Shabab B., Slaugh, Rachel, Drewes Williams, Sarah, O'Grady, Lauren, Kanca, Oguz, Person, Richard, Carter, Melissa T., Platzer, Konrad, Schnabel, Franziska, Abou Jamra, Rami, Roberts, Amy E., Newburger, Jane W., Revah-Politi, Anya, Granadillo, Jorge L., Stegmann, Alexander P.A., Sinnema, Margje, Accogli, Andrea, Salpietro, Vincenzo, Capra, Valeria, Ghaloul-Gonzalez, Lina, Brueckner, Martina, Simon, Marleen E.H., Sweetser, David A., Glinton, Kevin E., Kirk, Susan E., Wangler, Michael F., Yamamoto, Shinya, Chung, Wendy K., and Bellen, Hugo J.

Published
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

Author

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.

Published
2023
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4. Truncating variants in the SHANK1 gene are associated with a spectrum of neurodevelopmental disorders

Author

May, Halie J., Jeong, Jaehoon, Revah-Politi, Anya, Cohen, Julie S., Chassevent, Anna, Baptista, Julia, Baugh, Evan H., Bier, Louise, Bottani, Armand, Te Carminho A. Rodrigues, Maria resa, Conlon, Charles, Fluss, Joel, Guipponi, Michel, Kim, Chong Ae, Matsumoto, Naomichi, Person, Richard, Primiano, Michelle, Rankin, Julia, Shinawi, Marwan, Smith-Hicks, Constance, Telegrafi, Aida, Toy, Samantha, Uchiyama, Yuri, Aggarwal, Vimla, Goldstein, David B., Roche, Katherine W., and Anyane-Yeboa, Kwame

Published
2021
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5. Developmental epileptic encephalopathy in DLG4-related synaptopathy

Author

Kassabian, Benedetta, Levy, Amanda M., Gardella, Elena, Aledo-Serrano, Angel, Ananth, Amitha L., Brea-Fernández, Alejandro J., Caumes, Roseline, Chatron, Nicolas, Dainelli, Alice, De Wachter, Matthias, Denommé-Pichon, Anne-Sophie, Dye, Thomas J., Fazzi, Elisa, Felt, Roxanne, Fernández-Jaén, Alberto, Fernández-Prieto, Montse, Gantz, Emily, Gasperowicz, Piotr, Gil-Nagel, Antonio, Gómez-Andrés, David, Greiner, Hansel M., Guerrini, Renzo, Haanpää, Maria K., Helin, Minttu, Hoyer, Juliane, Hurst, Anna C. E., Kallish, Staci, Karkare, Shefali N., Khan, Amjad, Kleinendorst, Lotte, Koch, Johannes, Kothare, Sanjeev V., Koudijs, Suzanna M., Lagae, Lieven, Lakeman, Phillis, Leppig, Kathleen A., Lesca, Gaetan, Lopergolo, Diego, Lusk, Laina, Mackenzie, Alex, Mei, Davide, Møller, Rikke S., Pereira, Elaine M., Platzer, Konrad, Quelin, Chloe, Revah-Politi, Anya, Rheims, Sylvain, Rodríguez-Palmero, Agustí, Rossi, Andrea, Santorelli, Filippo, Seinfeld, Syndi, Sell, Erick, Stephenson, Donna, Szczaluba, Krzysztof, Trinka, Eugen, Umair, Muhammad, Van Esch, Hilde, van Haelst, Mieke M., Veenma, Danielle C. M., Weber, Sacha, Weckhuysen, Sarah, Zacher, Pia, Tümer, Zeynep, Rubboli, Guido, Kassabian, Benedetta, Levy, Amanda M., Gardella, Elena, Aledo-Serrano, Angel, Ananth, Amitha L., Brea-Fernández, Alejandro J., Caumes, Roseline, Chatron, Nicolas, Dainelli, Alice, De Wachter, Matthias, Denommé-Pichon, Anne-Sophie, Dye, Thomas J., Fazzi, Elisa, Felt, Roxanne, Fernández-Jaén, Alberto, Fernández-Prieto, Montse, Gantz, Emily, Gasperowicz, Piotr, Gil-Nagel, Antonio, Gómez-Andrés, David, Greiner, Hansel M., Guerrini, Renzo, Haanpää, Maria K., Helin, Minttu, Hoyer, Juliane, Hurst, Anna C. E., Kallish, Staci, Karkare, Shefali N., Khan, Amjad, Kleinendorst, Lotte, Koch, Johannes, Kothare, Sanjeev V., Koudijs, Suzanna M., Lagae, Lieven, Lakeman, Phillis, Leppig, Kathleen A., Lesca, Gaetan, Lopergolo, Diego, Lusk, Laina, Mackenzie, Alex, Mei, Davide, Møller, Rikke S., Pereira, Elaine M., Platzer, Konrad, Quelin, Chloe, Revah-Politi, Anya, Rheims, Sylvain, Rodríguez-Palmero, Agustí, Rossi, Andrea, Santorelli, Filippo, Seinfeld, Syndi, Sell, Erick, Stephenson, Donna, Szczaluba, Krzysztof, Trinka, Eugen, Umair, Muhammad, Van Esch, Hilde, van Haelst, Mieke M., Veenma, Danielle C. M., Weber, Sacha, Weckhuysen, Sarah, Zacher, Pia, Tümer, Zeynep, and Rubboli, Guido

Abstract

Objective: The postsynaptic density protein of excitatory neurons PSD-95 is encoded by discs large MAGUK scaffold protein 4 (DLG4), de novo pathogenic variants of which lead to DLG4-related synaptopathy. The major clinical features are developmental delay, intellectual disability (ID), hypotonia, sleep disturbances, movement disorders, and epilepsy. Even though epilepsy is present in 50% of the individuals, it has not been investigated in detail. We describe here the phenotypic spectrum of epilepsy and associated comorbidities in patients with DLG4-related synaptopathy. Methods: We included 35 individuals with a DLG4 variant and epilepsy as part of a multicenter study. The DLG4 variants were detected by the referring laboratories. The degree of ID, hypotonia, developmental delay, and motor disturbances were evaluated by the referring clinician. Data on awake and sleep electroencephalography (EEG) and/or video-polygraphy and brain magnetic resonance imaging were collected. Antiseizure medication response was retrospectively assessed by the referring clinician. Results: A large variety of seizure types was reported, although focal seizures were the most common. Encephalopathy related to status epilepticus during slow-wave sleep (ESES)/developmental epileptic encephalopathy with spike–wave activation during sleep (DEE-SWAS) was diagnosed in >25% of the individuals. All but one individual presented with neurodevelopmental delay. Regression in verbal and/or motor domains was observed in all individuals who suffered from ESES/DEE-SWAS, as well as some who did not. We could not identify a clear genotype–phenotype relationship even between individuals with the same DLG4 variants. Significance: Our study shows that a subgroup of individuals with DLG4-related synaptopathy have DEE, and approximately one fourth of them have ESES/DEE-SWAS. Our study confirms DEE as part of the DLG4-related phenotypic spectrum. Occurrence of ESES/DEE-SWAS in DLG4-related synaptopathy requi

Published
2024

6. DLG4-related synaptopathy: a new rare brain disorder

Author

Rodríguez-Palmero, Agustí, Boerrigter, Melissa Maria, Gómez-Andrés, David, Aldinger, Kimberly A., Marcos-Alcalde, Íñigo, Popp, Bernt, Everman, David B., Lovgren, Alysia Kern, Arpin, Stephanie, Bahrambeigi, Vahid, Beunders, Gea, Bisgaard, Anne-Marie, Bjerregaard, V. A., Bruel, Ange-Line, Challman, Thomas D., Cogné, Benjamin, Coubes, Christine, de Man, Stella A., Denommé-Pichon, Anne-Sophie, Dye, Thomas J., Elmslie, Frances, Feuk, Lars, García-Miñaúr, Sixto, Gertler, Tracy, Giorgio, Elisa, Gruchy, Nicolas, Haack, Tobias B., Haldeman-Englert, Chad R., Haukanes, Bjørn Ivar, Hoyer, Juliane, Hurst, Anna C. E., Isidor, Bertrand, Soller, Maria Johansson, Kushary, Sulagna, Kvarnung, Malin, Landau, Yuval E., Leppig, Kathleen A., Lindstrand, Anna, Kleinendorst, Lotte, MacKenzie, Alex, Mandrile, Giorgia, Mendelsohn, Bryce A., Moghadasi, Setareh, Morton, Jenny E., Moutton, Sebastien, Müller, Amelie J., O’Leary, Melanie, Pacio-Míguez, Marta, Palomares-Bralo, Maria, Parikh, Sumit, Pfundt, Rolph, Pode-Shakked, Ben, Rauch, Anita, Repnikova, Elena, Revah-Politi, Anya, Ross, Meredith J., Ruivenkamp, Claudia A. L., Sarrazin, Elisabeth, Savatt, Juliann M., Schlüter, Agatha, Schönewolf-Greulich, Bitten, Shad, Zohra, Shaw-Smith, Charles, Shieh, Joseph T., Shohat, Motti, Spranger, Stephanie, Thiese, Heidi, Mau-Them, Frederic Tran, van Bon, Bregje, van de Burgt, Ineke, van de Laar, Ingrid M. B. H., van Drie, Esmée, van Haelst, Mieke M., van Ravenswaaij-Arts, Conny M., Verdura, Edgard, Vitobello, Antonio, Waldmüller, Stephan, Whiting, Sharon, Zweier, Christiane, Prada, Carlos E., de Vries, Bert B. A., Dobyns, William B., Reiter, Simone F., Gómez-Puertas, Paulino, Pujol, Aurora, and Tümer, Zeynep

Published
2021
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7. De novo variants in FRYL are associated with developmental delay, intellectual disability, and dysmorphic features

Author

Pan, Xueyang, primary, Tao, Alice M., additional, Lu, Shenzhao, additional, Ma, Mengqi, additional, Hannan, Shabab B., additional, Slaugh, Rachel, additional, Drewes Williams, Sarah, additional, O'Grady, Lauren, additional, Kanca, Oguz, additional, Person, Richard, additional, Carter, Melissa T., additional, Platzer, Konrad, additional, Schnabel, Franziska, additional, Abou Jamra, Rami, additional, Roberts, Amy E., additional, Newburger, Jane W., additional, Revah-Politi, Anya, additional, Granadillo, Jorge L., additional, Stegmann, Alexander P.A., additional, Sinnema, Margje, additional, Accogli, Andrea, additional, Salpietro, Vincenzo, additional, Capra, Valeria, additional, Ghaloul-Gonzalez, Lina, additional, Brueckner, Martina, additional, Simon, Marleen E.H., additional, Sweetser, David A., additional, Glinton, Kevin E., additional, Kirk, Susan E., additional, Wangler, Michael F., additional, Yamamoto, Shinya, additional, Chung, Wendy K., additional, Bellen, Hugo J., additional, Burrage, Lindsay C., additional, Heaney, Jason D., additional, Kim, Seon-Young, additional, Lanza, Denise G., additional, Liu, Zhandong, additional, Mao, Dongxue, additional, Milosavljevic, Aleksander, additional, Nagamani, Sandesh C.S., additional, Posey, Jennifer E., additional, Ramamurthy, Uma, additional, Ramanathan, Vivek, additional, Rogers, Jeffrey, additional, Rosenfeld, Jill A., additional, Roth, Matthew, additional, and Zahedi Darshoori, Ramin, additional

Published
2024
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8. Dominant mutations in ITPR3 cause Charcot‐Marie‐Tooth disease

Author

Julius Rönkkö, Svetlana Molchanova, Anya Revah‐Politi, Elaine M. Pereira, Mari Auranen, Jussi Toppila, Jouni Kvist, Anastasia Ludwig, Julika Neumann, Geert Bultynck, Stéphanie Humblet‐Baron, Adrian Liston, Anders Paetau, Claudio Rivera, Matthew B. Harms, Henna Tyynismaa, and Emil Ylikallio

Subjects
Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571, Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract Objective ITPR3, encoding inositol 1,4,5‐trisphosphate receptor type 3, was previously reported as a potential candidate disease gene for Charcot‐Marie‐Tooth neuropathy. Here, we present genetic and functional evidence that ITPR3 is a Charcot‐Marie‐Tooth disease gene. Methods Whole‐exome sequencing of four affected individuals in an autosomal dominant family and one individual who was the only affected individual in his family was used to identify disease‐causing variants. Skin fibroblasts from two individuals of the autosomal dominant family were analyzed functionally by western blotting, quantitative reverse transcription PCR, and Ca2+ imaging. Results Affected individuals in the autosomal dominant family had onset of symmetrical neuropathy with demyelinating and secondary axonal features at around age 30, showing signs of gradual progression with severe distal leg weakness and hand involvement in the proband at age 64. Exome sequencing identified a heterozygous ITPR3 p.Val615Met variant segregating with the disease. The individual who was the only affected in his family had disease onset at age 4 with demyelinating neuropathy. His condition was progressive, leading to severe muscle atrophy below knees and atrophy of proximal leg and hand muscles by age 16. Trio exome sequencing identified a de novo ITPR3 variant p.Arg2524Cys. Altered Ca2+‐transients in p.Val615Met patient fibroblasts suggested that the variant has a dominant‐negative effect on inositol 1,4,5‐trisphosphate receptor type 3 function. Interpretation Together with two previously identified variants, our report adds further evidence that ITPR3 is a disease‐causing gene for CMT and indicates altered Ca2+ homeostasis in disease pathogenesis.

Published
2020
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9. Developmental epileptic encephalopathy in DLG4‐related synaptopathy

Author

Kassabian, Benedetta, primary, Levy, Amanda M., additional, Gardella, Elena, additional, Aledo‐Serrano, Angel, additional, Ananth, Amitha L., additional, Brea‐Fernández, Alejandro J., additional, Caumes, Roseline, additional, Chatron, Nicolas, additional, Dainelli, Alice, additional, De Wachter, Matthias, additional, Denommé‐Pichon, Anne‐Sophie, additional, Dye, Thomas J., additional, Fazzi, Elisa, additional, Felt, Roxanne, additional, Fernández‐Jaén, Alberto, additional, Fernández‐Prieto, Montserrat, additional, Gantz, Emily, additional, Gasperowicz, Piotr, additional, Gil‐Nagel, Antonio, additional, Gómez‐Andrés, David, additional, Greiner, Hansel M., additional, Guerrini, Renzo, additional, Haanpää, Maria K., additional, Helin, Minttu, additional, Hoyer, Juliane, additional, Hurst, Anna C. E., additional, Kallish, Staci, additional, Karkare, Shefali N., additional, Khan, Amjad, additional, Kleinendorst, Lotte, additional, Koch, Johannes, additional, Kothare, Sanjeev V., additional, Koudijs, Suzanna V., additional, Lagae, Lieven, additional, Lakeman, Phillis, additional, Leppig, Kathleen A., additional, Lesca, Gaetan, additional, Lopergolo, Diego, additional, Lusk, Laina, additional, Mackenzie, Alex, additional, Mei, Davide, additional, Møller, Rikke S., additional, Pereira, Elaine M., additional, Platzer, Konrad, additional, Quelin, Chloe, additional, Revah‐Politi, Anya, additional, Rheims, Sylvain, additional, Rodríguez‐Palmero, Agustí, additional, Rossi, Andrea, additional, Santorelli, Filippo, additional, Seinfeld, Syndi, additional, Sell, Erick, additional, Stephenson, Donna, additional, Szczaluba, Krzysztof, additional, Trinka, Eugen, additional, Umair, Muhammad, additional, Van Esch, Hilde, additional, van Haelst, Mieke M., additional, Veenma, Danielle C. M., additional, Weber, Sacha, additional, Weckhuysen, Sarah, additional, Zacher, Pia, additional, Tümer, Zeynep, additional, and Rubboli, Guido, additional

Published
2023
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10. Evaluation of the cost and effectiveness of diverse recruitment methods for a genetic screening study

Author

Milo Rasouly, Hila, Wynn, Julia, Marasa, Maddalena, Reingold, Rachel, Chatterjee, Debanjana, Kapoor, Sheena, Piva, Stacy, Kil, Byum Hee, Mu, Xueru, Alvarez, Maria, Nestor, Jordan, Mehl, Karla, Revah-Politi, Anya, Lippa, Natalie, Ernst, Michelle E., Bier, Louise, Espinal, Aileen, Haser, Bianca, Sinha, Anoushka, Halim, Ian, Fasel, David, Cuneo, Nicole, Thompson, Jacqueline J., Verbitsky, Miguel, Cohn, Elizabeth G., Goldman, Jill, Marder, Karen, Klitzman, Robert L., Orjuela, Manuela A., So, Yat S., Fedotov, Alex, Crew, Katherine D., Kiryluk, Krzysztof, Appelbaum, Paul S., Weng, Chunhua, Siegel, Karolynn, Gharavi, Ali G., and Chung, Wendy K.

Published
2019
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11. Heterozygous loss-of-function variants of MEIS2 cause a triad of palatal defects, congenital heart defects, and intellectual disability

Author

Verheije, Rosalind, Kupchik, Gabriel S., Isidor, Bertrand, Kroes, Hester Y., Lynch, Sally Ann, Hawkes, Lara, Hempel, Maja, Gelb, Bruce D., Ghoumid, Jamal, D’Amours, Guylaine, Chandler, Kate, Dubourg, Christèle, Loddo, Sara, Tümer, Zeynep, Shaw-Smith, Charles, Nizon, Mathilde, Shevell, Michael, Van Hoof, Evelien, Anyane-Yeboa, Kwame, Cerbone, Gaetana, Clayton-Smith, Jill, Cogné, Benjamin, Corre, Pierre, Corveleyn, Anniek, De Borre, Marie, Hjortshøj, Tina Duelund, Fradin, Mélanie, Gewillig, Marc, Goldmuntz, Elizabeth, Hens, Greet, Lemyre, Emmanuelle, Journel, Hubert, Kini, Usha, Kortüm, Fanny, Le Caignec, Cedric, Novelli, Antonio, Odent, Sylvie, Petit, Florence, Revah-Politi, Anya, Stong, Nicholas, Strom, Tim M., van Binsbergen, Ellen, DDD study, Devriendt, Koenraad, and Breckpot, Jeroen

Published
2019
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12. Clinical Real-Time Genome Sequencing to Solve the Complex and Confounded Presentation of a Child With Focal Segmental Glomerulosclerosis and Multiple Malignancies

Author

Namrata G. Jain, Dina F. Ahram, Maddalena Marasa, Ateeq U. Rehman, Halie J. May, Stergios Zacharoulis, Anya Revah-Politi, Michelle E. Florido, Gregory B. Whittemore, Vimla S. Aggarwal, Gunnar Hargus, Kwame Anyane-Yeboa, Vivette D. D’Agati, Fangming Lin, Vaidehi Jobanputra, and Simone Sanna-Cherchi

Subjects
Nephrology
Published
2022
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15. De novo mutations in the GTP/GDP-binding region of RALA, a RAS-like small GTPase, cause intellectual disability and developmental delay.

Author

Susan M Hiatt, Matthew B Neu, Ryne C Ramaker, Andrew A Hardigan, Jeremy W Prokop, Miroslava Hancarova, Darina Prchalova, Marketa Havlovicova, Jan Prchal, Viktor Stranecky, Dwight K C Yim, Zöe Powis, Boris Keren, Caroline Nava, Cyril Mignot, Marlene Rio, Anya Revah-Politi, Parisa Hemati, Nicholas Stong, Alejandro D Iglesias, Sharon F Suchy, Rebecca Willaert, Ingrid M Wentzensen, Patricia G Wheeler, Lauren Brick, Mariya Kozenko, Anna C E Hurst, James W Wheless, Yves Lacassie, Richard M Myers, Gregory S Barsh, Zdenek Sedlacek, and Gregory M Cooper

Subjects
Genetics, QH426-470
Abstract

Mutations that alter signaling of RAS/MAPK-family proteins give rise to a group of Mendelian diseases known as RASopathies. However, among RASopathies, the matrix of genotype-phenotype relationships is still incomplete, in part because there are many RAS-related proteins and in part because the phenotypic consequences may be variable and/or pleiotropic. Here, we describe a cohort of ten cases, drawn from six clinical sites and over 16,000 sequenced probands, with de novo protein-altering variation in RALA, a RAS-like small GTPase. All probands present with speech and motor delays, and most have intellectual disability, low weight, short stature, and facial dysmorphism. The observed rate of de novo RALA variants in affected probands is significantly higher (p = 4.93 x 10(-11)) than expected from the estimated random mutation rate. Further, all de novo variants described here affect residues within the GTP/GDP-binding region of RALA; in fact, six alleles arose at only two codons, Val25 and Lys128. The affected residues are highly conserved across both RAL- and RAS-family genes, are devoid of variation in large human population datasets, and several are homologous to positions at which disease-associated variants have been observed in other GTPase genes. We directly assayed GTP hydrolysis and RALA effector-protein binding of the observed variants, and found that all but one tested variant significantly reduced both activities compared to wild-type. The one exception, S157A, reduced GTP hydrolysis but significantly increased RALA-effector binding, an observation similar to that seen for oncogenic RAS variants. These results show the power of data sharing for the interpretation and analysis of rare variation, expand the spectrum of molecular causes of developmental disability to include RALA, and provide additional insight into the pathogenesis of human disease caused by mutations in small GTPases.

Published
2018
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16. Clinical Real-Time Genome Sequencing to Solve the Complex and Confounded Presentation of a Child With Focal Segmental Glomerulosclerosis and Multiple Malignancies

Author

Jain, Namrata G., primary, Ahram, Dina F., additional, Marasa, Maddalena, additional, Rehman, Ateeq U., additional, May, Halie J., additional, Zacharoulis, Stergios, additional, Revah-Politi, Anya, additional, Florido, Michelle E., additional, Whittemore, Gregory B., additional, Aggarwal, Vimla S., additional, Hargus, Gunnar, additional, Anyane-Yeboa, Kwame, additional, D’Agati, Vivette D., additional, Lin, Fangming, additional, Jobanputra, Vaidehi, additional, and Sanna-Cherchi, Simone, additional

Published
2022
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17. Germline variants in tumor suppressor FBXW7 lead to impaired ubiquitination and a neurodevelopmental syndrome

Author

Sarah E.M. Stephenson, Gregory Costain, Laura E.R. Blok, Michael A. Silk, Thanh Binh Nguyen, Xiaomin Dong, Dana E. Alhuzaimi, James J. Dowling, Susan Walker, Kimberly Amburgey, Robin Z. Hayeems, Lance H. Rodan, Marc A. Schwartz, Jonathan Picker, Sally A. Lynch, Aditi Gupta, Kristen J. Rasmussen, Lisa A. Schimmenti, Eric W. Klee, Zhiyv Niu, Katherine E. Agre, Ilana Chilton, Wendy K. Chung, Anya Revah-Politi, P.Y. Billie Au, Christopher Griffith, Melissa Racobaldo, Annick Raas-Rothschild, Bruria Ben Zeev, Ortal Barel, Sebastien Moutton, Fanny Morice-Picard, Virginie Carmignac, Jenny Cornaton, Nathalie Marle, Orrin Devinsky, Chandler Stimach, Stephanie Burns Wechsler, Bryan E. Hainline, Katie Sapp, Marjolaine Willems, Ange-line Bruel, Kerith-Rae Dias, Carey-Anne Evans, Tony Roscioli, Rani Sachdev, Suzanna E.L. Temple, Ying Zhu, Joshua J. Baker, Ingrid E. Scheffer, Fiona J. Gardiner, Amy L. Schneider, Alison M. Muir, Heather C. Mefford, Amy Crunk, Elizabeth M. Heise, Francisca Millan, Kristin G. Monaghan, Richard Person, Lindsay Rhodes, Sarah Richards, Ingrid M. Wentzensen, Benjamin Cogné, Bertrand Isidor, Mathilde Nizon, Marie Vincent, Thomas Besnard, Amelie Piton, Carlo Marcelis, Kohji Kato, Norihisa Koyama, Tomoo Ogi, Elaine Suk-Ying Goh, Christopher Richmond, David J. Amor, Jessica O. Boyce, Angela T. Morgan, Michael S. Hildebrand, Antony Kaspi, Melanie Bahlo, Rún Friðriksdóttir, Hildigunnur Katrínardóttir, Patrick Sulem, Kári Stefánsson, Hans Tómas Björnsson, Simone Mandelstam, Manuela Morleo, Milena Mariani, Marcello Scala, Andrea Accogli, Annalaura Torella, Valeria Capra, Mathew Wallis, Sandra Jansen, Quinten Waisfisz, Hugoline de Haan, Simon Sadedin, Sze Chern Lim, Susan M. White, David B. Ascher, Annette Schenck, Paul J. Lockhart, John Christodoulou, Tiong Yang Tan, Stephenson, S. E. M., Costain, G., Blok, L. E. R., Silk, M. A., Nguyen, T. B., Dong, X., Alhuzaimi, D. E., Dowling, J. J., Walker, S., Amburgey, K., Hayeems, R. Z., Rodan, L. H., Schwartz, M. A., Picker, J., Lynch, S. A., Gupta, A., Rasmussen, K. J., Schimmenti, L. A., Klee, E. W., Niu, Z., Agre, K. E., Chilton, I., Chung, W. K., Revah-Politi, A., Au, P. Y. B., Griffith, C., Racobaldo, M., Raas-Rothschild, A., Ben Zeev, B., Barel, O., Moutton, S., Morice-Picard, F., Carmignac, V., Cornaton, J., Marle, N., Devinsky, O., Stimach, C., Wechsler, S. B., Hainline, B. E., Sapp, K., Willems, M., Bruel, A. -L., Dias, K. -R., Evans, C. -A., Roscioli, T., Sachdev, R., Temple, S. E. L., Zhu, Y., Baker, J. J., Scheffer, I. E., Gardiner, F. J., Schneider, A. L., Muir, A. M., Mefford, H. C., Crunk, A., Heise, E. M., Millan, F., Monaghan, K. G., Person, R., Rhodes, L., Richards, S., Wentzensen, I. M., Cogne, B., Isidor, B., Nizon, M., Vincent, M., Besnard, T., Piton, A., Marcelis, C., Kato, K., Koyama, N., Ogi, T., Goh, E. S. -Y., Richmond, C., Amor, D. J., Boyce, J. O., Morgan, A. T., Hildebrand, M. S., Kaspi, A., Bahlo, M., Fridriksdottir, R., Katrinardottir, H., Sulem, P., Stefansson, K., Bjornsson, H. T., Mandelstam, S., Morleo, M., Mariani, M., Scala, M., Accogli, A., Torella, A., Capra, V., Wallis, M., Jansen, S., Weisfisz, Q., de Haan, H., Sadedin, S., Lim, S. C., White, S. M., Ascher, D. B., Schenck, A., Lockhart, P. J., Christodoulou, J., Tan, T. Y., and Human genetics

Subjects
F-box protein, Ubiquitin-Protein Ligase, Proteasome Endopeptidase Complex, F-Box-WD Repeat-Containing Protein 7, Ubiquitin-Protein Ligases, Neurodevelopment, global developmental delay, macrocephaly, Germ Cell, Article, All institutes and research themes of the Radboud University Medical Center, FBXW7, Neurodevelopmental Disorder, Genetics, Humans, hypotonia, Germ-Line Mutation, Genetics (clinical), Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], brain malformation, Ubiquitination, gastrointestinal issue, Germ Cells, intellectual disability, Neurodevelopmental Disorders, epilepsy, Human
Abstract

Neurodevelopmental disorders are highly heterogenous conditions resulting from abnormalities of brain architecture and/or function. FBXW7 (F-box and WD-repeat-domain-containing 7), a recognized developmental regulator and tumor suppressor, has been shown to regulate cell-cycle progression and cell growth and survival by targeting substrates including CYCLIN E1/2 and NOTCH for degradation via the ubiquitin proteasome system. We used a genotype-first approach and global data-sharing platforms to identify 35 individuals harboring de novo and inherited FBXW7 germline monoallelic chromosomal deletions and nonsense, frameshift, splice-site, and missense variants associated with a neurodevelopmental syndrome. The FBXW7 neurodevelopmental syndrome is distinguished by global developmental delay, borderline to severe intellectual disability, hypotonia, and gastrointestinal issues. Brain imaging detailed variable underlying structural abnormalities affecting the cerebellum, corpus collosum, and white matter. A crystal-structure model of FBXW7 predicted that missense variants were clustered at the substrate-binding surface of the WD40 domain and that these might reduce FBXW7 substrate binding affinity. Expression of recombinant FBXW7 missense variants in cultured cells demonstrated impaired CYCLIN E1 and CYCLIN E2 turnover. Pan-neuronal knockdown of the Drosophila ortholog, archipelago, impaired learning and neuronal function. Collectively, the data presented herein provide compelling evidence of an F-Box protein-related, phenotypically variable neurodevelopmental disorder associated with monoallelic variants in FBXW7.

Published
2022
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18. The clinical and molecular spectrum of QRICH1 associated neurodevelopmental disorder

Author

Kumble, Smitha, Levy, Amanda, Punetha, Jaya, Gao, Hua, Ah Mew, Nicholas, Anyane-Yeboa, Kwame, Benke, Paul, Berger, Sara, Bjerglund, Lise, Campos-Xavier, Belinda, Ciliberto, Michael, Cohen, Julie, Comi, Anne, Curry, Cynthia, Damaj, Lena, Denommé-Pichon, Anne-Sophie, Emrick, Lisa, Faivre, Laurence, Fasano, Mary Beth, Fiévet, Alice, Finkel, Richard, García-Miñaúr, Sixto, Gerard, Amanda, Gomez-Puertas, Paulino, Guillen Sacoto, Maria, Hoffman, Trevor, Howard, Lillian, Iglesias, Alejandro, Izumi, Kosuke, Larson, Austin, Leiber, Anja, Lozano, Reymundo, Marcos-Alcalde, Iñigo, Mintz, Cassie, Mullegama, Sureni, Møller, Rikke, Odent, Sylvie, Oppermann, Henry, Ostergaard, Elsebet, Pacio-Míguez, Marta, Palomares-Bralo, Maria, Parikh, Sumit, Paulson, Anna, Platzer, Konrad, Posey, Jennifer, Potocki, Lorraine, Revah-Politi, Anya, Rio, Marlene, Ritter, Alyssa, Robinson, Scott, Rosenfeld, Jill, Santos-Simarro, Fernando, Anyane‐Yeboa, Kwame, Campos‐Xavier, Belinda, Denommé‐Pichon, Anne‐Sophie, García‐Miñaúr, Sixto, Gomez‐Puertas, Paulino, Marcos‐Alcalde, Iñigo, Pacio‐Míguez, Marta, Palomares‐Bralo, Maria, Revah‐Politi, Anya, Santos‐Simarro, Fernando, Sombra, Sérgio Sousa, Wéber, Mathys, Xie, Yili, Chung, Wendy K., Brown, Natasha, Tümer, Zeynep, Murdoch Children's Research Institute (MCRI), Copenhagen University Hospital, Baylor College of Medicine (BCM), Baylor University, Icahn School of Medicine at Mount Sinai [New York] (MSSM), CHU Pontchaillou [Rennes], Université Bourgogne Franche-Comté [COMUE] (UBFC), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Institut Gustave Roussy (IGR), Institut de Génétique et Développement de Rennes (IGDR), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Centre de référence Maladies Rares CLAD-Ouest [Rennes], CIBER de Enfermedades Raras (CIBERER), GeneDx [Gaithersburg, MD, USA], Columbia University Irving Medical Center (CUIMC), University of Melbourne, University of Copenhagen = Københavns Universitet (KU), Spanish Ministry of Science / State Research Agency projects. Grant Numbers: DTS20-00024, RTC-2017-6494-1, RTI2018-094434-B-I00 SFARI and JPB Foundation, Raregenomics network, financed by the Consejería de Educación de la C. de Madrid. Grant Number: S2017 / BMD-3721, European Comission JPIAMR projects CONNECT and AEPIC, National Center for Advancing Translational Sciences, National Institutes of Health. Grant Number: UL1TR001873, National Human Genome Research Institute (NHGRI) and National Heart, Lung, and Blood Institute (NHLBI). Grant Number: UM1 HG006542 Undiagnosed Diseases Network, European Social Fund, Rashid Family Fund, NIH Common Fund, through the Office of Strategic Coordination/Office of the NIH Director. Grant Number: U01HG007709, ISCIII, Ministerio de Ciencia e Innovación. Grant Number: PI19/01681, Baylor Hopkins Center for Mendelian Genomics. Grant Numbers: NHGRI K08 HG008986, NHGRI/NLHBI UM1 HG006542, Centro Portugal Regional Operational Programme (CENTRO 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (ERDF). Grant Number: CENTRO-01-0247-FEDER-017800, Département de biologie et pathologie médicales [Gustave Roussy], Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and University of Copenhagen = Københavns Universitet (UCPH)

Subjects
Autism Spectrum Disorder, [SDV]Life Sciences [q-bio], Dwarfism, Biology, Bioinformatics, Weight Gain, Short stature, 03 medical and health sciences, 0302 clinical medicine, Neurodevelopmental disorder, Neuroimaging, Seizures, variable expressivity, Intellectual disability, Genetics, medicine, Missense mutation, Humans, QRICH1, hypotonia, Genetics (clinical), 030304 developmental biology, 0303 health sciences, medicine.disease, Hypotonia, short stature, Scoliosis, variant, Autism spectrum disorder, Neurodevelopmental Disorders, intellectual disability, Muscle Hypotonia, medicine.symptom, 030217 neurology & neurosurgery
Abstract

De novo variants in QRICH1 (Glutamine-rich protein 1) has recently been reported in 11 individuals with intellectual disability. The function of QRICH1 is largely unknown but it is likely to play a key role in the unfolded response of endoplasmic reticulum (ER) stress through transcriptional control of proteostasis. In this study, we present 27 additional individuals and delineate the clinical and molecular spectrum of the individuals (n=38) with QRICH1 variants. The main clinical features were mild to moderate developmental delay/intellectual disability (71%), non-specific facial dysmorphism (92%) and hypotonia (39%). Additional findings included poor weight gain (29%), short stature (29%), autism spectrum disorder (29%), seizures (24%) and scoliosis (18%). Minor structural brain abnormalities were reported in 52% of the individuals with brain imaging. Truncating or splice variants were found in 28 individuals and 10 had missense variants. Four variants were inherited from mildly affected parents. This study confirms that heterozygous QRICH1 variants cause a neurodevelopmental disorder including short stature and expands the phenotypic spectrum to include poor weight gain, scoliosis, hypotonia, minor structural brain anomalies, and seizures. Inherited variants from mildly affected parents are reported for the first time, suggesting variable expressivity. This article is protected by copyright. All rights reserved.

Published
2021
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19. ZTTK syndrome: Clinical and molecular findings of 15 cases and a review of the literature

Author

Kushary, S.T., Revah-Politi, A., Barua, S., Ganapathi, M., Accogli, A., Aggarwal, V., Brunetti-Pierri, N., Cappuccio, G., Capra, V., Fagerberg, C.R., Gazdagh, G., Guzman, E., Hadonou, M., Harrison, V., Havelund, K., Iancu, D., Kraus, A., Lippa, N.C., Mansukhani, M., McBrian, D., McEntagart, M., Pacio-Miguez, M., Palomares-Bralo, M., Pottinger, C., Ruivenkamp, C.A.L., Sacco, O., Santen, G.W.E., Santos-Simarro, F., Scala, M., Short, J., Sorensen, K.P., Woods, C.G., Yeboa, K.A., DDD Study, TUDP Consortium, Kushary, S. T., Revah-Politi, A., Barua, S., Ganapathi, M., Accogli, A., Aggarwal, V., Brunetti Pierri, N., Cappuccio, G., Capra, V., Fagerberg, C. R., Gazdagh, G., Guzman, E., Hadonou, M., Harrison, V., Havelund, K., Iancu, D., Kraus, A., Lippa, N. C., Mansukhani, M., Mcbrian, D., Mcentagart, M., Pacio-Miguez, M., Palomares-Bralo, M., Pottinger, C., Ruivenkamp, C. A. L., Sacco, O., Santen, G. W. E., Santos-Simarro, F., Scala, M., Short, J., Sorensen, K. P., Woods, C. G., and Anyane Yeboa, K.

Subjects
Male, Genotype, Mutation, Missense, genotype-phenotype correlation, Article, Congenital Abnormalities, whole exome sequencing, Minor Histocompatibility Antigens, Neuroimaging, Seizures, Intellectual Disability, Intellectual disability, Exome Sequencing, Genetics, Medicine, Missense mutation, Humans, Genetic Predisposition to Disease, Gene, Genetics (clinical), Exome sequencing, Genetic Association Studies, business.industry, Brain, genotype–phenotype correlation, medicine.disease, SON, DNA-Binding Proteins, Phenotype, Variable dysmorphic features, Female, business, multisystemic disorder
Abstract

Zhu-Tokita-Takenouchi-Kim (ZTTK) syndrome is caused by de novo loss-of-function variants in the SON gene (MIM #617140). This multisystemic disorder is characterized by intellectual disability, seizures, abnormal brain imaging, variable dysmorphic features, and various congenital anomalies. The wide application and increasing accessibility of whole exome sequencing (WES) has helped to identify new cases of ZTTK syndrome over the last few years. To date, there have been approximately 45 cases reported in the literature. Here, we describe 15 additional individuals with variants in the SON gene, including those with missense variants bringing the total number of known cases to 60. We have reviewed the clinical and molecular data of these new cases and all previously reported cases to further delineate the most common as well as emerging clinical findings related to this syndrome. Furthermore, we aim to delineate any genotype–phenotype correlations specifically for a recurring pathogenic four base pair deletion (c.5753_5756del) along with discussing the impact of missense variants seen in the SON gene.

Published
2021
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20. The clinical and molecular spectrum of QRICH1 associated neurodevelopmental disorder

Author

Kumble, S, Levy, AM, Punetha, J, Gao, H, Ah Mew, N, Anyane-Yeboa, K, Benke, PJ, Berger, SM, Bjerglund, L, Campos-Xavier, B, Ciliberto, M, Cohen, JS, Comi, AM, Curry, C, Damaj, L, Denomme-Pichon, A-S, Emrick, L, Faivre, L, Fasano, MB, Fievet, A, Finkel, RS, Garcia-Minaur, S, Gerard, A, Gomez-Puertas, P, Guillen Sacoto, MJ, Hoffman, TL, Howard, L, Iglesias, AD, Izumi, K, Larson, A, Leiber, A, Lozano, R, Marcos-Alcalde, I, Mintz, CS, Mullegama, SV, Moller, RS, Odent, S, Oppermann, H, Ostergaard, E, Pacio-Miguez, M, Palomares-Bralo, M, Parikh, S, Paulson, AM, Platzer, K, Posey, JE, Potocki, L, Revah-Politi, A, Rio, M, Ritter, AL, Robinson, S, Rosenfeld, JA, Santos-Simarro, F, Sousa, SB, Weber, M, Xie, Y, Chung, WK, Brown, NJ, Tumer, Z, Kumble, S, Levy, AM, Punetha, J, Gao, H, Ah Mew, N, Anyane-Yeboa, K, Benke, PJ, Berger, SM, Bjerglund, L, Campos-Xavier, B, Ciliberto, M, Cohen, JS, Comi, AM, Curry, C, Damaj, L, Denomme-Pichon, A-S, Emrick, L, Faivre, L, Fasano, MB, Fievet, A, Finkel, RS, Garcia-Minaur, S, Gerard, A, Gomez-Puertas, P, Guillen Sacoto, MJ, Hoffman, TL, Howard, L, Iglesias, AD, Izumi, K, Larson, A, Leiber, A, Lozano, R, Marcos-Alcalde, I, Mintz, CS, Mullegama, SV, Moller, RS, Odent, S, Oppermann, H, Ostergaard, E, Pacio-Miguez, M, Palomares-Bralo, M, Parikh, S, Paulson, AM, Platzer, K, Posey, JE, Potocki, L, Revah-Politi, A, Rio, M, Ritter, AL, Robinson, S, Rosenfeld, JA, Santos-Simarro, F, Sousa, SB, Weber, M, Xie, Y, Chung, WK, Brown, NJ, and Tumer, Z

Abstract

De novo variants in QRICH1 (Glutamine-rich protein 1) has recently been reported in 11 individuals with intellectual disability (ID). The function of QRICH1 is largely unknown but it is likely to play a key role in the unfolded response of endoplasmic reticulum stress through transcriptional control of proteostasis. In this study, we present 27 additional individuals and delineate the clinical and molecular spectrum of the individuals (n = 38) with QRICH1 variants. The main clinical features were mild to moderate developmental delay/ID (71%), nonspecific facial dysmorphism (92%) and hypotonia (39%). Additional findings included poor weight gain (29%), short stature (29%), autism spectrum disorder (29%), seizures (24%) and scoliosis (18%). Minor structural brain abnormalities were reported in 52% of the individuals with brain imaging. Truncating or splice variants were found in 28 individuals and 10 had missense variants. Four variants were inherited from mildly affected parents. This study confirms that heterozygous QRICH1 variants cause a neurodevelopmental disorder including short stature and expands the phenotypic spectrum to include poor weight gain, scoliosis, hypotonia, minor structural brain anomalies, and seizures. Inherited variants from mildly affected parents are reported for the first time, suggesting variable expressivity.

Published
2022

21. Germline variants in tumor suppressor FBXW7 lead to impaired ubiquitination and a neurodevelopmental syndrome

Author

Stephenson, SEM, Costain, G, Blok, LER, Silk, MA, Nguyen, TB, Dong, X, Alhuzaimi, DE, Dowling, JJ, Walker, S, Amburgey, K, Hayeems, RZ, Rodan, LH, Schwartz, MA, Picker, J, Lynch, SA, Gupta, A, Rasmussen, KJ, Schimmenti, LA, Klee, EW, Niu, Z, Agre, KE, Chilton, I, Chung, WK, Revah-Politi, A, Au, PYB, Griffith, C, Racobaldo, M, Raas-Rothschild, A, Ben Zeev, B, Barel, O, Moutton, S, Morice-Picard, F, Carmignac, V, Cornaton, J, Marle, N, Devinsky, O, Stimach, C, Wechsler, SB, Hainline, BE, Sapp, K, Willems, M, Bruel, A, Dias, K-R, Evans, C-A, Roscioli, T, Sachdev, R, Temple, SEL, Zhu, Y, Baker, JJ, Scheffer, IE, Gardiner, FJ, Schneider, AL, Muir, AM, Mefford, HC, Crunk, A, Heise, EM, Millan, F, Monaghan, KG, Person, R, Rhodes, L, Richards, S, Wentzensen, IM, Cogne, B, Isidor, B, Nizon, M, Vincent, M, Besnard, T, Piton, A, Marcelis, C, Kato, K, Koyama, N, Ogi, T, Goh, ES-Y, Richmond, C, Amor, DJ, Boyce, JO, Morgan, AT, Hildebrand, MS, Kaspi, A, Bahlo, M, Fridriksdottir, R, Katrinardottir, H, Sulem, P, Stefansson, K, Bjornsson, HT, Mandelstam, S, Morleo, M, Mariani, M, Scala, M, Accogli, A, Torella, A, Capra, V, Wallis, M, Jansen, S, Waisfisz, Q, de Haan, H, Sadedin, S, Lim, SC, White, SM, Ascher, DB, Schenck, A, Lockhart, PJ, Christodoulou, J, Tan, TY, Stephenson, SEM, Costain, G, Blok, LER, Silk, MA, Nguyen, TB, Dong, X, Alhuzaimi, DE, Dowling, JJ, Walker, S, Amburgey, K, Hayeems, RZ, Rodan, LH, Schwartz, MA, Picker, J, Lynch, SA, Gupta, A, Rasmussen, KJ, Schimmenti, LA, Klee, EW, Niu, Z, Agre, KE, Chilton, I, Chung, WK, Revah-Politi, A, Au, PYB, Griffith, C, Racobaldo, M, Raas-Rothschild, A, Ben Zeev, B, Barel, O, Moutton, S, Morice-Picard, F, Carmignac, V, Cornaton, J, Marle, N, Devinsky, O, Stimach, C, Wechsler, SB, Hainline, BE, Sapp, K, Willems, M, Bruel, A, Dias, K-R, Evans, C-A, Roscioli, T, Sachdev, R, Temple, SEL, Zhu, Y, Baker, JJ, Scheffer, IE, Gardiner, FJ, Schneider, AL, Muir, AM, Mefford, HC, Crunk, A, Heise, EM, Millan, F, Monaghan, KG, Person, R, Rhodes, L, Richards, S, Wentzensen, IM, Cogne, B, Isidor, B, Nizon, M, Vincent, M, Besnard, T, Piton, A, Marcelis, C, Kato, K, Koyama, N, Ogi, T, Goh, ES-Y, Richmond, C, Amor, DJ, Boyce, JO, Morgan, AT, Hildebrand, MS, Kaspi, A, Bahlo, M, Fridriksdottir, R, Katrinardottir, H, Sulem, P, Stefansson, K, Bjornsson, HT, Mandelstam, S, Morleo, M, Mariani, M, Scala, M, Accogli, A, Torella, A, Capra, V, Wallis, M, Jansen, S, Waisfisz, Q, de Haan, H, Sadedin, S, Lim, SC, White, SM, Ascher, DB, Schenck, A, Lockhart, PJ, Christodoulou, J, and Tan, TY

Abstract

Neurodevelopmental disorders are highly heterogenous conditions resulting from abnormalities of brain architecture and/or function. FBXW7 (F-box and WD-repeat-domain-containing 7), a recognized developmental regulator and tumor suppressor, has been shown to regulate cell-cycle progression and cell growth and survival by targeting substrates including CYCLIN E1/2 and NOTCH for degradation via the ubiquitin proteasome system. We used a genotype-first approach and global data-sharing platforms to identify 35 individuals harboring de novo and inherited FBXW7 germline monoallelic chromosomal deletions and nonsense, frameshift, splice-site, and missense variants associated with a neurodevelopmental syndrome. The FBXW7 neurodevelopmental syndrome is distinguished by global developmental delay, borderline to severe intellectual disability, hypotonia, and gastrointestinal issues. Brain imaging detailed variable underlying structural abnormalities affecting the cerebellum, corpus collosum, and white matter. A crystal-structure model of FBXW7 predicted that missense variants were clustered at the substrate-binding surface of the WD40 domain and that these might reduce FBXW7 substrate binding affinity. Expression of recombinant FBXW7 missense variants in cultured cells demonstrated impaired CYCLIN E1 and CYCLIN E2 turnover. Pan-neuronal knockdown of the Drosophila ortholog, archipelago, impaired learning and neuronal function. Collectively, the data presented herein provide compelling evidence of an F-Box protein-related, phenotypically variable neurodevelopmental disorder associated with monoallelic variants in FBXW7.

Published
2022

23. Correction: Evaluation of the cost and effectiveness of diverse recruitment methods for a genetic screening study

Author

Rasouly, Hila Milo, Wynn, Julia, Marasa, Maddalena, Reingold, Rachel, Chatterjee, Debanjana, Kapoor, Sheena, Piva, Stacy, Kil, Byum Hee, Mu, Xueru, Alvarez, Maria, Nestor, Jordan, Mehl, Karla, Revah-Politi, Anya, Lippa, Natalie, Ernst, Michelle E., Bier, Louise, Espinal, Aileen, Haser, Bianca, Sinha, Anoushka, Halim, Ian, Fasel, David, Cuneo, Nicole, Thompson, Jacqueline J., Verbitsky, Miguel, Cohn, Elizabeth G., Goldman, Jill, Marder, Karen, Klitzman, Robert L., Orjuela, Manuela A., So, Yat S., Fedotov, Alex, Crew, Katherine D., Kiryluk, Krzysztof, Appelbaum, Paul S., Weng, Chunhua, Siegel, Karolynn, Gharavi, Ali G., and Chung, Wendy K.

Published
2019
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24. Diagnostic sequencing to support genetically stratified medicine in a tertiary care setting

Author

Lippa, Natalie, primary, Bier, Louise, additional, Revah-Politi, Anya, additional, May, Halie, additional, Kushary, Sulagna, additional, Vena, Natalie, additional, Giordano, Jessica L., additional, Rasouly, Hila Milo, additional, Cocchi, Enrico, additional, Sands, Tristan T., additional, Wapner, Ronald J., additional, Anyane-Yeboa, Kwame, additional, Gharavi, Ali G., additional, and Goldstein, David B., additional

Published
2022
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25. Germline variants in tumor suppressor FBXW7 lead to impaired ubiquitination and a neurodevelopmental syndrome

Author

Stephenson, Sarah E.M., primary, Costain, Gregory, additional, Blok, Laura E.R., additional, Silk, Michael A., additional, Nguyen, Thanh Binh, additional, Dong, Xiaomin, additional, Alhuzaimi, Dana E., additional, Dowling, James J., additional, Walker, Susan, additional, Amburgey, Kimberly, additional, Hayeems, Robin Z., additional, Rodan, Lance H., additional, Schwartz, Marc A., additional, Picker, Jonathan, additional, Lynch, Sally A., additional, Gupta, Aditi, additional, Rasmussen, Kristen J., additional, Schimmenti, Lisa A., additional, Klee, Eric W., additional, Niu, Zhiyv, additional, Agre, Katherine E., additional, Chilton, Ilana, additional, Chung, Wendy K., additional, Revah-Politi, Anya, additional, Au, P.Y. Billie, additional, Griffith, Christopher, additional, Racobaldo, Melissa, additional, Raas-Rothschild, Annick, additional, Ben Zeev, Bruria, additional, Barel, Ortal, additional, Moutton, Sebastien, additional, Morice-Picard, Fanny, additional, Carmignac, Virginie, additional, Cornaton, Jenny, additional, Marle, Nathalie, additional, Devinsky, Orrin, additional, Stimach, Chandler, additional, Wechsler, Stephanie Burns, additional, Hainline, Bryan E., additional, Sapp, Katie, additional, Willems, Marjolaine, additional, Bruel, Ange-line, additional, Dias, Kerith-Rae, additional, Evans, Carey-Anne, additional, Roscioli, Tony, additional, Sachdev, Rani, additional, Temple, Suzanna E.L., additional, Zhu, Ying, additional, Baker, Joshua J., additional, Scheffer, Ingrid E., additional, Gardiner, Fiona J., additional, Schneider, Amy L., additional, Muir, Alison M., additional, Mefford, Heather C., additional, Crunk, Amy, additional, Heise, Elizabeth M., additional, Millan, Francisca, additional, Monaghan, Kristin G., additional, Person, Richard, additional, Rhodes, Lindsay, additional, Richards, Sarah, additional, Wentzensen, Ingrid M., additional, Cogné, Benjamin, additional, Isidor, Bertrand, additional, Nizon, Mathilde, additional, Vincent, Marie, additional, Besnard, Thomas, additional, Piton, Amelie, additional, Marcelis, Carlo, additional, Kato, Kohji, additional, Koyama, Norihisa, additional, Ogi, Tomoo, additional, Goh, Elaine Suk-Ying, additional, Richmond, Christopher, additional, Amor, David J., additional, Boyce, Jessica O., additional, Morgan, Angela T., additional, Hildebrand, Michael S., additional, Kaspi, Antony, additional, Bahlo, Melanie, additional, Friðriksdóttir, Rún, additional, Katrínardóttir, Hildigunnur, additional, Sulem, Patrick, additional, Stefánsson, Kári, additional, Björnsson, Hans Tómas, additional, Mandelstam, Simone, additional, Morleo, Manuela, additional, Mariani, Milena, additional, Scala, Marcello, additional, Accogli, Andrea, additional, Torella, Annalaura, additional, Capra, Valeria, additional, Wallis, Mathew, additional, Jansen, Sandra, additional, Waisfisz, Quinten, additional, de Haan, Hugoline, additional, Sadedin, Simon, additional, Lim, Sze Chern, additional, White, Susan M., additional, Ascher, David B., additional, Schenck, Annette, additional, Lockhart, Paul J., additional, Christodoulou, John, additional, and Tan, Tiong Yang, additional

Published
2022
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26. Dominant mutations in ITPR3 cause Charcot‐Marie‐Tooth disease

Author

Svetlana M. Molchanova, Elaine M. Pereira, Jussi Toppila, Anders Paetau, Anya Revah-Politi, Julius Rönkkö, Adrian Liston, Claudio Rivera, Mari Auranen, Anastasia Ludwig, Emil Ylikallio, Matthew B. Harms, Julika Neumann, Stephanie Humblet-Baron, Jouni Kvist, Henna Tyynismaa, Geert Bultynck, Rönkkö, Julius [0000-0003-4238-2425], Liston, Adrian [0000-0002-6272-4085], Ylikallio, Emil [0000-0001-5178-0703], Apollo - University of Cambridge Repository, University of Helsinki, Columbia University Irving Medical Center (CUIMC), Institut de Neurobiologie de la Méditerranée [Aix-Marseille Université] (INMED - INSERM U1249), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Helsingin yliopisto = Helsingfors universitet = University of Helsinki, STEMM - Stem Cells and Metabolism Research Program, Faculty of Medicine, Research Programs Unit, Molecular and Integrative Biosciences Research Programme, Faculty of Biological and Environmental Sciences, HUS Neurocenter, Neurologian yksikkö, Department of Neurosciences, Helsinki University Hospital Area, HUS Medical Imaging Center, Department of Diagnostics and Therapeutics, Kliinisen neurofysiologian yksikkö, Neuroscience Center, Helsinki Institute of Life Science HiLIFE, HUSLAB, Department of Pathology, Centre of Excellence in Stem Cell Metabolism, Department of Medical and Clinical Genetics, Henna Tyynismaa / Principal Investigator, Clinicum, and Basal ganglia circuits

Subjects
Adult, 0301 basic medicine, Proband, Heterozygote, Genes, Recessive, Neurosciences. Biological psychiatry. Neuropsychiatry, Disease, CALCIUM, 3124 Neurology and psychiatry, ITPR3, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Atrophy, Charcot-Marie-Tooth Disease, Humans, Inositol 1,4,5-Trisphosphate Receptors, Medicine, RC346-429, Gene, Research Articles, ComputingMilieux_MISCELLANEOUS, Exome sequencing, Aged, Arthrogryposis, Genetics, biology, business.industry, General Neuroscience, NEUROPATHY, 3112 Neurosciences, Middle Aged, medicine.disease, Muscle atrophy, Pedigree, Blot, Phenotype, 030104 developmental biology, NODES, Mutation, biology.protein, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neurology (clinical), Neurology. Diseases of the nervous system, medicine.symptom, business, 030217 neurology & neurosurgery, Research Article, RC321-571
Abstract

OBJECTIVE: ITPR3, encoding inositol 1,4,5-trisphosphate receptor type 3, was previously reported as a potential candidate disease gene for Charcot-Marie-Tooth neuropathy. Here, we present genetic and functional evidence that ITPR3 is a Charcot-Marie-Tooth disease gene. METHODS: Whole-exome sequencing of four affected individuals in an autosomal dominant family and one individual who was the only affected individual in his family was used to identify disease-causing variants. Skin fibroblasts from two individuals of the autosomal dominant family were analyzed functionally by western blotting, quantitative reverse transcription PCR, and Ca2+ imaging. RESULTS: Affected individuals in the autosomal dominant family had onset of symmetrical neuropathy with demyelinating and secondary axonal features at around age 30, showing signs of gradual progression with severe distal leg weakness and hand involvement in the proband at age 64. Exome sequencing identified a heterozygous ITPR3 p.Val615Met variant segregating with the disease. The individual who was the only affected in his family had disease onset at age 4 with demyelinating neuropathy. His condition was progressive, leading to severe muscle atrophy below knees and atrophy of proximal leg and hand muscles by age 16. Trio exome sequencing identified a de novo ITPR3 variant p.Arg2524Cys. Altered Ca2+ -transients in p.Val615Met patient fibroblasts suggested that the variant has a dominant-negative effect on inositol 1,4,5-trisphosphate receptor type 3 function. INTERPRETATION: Together with two previously identified variants, our report adds further evidence that ITPR3 is a disease-causing gene for CMT and indicates altered Ca2+ homeostasis in disease pathogenesis. ispartof: ANNALS OF CLINICAL AND TRANSLATIONAL NEUROLOGY vol:7 issue:10 pages:1962-1972 ispartof: location:United States status: published

Published
2020
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27. Causal Genetic Variants in Stillbirth

Author

Christie M. Buchovecky, Corette B. Parker, George R. Saade, Robert L. Goldenberg, Natalie Lippa, Halie Holmes, Andrew S. Allen, Joseph Hostyk, Mythily Ganapathi, Jessica L. Giordano, Vanessa Thorsten, Avinash V. Dharmadhikari, Halit Pinar, Ronald J. Wapner, Robert M. Silver, Uma M. Reddy, Jun Liao, David Goldstein, Anya Revah-Politi, Vimla Aggarwal, Carol J. R. Hogue, Kate E. Stanley, Gundula Povysil, Donald J. Dudley, Amanda Thomas, and Michelle E. Ernst

Subjects
Genetics, 2019-20 coronavirus outbreak, Pregnancy, medicine.medical_specialty, Coronavirus disease 2019 (COVID-19), business.industry, Obstetrics, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Genetic variants, General Medicine, 030204 cardiovascular system & hematology, medicine.disease, female genital diseases and pregnancy complications, Loss of function mutation, 03 medical and health sciences, 0302 clinical medicine, Genetic variation, population characteristics, Medicine, 030212 general & internal medicine, business, reproductive and urinary physiology, Exome sequencing
Abstract

Background In the majority of cases, the cause of stillbirth remains unknown despite detailed clinical and laboratory evaluation. Approximately 10 to 20% of stillbirths are attributed to c...

Published
2020
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28. Bi-allelic KARS1 pathogenic variants affecting functions of cytosolic and mitochondrial isoforms are associated with a progressive and multisystem disease

Author

Paola Goffrini, Felice D'Arco, Enrico Baruffini, Adeline Vanderver, Tamison Jewett, Enrico Bertini, Anya Revah-Politi, Eirik Bratland, Vandana Shashi, Alessandra D'Amico, Camilla Ceccatelli Berti, Vimla Aggarwal, Silvia Maitz, Kwame Anyane-Yeboa, Tara H. Stamper, Francesco Canonico, Gabriel S Kupchik, Andreas Benneche, César Augusto Pinheiro Ferreira Alves, Daniela Longo, Gerarda Cappuccio, Annalaura Torella, Vincenzo Nigro, Nicola Brunetti-Pierri, Marjo S van der Knaap, Siren Berland, Jennifer A. Sullivan, Pediatrics, Amsterdam Neuroscience - Cellular & Molecular Mechanisms, Functional Genomics, Cappuccio, G., Ceccatelli Berti, C., Baruffini, E., Sullivan, J., Shashi, V., Jewett, T., Stamper, T., Maitz, S., Canonico, F., Revah-Politi, A., Kupchik, G. S., Anyane-Yeboa, K., Aggarwal, V., Benneche, A., Bratland, E., Berland, S., D'Arco, F., Alves, C. A., Vanderver, A., Longo, D., Bertini, E., Torella, A., Nigro, V., D'Amico, A., van der Knaap, M. S., Goffrini, P., Brunetti Pierri, N., and Brunetti-Pierri, N.

Subjects
Lysine-tRNA Ligase, Male, Mitochondrion, lysyl-transfer RNA synthetase, Cohort Studies, Cytosol, KARS, lysyl‐transfer RNA synthetase, Child, Research Articles, Muscular Dystrophie, Genetics (clinical), Allele, Genetics, 0303 health sciences, Progressive microcephaly, Homozygote, 030305 genetics & heredity, Phenotype, Mitochondria, Pedigree, Isoenzymes, mitochondrial disease, Child, Preschool, Transfer RNA, Disease Progression, Microcephaly, Female, KARS1, Research Article, Human, Gene isoform, Adolescent, Mitochondrial disease, Saccharomyces cerevisiae, Biology, 03 medical and health sciences, SDG 3 - Good Health and Well-being, medicine, Humans, Abnormalities, Multiple, Alleles, 030304 developmental biology, Organisms, Genetically Modified, Leukodystrophy, Brain Diseases, Metabolic, Inborn, Infant, LysRS, medicine.disease, Isoenzyme, Cohort Studie
Abstract

KARS1 encodes a lysyl-transfer RNA synthetase (LysRS) that links lysine to its cognate tRNA. Two different KARS1 isoforms exert functional effects in cytosol and mitochondria. Bi-allelic pathogenic variants in KARS1 have been associated to sensorineural hearing and visual loss, neuropathy, seizures, and leukodystrophy. We report the clinical, biochemical and neuroradiological features of nine individuals with KARS1-related disorder carrying 12 different variants with nine of them being novel. The consequences of these variants on the cytosol and/or mitochondrial LysRS were functionally validated in yeast mutants. Most cases presented with severe neurological features including congenital and progressive microcephaly, seizures, developmental delay/intellectual disability, and cerebral atrophy. Oculo-motor dysfunction and immuno-hematological problems were present in six and three cases, respectively. A yeast growth defect of variable severity was detected for most variants on both cytosolic and mitochondrial isoforms. The detrimental effects of two variants on yeast growth were partially rescued by lysine supplementation. Congenital progressive microcephaly, oculo-motor dysfunction and immuno-hematological problems are emerging phenotypes in KARS1-related disorders. The data in yeast emphasize the role of both mitochondrial and cytosolic isoforms in the pathogenesis of KARS1-related disorder and supports the therapeutic potential of lysine supplementation at least in a subset of patients. This article is protected by copyright. All rights reserved.

Published
2021
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29. eP435: Issues in interpreting results in research genomic testing for common disorders: an example within an OCD cohort

Author

Revah-Politi, Anya, primary, Kushary, Sulagna (Tina), additional, Vena, Natalie, additional, May, Halie, additional, Lippa, Natalie, additional, Bier, Louise, additional, Goldman, Jill, additional, Alkelai, Anna, additional, Baugh, Evan, additional, Zoghbi, Anthony, additional, Kayser, Reilly, additional, Goldstein, David, additional, and Simpson, H. Blair, additional

Published
2022
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30. Casual Genetic Variants in Stillbirth

Author

Jessica L. Giordano, Mythily Ganapathi, Michelle E. Ernst, Ronald J. Wapner, Jun Liao, Gundula Povysil, Halit Pinar, Avinash V. Dharmadhikari, Anya Revah-Politi, Amanda Thomas, Natalie Lippa, Robert M. Silver, Vimla Aggarwal, Joseph Hostyk, David Goldstein, Halie Holmes, Andrew S. Allen, Robert L. Goldenberg, Corette B. Parker, Carol J. R. Hogue, Donald J. Dudley, Kate E. Stanley, Christie M. Buchovecky, Uma M. Reddy, George R. Saade, and Vanessa Thorsten

Subjects
Genetics, Casual, business.industry, Genetic variants, Obstetrics and Gynecology, Medicine, General Medicine, business
Published
2021
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32. Evaluation of the cost and effectiveness of diverse recruitment methods for a genetic screening study

Author

Alexander Fedotov, Karen Marder, Anya Revah-Politi, Robert L. Klitzman, M. Verbitsky, Xueru Mu, Julia Wynn, Ian Halim, Hila Milo Rasouly, Karolynn Siegel, Sheena Kapoor, Stacy Piva, Manuela Orjuela, Elizabeth Cohn, Louise Bier, Jordan G. Nestor, Nicole Cuneo, Wendy K. Chung, Paul S. Appelbaum, Maria C. Alvarez, David Fasel, Anoushka Sinha, Yat S. So, Ali G. Gharavi, Karla Mehl, Natalie Lippa, Maddalena Marasa, Aileen Espinal, Krzysztof Kiryluk, Bianca Haser, Chunhua Weng, Rachel Reingold, Jill Goldman, Debanjana Chatterjee, Byum Hee Kil, Michelle E. Ernst, Jacqueline Jamir Thompson, and Katherine D. Crew

Subjects
0301 basic medicine, Medical education, Cost efficiency, business.industry, Published Erratum, Genomic research, MEDLINE, Research--Moral and ethical aspects, 030105 genetics & heredity, Personalized medicine, Article, Multiculturalism, 03 medical and health sciences, Medicine--Research, 030104 developmental biology, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, Genetics—Research, Recruitment methods, Psychology, business, Genetics (clinical), Screening study
Abstract

Purpose: Recruitment of participants from diverse backgrounds is crucial to the generalizability of genetic research, but has proven challenging. We retrospectively evaluated recruitment methods used for a study on return of genetic results. Methods: The costs of study design, development, and participant enrollment were calculated, and the characteristics of the participants enrolled through the seven recruitment methods were examined. Results: A total of 1118 participants provided consent, a blood sample, and questionnaire data. The estimated cost across recruitment methods ranged from $579 to $1666 per participant and required a large recruitment team. Recruitment methods using flyers and staff networks were the most cost-efficient and resulted in the highest completion rate. Targeted sampling that emphasized the importance of Latino/a participation, utilization of translated materials, and in-person recruitments contributed to enrolling a demographically diverse sample. Conclusions: Although all methods were deployed in the same hospital or neighborhood and shared the same staff, each recruitment method was different in terms of cost and characteristics of the enrolled participants, suggesting the importance of carefully choosing the recruitment methods based on the desired composition of the final study sample. This analysis provides information about the effectiveness and cost of different methods to recruit adults for genetic research.

Published
2019
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33. Genetic testing in individuals with cerebral palsy

Author

Anya Revah-Politi, Halie J. May, Louise Bier, Jennifer M. Bain, Evan H. Baugh, David Goldstein, Jason B. Carmel, David P. Roye, and Jennifer A Fasheun

Subjects
Adult, Male, 030506 rehabilitation, Pediatrics, medicine.medical_specialty, Adolescent, Cerebral palsy, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Developmental Neuroscience, Intellectual disability, Exome Sequencing, medicine, Humans, Extreme Preterm Birth, Global developmental delay, Genetic Testing, Child, Stroke, Genetic testing, Aged, Asphyxia, medicine.diagnostic_test, business.industry, Cerebral Palsy, Infant, Newborn, Genetic Variation, Infant, Middle Aged, medicine.disease, Child, Preschool, Pediatrics, Perinatology and Child Health, Cohort, Premature Birth, Female, Neurology (clinical), medicine.symptom, 0305 other medical science, business, 030217 neurology & neurosurgery
Abstract

AIM To determine which patients with cerebral palsy (CP) should undergo genetic testing, we compared the rate of likely causative genetic variants from whole-exome sequencing in individuals with and without environmental risk factors. METHOD Patients were part of a convenience and physician-referred cohort recruited from a single medical center, and research whole-exome sequencing was completed. Participants were evaluated for the following risk factors: extreme preterm birth, brain bleed or stroke, birth asphyxia, brain malformations, and intrauterine infection. RESULTS A total of 151 unrelated individuals with CP (81 females, 70 males; mean age 25y 7mo [SD 17y 5mo], range 3wks-72y) participated. Causative genetic variants were identified in 14 participants (9.3%). There was no significant difference in diagnostic rate between individuals with risk factors (10 out of 123; 8.1%) and those without (4 out of 28; 14.3%) (Fisher's exact p=0.3). INTERPRETATION While the rate of genetic diagnoses among individuals without risk factors was higher than those with risk factors, the difference was not statistically significant at this sample size. The identification of genetic diagnoses in over 8% of cases with risk factors suggests that these might confer susceptibility to environmental factors, and that further research should include individuals with risk factors. What this paper adds There is no significant difference in diagnostic rate between individuals with and without risk factors. Genetic variants may confer susceptibility to environmental risk factors. Six causative variants were identified in genes not previously associated with cerebral palsy. Global developmental delay/intellectual disability is positively associated with a genetic etiology. Extreme preterm birth, stroke/brain hemorrhage, and older age are negatively associated with a genetic etiology.

Published
2021

34. DLG4-related synaptopathy: a new rare brain disorder

Author

Edgard Verdura, Alex MacKenzie, Rolph Pfundt, Tobias B. Haack, Ange Line Bruel, Paulino Gómez-Puertas, Anna C.E. Hurst, Bert B.A. de Vries, Stella A. de Man, Maria Johansson Soller, Bregje W.M. van Bon, Elisabeth Sarrazin, Agustí Rodríguez-Palmero, Stephan Waldmüller, Melanie O’Leary, Anne Sophie Denommé-Pichon, Bitten Schönewolf-Greulich, Joseph T. Shieh, V. A. Bjerregaard, Vahid Bahrambeigi, Malin Kvarnung, Agatha Schlüter, Anne Marie Bisgaard, Ingrid M.B.H. van de Laar, Elisa Giorgio, Lars Feuk, Mieke M. van Haelst, Thomas D. Challman, Ineke van de Burgt, Sulagna Kushary, Simone F. Reiter, David B. Everman, Zeynep Tümer, Giorgia Mandrile, Conny M. A. van Ravenswaaij-Arts, Charles Shaw-Smith, Juliane Hoyer, Chad R. Haldeman-Englert, Lotte Kleinendorst, Bryce A. Mendelsohn, Anna Lindstrand, Christine Coubes, Gea Beunders, Sixto García-Miñaur, Antonio Vitobello, Melissa Maria Boerrigter, Alysia Kern Lovgren, Anya Revah-Politi, Carlos E. Prada, Bertrand Isidor, Elena Repnikova, Stephanie Spranger, Esmée van Drie, Frédéric Tran Mau-Them, Zohra Shad, Ben Pode-Shakked, Aurora Pujol, Christiane Zweier, Bjørn Ivar Haukanes, David Gómez-Andrés, Kathleen A. Leppig, Marta Pacio-Míguez, Motti Shohat, Yuval Landau, Benjamin Cogné, Frances Elmslie, Kimberly A. Aldinger, Anita Rauch, Juliann M. Savatt, Nicolas Gruchy, Sharon Whiting, William B. Dobyns, Thomas J. Dye, Sebastien Moutton, Heidi Thiese, Setareh Moghadasi, Iñigo Marcos-Alcalde, Jenny Morton, Sumit Parikh, María Palomares-Bralo, Stéphanie Arpin, Tracy S. Gertler, Meredith J. Ross, Bernt Popp, Amelie J. Müller, Claudia A. L. Ruivenkamp, Institut d'Investigació Biomèdica de Bellvitge [Barcelone] (IDIBELL), CIBER de Enfermedades Raras (CIBERER), Hospital Universitario Germans Trias I Pujol, Vall d'Hebron University Hospital [Barcelona], Center for Integrative Brain Research [Seattle, WA, USA], University of Washington [Seattle]-Seattle Children's Research Institute, Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Service de génétique [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Department of Molecular and Human Genetics (Baylor College of Medicine), Baylor College of Medecine, Biologie, génétique et thérapies ostéoarticulaires et respiratoires (BIOTARGEN), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU), Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Clinical Genetics, Human Genetics, Graduate School, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, ARD - Amsterdam Reproduction and Development, Clinical Cognitive Neuropsychiatry Research Program (CCNP), Human genetics, Amsterdam Neuroscience - Complex Trait Genetics, and Amsterdam Reproduction & Development (AR&D)

Subjects
0301 basic medicine, Autism Spectrum Disorder, [SDV]Life Sciences [q-bio], 030105 genetics & heredity, Biology, 03 medical and health sciences, Intellectual Disability, Intellectual disability, medicine, Missense mutation, Humans, Global developmental delay, Exome, Genetics (clinical), Genetics, Brain Diseases, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Brain, medicine.disease, 030104 developmental biology, Phenotype, Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11], Autism spectrum disorder, Neurodevelopmental Disorders, Synaptopathy, DLG4, Postsynaptic density, Disks Large Homolog 4 Protein
Abstract

Contains fulltext : 245031.pdf (Publisher’s version ) (Closed access) PURPOSE: Postsynaptic density protein-95 (PSD-95), encoded by DLG4, regulates excitatory synaptic function in the brain. Here we present the clinical and genetic features of 53 patients (42 previously unpublished) with DLG4 variants. METHODS: The clinical and genetic information were collected through GeneMatcher collaboration. All the individuals were investigated by local clinicians and the gene variants were identified by clinical exome/genome sequencing. RESULTS: The clinical picture was predominated by early onset global developmental delay, intellectual disability, autism spectrum disorder, and attention deficit-hyperactivity disorder, all of which point to a brain disorder. Marfanoid habitus, which was previously suggested to be a characteristic feature of DLG4-related phenotypes, was found in only nine individuals and despite some overlapping features, a distinct facial dysmorphism could not be established. Of the 45 different DLG4 variants, 39 were predicted to lead to loss of protein function and the majority occurred de novo (four with unknown origin). The six missense variants identified were suggested to lead to structural or functional changes by protein modeling studies. CONCLUSION: The present study shows that clinical manifestations associated with DLG4 overlap with those found in other neurodevelopmental disorders of synaptic dysfunction; thus, we designate this group of disorders as DLG4-related synaptopathy.

Published
2021
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35. Truncating variants in the SHANK1 gene are associated with a spectrum of neurodevelopmental disorders

Author

Chong Ae Kim, Marwan Shinawi, Naomichi Matsumoto, Anya Revah-Politi, Julia Baptista, Halie J. May, Julie S. Cohen, Julia Rankin, Samantha Toy, Kwame Anyane-Yeboa, Michelle Primiano, Evan H. Baugh, David Goldstein, Richard E. Person, Constance Smith-Hicks, Louise Bier, Katherine W. Roche, Anna Chassevent, Yuri Uchiyama, Michel Guipponi, Joel Victor Fluss, Charles Conlon, Armand Bottani, Jaehoon Jeong, Vimla Aggarwal, Maria resa Te Carminho A. Rodrigues, and Aida Telegrafi

Subjects
Genetics, Neurons, Dendritic spine, HEK 293 cells, HOMER1, Nerve Tissue Proteins, Biology, Phenotype, Article, HEK293 Cells, Cell culture, Neurodevelopmental Disorders, Complementary DNA, Exome Sequencing, Humans, Gene, Genetics (clinical), Exome sequencing
Abstract

Purpose In this study, we aimed to characterize the clinical phenotype of a SHANK1-related disorder and define the functional consequences of SHANK1 truncating variants. Methods Exome sequencing (ES) was performed for six individuals who presented with neurodevelopmental disorders. Individuals were ascertained with the use of GeneMatcher and Database of Chromosomal Imbalance and Phenotype in Humans Using Ensembl Resources (DECIPHER). We evaluated potential nonsense-mediated decay (NMD) of two variants by making knock-in cell lines of endogenous truncated SHANK1, and expressed the truncated SHANK1 complementary DNA (cDNA) in HEK293 cells and cultured hippocampal neurons to examine the proteins. Results ES detected de novo truncating variants in SHANK1 in six individuals. Evaluation of NMD resulted in stable transcripts, and the truncated SHANK1 completely lost binding with Homer1, a linker protein that binds to the C-terminus of SHANK1. These variants may disrupt protein–protein networks in dendritic spines. Dispersed localization of the truncated SHANK1 variants within the spine and dendritic shaft was also observed when expressed in neurons, indicating impaired synaptic localization of truncated SHANK1. Conclusion This report expands the clinical spectrum of individuals with truncating SHANK1 variants and describes the impact these variants may have on the pathophysiology of neurodevelopmental disorders.

Published
2021

36. DLG4-related synaptopathy: a new rare brain disorder

Author

Rodríguez-Palmero, A., Boerrigter, M.M., Gómez-Andrés, D., Aldinger, K.A., Marcos-Alcalde, Í., Popp, B., Everman, D.B., Lovgren, A.K., Arpin, S., Bahrambeigi, V., Beunders, G., Bisgaard, A.M., Bjerregaard, V.A., Bruel, A.L., Challman, T.D., Cogné, B., Coubes, C., Man, S.A. de, Denommé-Pichon, A.S., Dye, T.J., Elmslie, F., Feuk, L., García-Miñaúr, S., Gertler, T., Giorgio, E., Gruchy, N., Haack, T.B., Haldeman-Englert, C.R., Haukanes, B.I., Hoyer, J., Hurst, A.C.E., Isidor, B., Soller, M.J., Kushary, S., Kvarnung, M., Landau, Y.E., Leppig, K.A., Lindstrand, A., Kleinendorst, L., Mackenzie, A., Mandrile, G., Mendelsohn, B.A., Moghadasi, S., Morton, J.E., Moutton, S., Müller, A.J., O'Leary, M., Pacio-Míguez, M., Palomares-Bralo, M., Parikh, S., Pfundt, R., Pode-Shakked, B., Rauch, A., Repnikova, E., Revah-Politi, A., Ross, M.J., Ruivenkamp, C.A.L., Sarrazin, E., Savatt, J.M., Schlüter, A., Schönewolf-Greulich, B., Shad, Z., Shaw-Smith, C., Shieh, J.T., Shohat, M., Spranger, S., Thiese, H., Mau-Them, F.T., Bon, B. van, Burgt, I. van der, Laar, I. van de, Drie, E. van, Haelst, M.M. van, Ravenswaaij-Arts, C.M.A. van, Verdura, E., Vitobello, A., Waldmüller, S., Whiting, S., Zweier, C., Prada, C.E., Vries, B.B. de, Dobyns, W.B., Reiter, S.F., Gómez-Puertas, P., Pujol, A., Tümer, Z., Rodríguez-Palmero, A., Boerrigter, M.M., Gómez-Andrés, D., Aldinger, K.A., Marcos-Alcalde, Í., Popp, B., Everman, D.B., Lovgren, A.K., Arpin, S., Bahrambeigi, V., Beunders, G., Bisgaard, A.M., Bjerregaard, V.A., Bruel, A.L., Challman, T.D., Cogné, B., Coubes, C., Man, S.A. de, Denommé-Pichon, A.S., Dye, T.J., Elmslie, F., Feuk, L., García-Miñaúr, S., Gertler, T., Giorgio, E., Gruchy, N., Haack, T.B., Haldeman-Englert, C.R., Haukanes, B.I., Hoyer, J., Hurst, A.C.E., Isidor, B., Soller, M.J., Kushary, S., Kvarnung, M., Landau, Y.E., Leppig, K.A., Lindstrand, A., Kleinendorst, L., Mackenzie, A., Mandrile, G., Mendelsohn, B.A., Moghadasi, S., Morton, J.E., Moutton, S., Müller, A.J., O'Leary, M., Pacio-Míguez, M., Palomares-Bralo, M., Parikh, S., Pfundt, R., Pode-Shakked, B., Rauch, A., Repnikova, E., Revah-Politi, A., Ross, M.J., Ruivenkamp, C.A.L., Sarrazin, E., Savatt, J.M., Schlüter, A., Schönewolf-Greulich, B., Shad, Z., Shaw-Smith, C., Shieh, J.T., Shohat, M., Spranger, S., Thiese, H., Mau-Them, F.T., Bon, B. van, Burgt, I. van der, Laar, I. van de, Drie, E. van, Haelst, M.M. van, Ravenswaaij-Arts, C.M.A. van, Verdura, E., Vitobello, A., Waldmüller, S., Whiting, S., Zweier, C., Prada, C.E., Vries, B.B. de, Dobyns, W.B., Reiter, S.F., Gómez-Puertas, P., Pujol, A., and Tümer, Z.

Abstract

Contains fulltext : 245031.pdf (Publisher’s version ) (Closed access), PURPOSE: Postsynaptic density protein-95 (PSD-95), encoded by DLG4, regulates excitatory synaptic function in the brain. Here we present the clinical and genetic features of 53 patients (42 previously unpublished) with DLG4 variants. METHODS: The clinical and genetic information were collected through GeneMatcher collaboration. All the individuals were investigated by local clinicians and the gene variants were identified by clinical exome/genome sequencing. RESULTS: The clinical picture was predominated by early onset global developmental delay, intellectual disability, autism spectrum disorder, and attention deficit-hyperactivity disorder, all of which point to a brain disorder. Marfanoid habitus, which was previously suggested to be a characteristic feature of DLG4-related phenotypes, was found in only nine individuals and despite some overlapping features, a distinct facial dysmorphism could not be established. Of the 45 different DLG4 variants, 39 were predicted to lead to loss of protein function and the majority occurred de novo (four with unknown origin). The six missense variants identified were suggested to lead to structural or functional changes by protein modeling studies. CONCLUSION: The present study shows that clinical manifestations associated with DLG4 overlap with those found in other neurodevelopmental disorders of synaptic dysfunction; thus, we designate this group of disorders as DLG4-related synaptopathy.

Published
2021

37. DLG4-related synaptopathy:a new rare brain disorder

Author

Rodríguez-Palmero, Agustí, Boerrigter, Melissa Maria, Gómez-Andrés, David, Aldinger, Kimberly A., Marcos-Alcalde, Íñigo, Popp, Bernt, Everman, David B., Lovgren, Alysia Kern, Arpin, Stephanie, Bahrambeigi, Vahid, Beunders, Gea, Bisgaard, Anne Marie, Bjerregaard, V. A., Bruel, Ange Line, Challman, Thomas D., Cogné, Benjamin, Coubes, Christine, de Man, Stella A., Denommé-Pichon, Anne Sophie, Dye, Thomas J., Elmslie, Frances, Feuk, Lars, García-Miñaúr, Sixto, Gertler, Tracy, Giorgio, Elisa, Gruchy, Nicolas, Haack, Tobias B., Haldeman-Englert, Chad R., Haukanes, Bjørn Ivar, Hoyer, Juliane, Hurst, Anna C.E., Isidor, Bertrand, Soller, Maria Johansson, Kushary, Sulagna, Kvarnung, Malin, Landau, Yuval E., Leppig, Kathleen A., Lindstrand, Anna, Kleinendorst, Lotte, MacKenzie, Alex, Mandrile, Giorgia, Mendelsohn, Bryce A., Moghadasi, Setareh, Morton, Jenny E., Moutton, Sebastien, Müller, Amelie J., O’Leary, Melanie, Pacio-Míguez, Marta, Palomares-Bralo, Maria, Parikh, Sumit, Pfundt, Rolph, Pode-Shakked, Ben, Rauch, Anita, Repnikova, Elena, Revah-Politi, Anya, Ross, Meredith J., Ruivenkamp, Claudia A.L., Sarrazin, Elisabeth, Savatt, Juliann M., Schlüter, Agatha, Schönewolf-Greulich, Bitten, Shad, Zohra, Shaw-Smith, Charles, Shieh, Joseph T., Shohat, Motti, Spranger, Stephanie, Thiese, Heidi, Mau-Them, Frederic Tran, van Bon, Bregje, van de Burgt, Ineke, van de Laar, Ingrid M.B.H., van Drie, Esmée, van Haelst, Mieke M., van Ravenswaaij-Arts, Conny M., Verdura, Edgard, Vitobello, Antonio, Waldmüller, Stephan, Whiting, Sharon, Zweier, Christiane, Prada, Carlos E., de Vries, Bert B.A., Dobyns, William B., Reiter, Simone F., Gómez-Puertas, Paulino, Pujol, Aurora, Tümer, Zeynep, Rodríguez-Palmero, Agustí, Boerrigter, Melissa Maria, Gómez-Andrés, David, Aldinger, Kimberly A., Marcos-Alcalde, Íñigo, Popp, Bernt, Everman, David B., Lovgren, Alysia Kern, Arpin, Stephanie, Bahrambeigi, Vahid, Beunders, Gea, Bisgaard, Anne Marie, Bjerregaard, V. A., Bruel, Ange Line, Challman, Thomas D., Cogné, Benjamin, Coubes, Christine, de Man, Stella A., Denommé-Pichon, Anne Sophie, Dye, Thomas J., Elmslie, Frances, Feuk, Lars, García-Miñaúr, Sixto, Gertler, Tracy, Giorgio, Elisa, Gruchy, Nicolas, Haack, Tobias B., Haldeman-Englert, Chad R., Haukanes, Bjørn Ivar, Hoyer, Juliane, Hurst, Anna C.E., Isidor, Bertrand, Soller, Maria Johansson, Kushary, Sulagna, Kvarnung, Malin, Landau, Yuval E., Leppig, Kathleen A., Lindstrand, Anna, Kleinendorst, Lotte, MacKenzie, Alex, Mandrile, Giorgia, Mendelsohn, Bryce A., Moghadasi, Setareh, Morton, Jenny E., Moutton, Sebastien, Müller, Amelie J., O’Leary, Melanie, Pacio-Míguez, Marta, Palomares-Bralo, Maria, Parikh, Sumit, Pfundt, Rolph, Pode-Shakked, Ben, Rauch, Anita, Repnikova, Elena, Revah-Politi, Anya, Ross, Meredith J., Ruivenkamp, Claudia A.L., Sarrazin, Elisabeth, Savatt, Juliann M., Schlüter, Agatha, Schönewolf-Greulich, Bitten, Shad, Zohra, Shaw-Smith, Charles, Shieh, Joseph T., Shohat, Motti, Spranger, Stephanie, Thiese, Heidi, Mau-Them, Frederic Tran, van Bon, Bregje, van de Burgt, Ineke, van de Laar, Ingrid M.B.H., van Drie, Esmée, van Haelst, Mieke M., van Ravenswaaij-Arts, Conny M., Verdura, Edgard, Vitobello, Antonio, Waldmüller, Stephan, Whiting, Sharon, Zweier, Christiane, Prada, Carlos E., de Vries, Bert B.A., Dobyns, William B., Reiter, Simone F., Gómez-Puertas, Paulino, Pujol, Aurora, and Tümer, Zeynep

Abstract

Purpose: Postsynaptic density protein-95 (PSD-95), encoded by DLG4, regulates excitatory synaptic function in the brain. Here we present the clinical and genetic features of 53 patients (42 previously unpublished) with DLG4 variants. Methods: The clinical and genetic information were collected through GeneMatcher collaboration. All the individuals were investigated by local clinicians and the gene variants were identified by clinical exome/genome sequencing. Results: The clinical picture was predominated by early onset global developmental delay, intellectual disability, autism spectrum disorder, and attention deficit–hyperactivity disorder, all of which point to a brain disorder. Marfanoid habitus, which was previously suggested to be a characteristic feature of DLG4-related phenotypes, was found in only nine individuals and despite some overlapping features, a distinct facial dysmorphism could not be established. Of the 45 different DLG4 variants, 39 were predicted to lead to loss of protein function and the majority occurred de novo (four with unknown origin). The six missense variants identified were suggested to lead to structural or functional changes by protein modeling studies. Conclusion: The present study shows that clinical manifestations associated with DLG4 overlap with those found in other neurodevelopmental disorders of synaptic dysfunction; thus, we designate this group of disorders as DLG4-related synaptopathy. [Figure not available: see fulltext.]

Published
2021

38. The Epilepsy Genetics Initiative: a final summary

Author

Kushary, Sulagna (Tina), primary, Bier, Louise, additional, Lippa, Natalie, additional, Revah-Politi, Anya, additional, May, Halie, additional, Vena, Natalie, additional, Sands, Tristan, additional, Aggarwal, Vimla, additional, Baugh, Evan, additional, Alkelai, Anna, additional, Hostyk, Joseph, additional, Jiang, Nan, additional, Dharmadhikari, Avinash, additional, Heinzen-Cox, Erin, additional, Lowenstein, Dan, additional, Berkovic, Sam, additional, and Goldstein, David, additional

Published
2021
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39. Whole exome sequencing across clinical specialties within a medical center

Author

Lippa, Natalie, primary, Bier, Louise, additional, Revah-Politi, Anya, additional, Kushary, Sulagna (Tina), additional, May, Halie, additional, Alkelai, Anna, additional, Baugh, Evan, additional, Hostyk, Joseph, additional, Sands, Tristan, additional, Bazil, Carl, additional, Harms, Matthew, additional, Carmel, Jason, additional, Kernie, Steven, additional, Motelow, Joshua, additional, Kuo, Sheng-Han, additional, Milner, Joshua, additional, Alcalay, Roy, additional, Anyane-Yeboa, Kwame, additional, Aggarwal, Vimla, additional, and Goldstein, David, additional

Published
2021
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40. LATE BREAKING NEWS E-POSTER PRESENTATION

Author

Claudio Rivera, Henna Tyynismaa, Emil Ylikallio, Adrian Liston, Julius Rönkkö, Matthew B. Harms, Anastasia Ludwig, Svetlana M. Molchanova, Stephanie Humblet-Baron, Elaine M. Pereira, Anya Revah-Politi, Geert Bultynck, Julika Neumann, Jouni Kvist, Mari Auranen, Jussi Toppila, Anders Patau, University of Helsinki, Faculty of Medecine [Helsinki], Faculty of Biological and Environmental Sciences [Helsinki], Columbia University Medical Center (CUMC), Columbia University [New York], Columbia University Irving Medical Center (CUIMC), HUS Medical Imaging Center [Helsinki] (HUS-MIC), HiLIFE - Neuroscience Center (NC), Helsinki Institute of Life Science (HiLIFE), University of Helsinki-University of Helsinki-Helsinki Institute of Life Science (HiLIFE), University of Helsinki-University of Helsinki, Neuroscience Center, University of Helsinki, Department of Microbiology, Immunology and Transplantation [Leuven], Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), VIB Center for Brain & Disease Research, Laboratory of Molecular and Cellular Signaling, VIB Center for the Biology of Disease [Louvain, Belgique] (VIB-CBD), Vlaams Instituut voor Biotechnologie [Ghent, Belgique] (VIB), Department of Pathology and Genetics [Helsinki, Finland] (HUSLAB), Helsinki University Central Hospital [Finland] (HUCH), Institut de Neurobiologie de la Méditerranée [Aix-Marseille Université] (INMED - INSERM U1249), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Neurology Columbia University 650 West 168th Street, Department of Medical and Clinical Genetics [Helsinki], Haartman Institute [Helsinki], University of Helsinki-University of Helsinki-Faculty of Medecine [Helsinki], Helsinki University Hospital [Helsinki, Finlande], Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsinki Institute of Life Science (HiLIFE), Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), and Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Faculty of Medecine [Helsinki]

Subjects
History, media_common.quotation_subject, Visual arts, 03 medical and health sciences, Presentation, 0302 clinical medicine, Neurology, 030225 pediatrics, Pediatrics, Perinatology and Child Health, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neurology (clinical), 030217 neurology & neurosurgery, Genetics (clinical), ComputingMilieux_MISCELLANEOUS, media_common
Abstract

International audience

Published
2020
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41. Causal Genetic Variants in Stillbirth

Author

Stanley, K.E., primary, Giordano, J., additional, Thorsten, V., additional, Buchovecky, C., additional, Thomas, A., additional, Ganapathi, M., additional, Liao, J., additional, Dharmadhikari, A.V., additional, Revah‐Politi, A., additional, Ernst, M., additional, Lippa, N., additional, Holmes, H., additional, Povysil, G., additional, Hostyk, J., additional, Parker, C.B., additional, Goldenberg, R., additional, Saade, G.R., additional, Dudley, D.J., additional, Pinar, H., additional, Hogue, C., additional, Reddy, U.M., additional, Silver, R.M., additional, Aggarwal, V., additional, Allen, A.S., additional, Wapner, R.J., additional, and Goldstein, D.B., additional

Published
2021
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42. Casual Genetic Variants in Stillbirth

Author

Stanley, Kate E., primary, Giordano, Jessica, additional, Thorsten, Vanessa, additional, Buchovecky, Christie, additional, Thomas, Amanda, additional, Ganapathi, Mythily, additional, Liao, Jun, additional, Dharmadhikari, Avinash V., additional, Revah-Politi, Anya, additional, Ernst, Michelle, additional, Lippa, Natalie, additional, Holmes, Halie, additional, Povysil, Gundula, additional, Hostyk, Joseph, additional, Parker, Corette B., additional, Goldenberg, Robert, additional, Saade, George R., additional, Dudley, Donald J., additional, Pinar, Halit, additional, Hogue, Carol, additional, Reddy, Uma M., additional, Silver, Robert M., additional, Aggarwal, Vimla, additional, Allen, Andrew S., additional, Wapner, Ronald J., additional, and Goldstein, David B., additional

Published
2021
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43. Whole exome sequencing across clinical specialties within a medical center

Author

Joshua E. Motelow, Jason B. Carmel, Sheng-Han Kuo, Joseph Hostyk, Halie May, Louise Bier, Evan H. Baugh, David Goldstein, Sulagna Kushary, Tristan T. Sands, Joshua D. Milner, Anya Revah-Politi, Matthew B. Harms, Anna Alkelai, Carl W. Bazil, Natalie Lippa, Vimla Aggarwal, Kwame Anyane-Yeboa, Steven G. Kernie, and Roy N. Alcalay

Subjects
medicine.medical_specialty, Endocrinology, business.industry, Endocrinology, Diabetes and Metabolism, Genetics, Medicine, Center (algebra and category theory), Medical physics, business, Molecular Biology, Biochemistry, Exome sequencing
Published
2021
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44. LATE BREAKING NEWS E-POSTER PRESENTATION

Author

Rönkkö, Julius, primary, Molchanova, Svetlana, additional, Revah-Politi, Anya, additional, Pereira, Elaine, additional, Auranen, Mari, additional, Toppila, Jussi, additional, Kvist, Jouni, additional, Ludwig, Anastasia, additional, Neumann, Julika, additional, Humblet-Baron, Stephanie, additional, Bultynck, Geert, additional, Liston, Adrian, additional, Patau, Anders, additional, Rivera, Claudio, additional, Harms, Matthew, additional, Tyynismaa, Henna, additional, and Ylikallio, Emil, additional

Published
2020
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45. Dominant mutations in ITPR3 cause Charcot‐Marie‐Tooth disease

Author

Rönkkö, Julius, primary, Molchanova, Svetlana, additional, Revah‐Politi, Anya, additional, Pereira, Elaine M., additional, Auranen, Mari, additional, Toppila, Jussi, additional, Kvist, Jouni, additional, Ludwig, Anastasia, additional, Neumann, Julika, additional, Bultynck, Geert, additional, Humblet‐Baron, Stéphanie, additional, Liston, Adrian, additional, Paetau, Anders, additional, Rivera, Claudio, additional, Harms, Matthew B., additional, Tyynismaa, Henna, additional, and Ylikallio, Emil, additional

Published
2020
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46. Causal Genetic Variants in Stillbirth

Author

Stanley, Kate E., primary, Giordano, Jessica, additional, Thorsten, Vanessa, additional, Buchovecky, Christie, additional, Thomas, Amanda, additional, Ganapathi, Mythily, additional, Liao, Jun, additional, Dharmadhikari, Avinash V., additional, Revah-Politi, Anya, additional, Ernst, Michelle, additional, Lippa, Natalie, additional, Holmes, Halie, additional, Povysil, Gundula, additional, Hostyk, Joseph, additional, Parker, Corette B., additional, Goldenberg, Robert, additional, Saade, George R., additional, Dudley, Donald J., additional, Pinar, Halit, additional, Hogue, Carol, additional, Reddy, Uma M., additional, Silver, Robert M., additional, Aggarwal, Vimla, additional, Allen, Andrew S., additional, Wapner, Ronald J., additional, and Goldstein, David B., additional

Published
2020
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47. De Novo Missense Mutations in DHX30 Impair Global Translation and Cause a Neurodevelopmental Disorder

Author

Naomi Meeks, Stefan Kindler, Anya Revah-Politi, Alexander P.A. Stegmann, Vinodh Narayanan, Dominique Bonneau, Claudia Schob, Jill A. Rosenfeld, Jennifer E. Posey, Tim M. Strom, LaDonna Immken, Tjitske Kleefstra, Jolanda H. Schieving, Katherine L. Helbig, Estelle Colin, Magalie Barth, Tamar Harel, Matthew J. Huentelman, James R. Lupski, Benjamin Cogné, Han G. Brunner, Yaping Yang, Sébastien Küry, Jenny Morton, Erica H. Gerkes, Keri Ramsey, Marine Tessarech, Zeynep Coban-Akdemir, Shimon Edvardson, Hans-Jürgen Kreienkamp, Nelly Oundjian, Davor Lessel, Christian Kubisch, Thomas Besnard, Jonas Denecke, Orly Elpeleg, Ana M. Claasen, Kelsey Zegar, Mohammad K. Eldomery, Sandra Mercier, Margot R.F. Reijnders, Stéphane Bézieau, Univ Angers, Okina, MUMC+: DA KG Lab Centraal Lab (9), Klinische Genetica, RS: GROW - R4 - Reproductive and Perinatal Medicine, MUMC+: DA Klinische Genetica (5), Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), and Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Central Nervous System, Male, DISRUPTION, INTELLECTUAL DISABILITY, Developmental Disabilities, PROTEIN, DISEASE, 0302 clinical medicine, Neurodevelopmental disorder, Intellectual disability, Missense mutation, Global developmental delay, Amino Acids, Child, Genetics (clinical), Genetics, Adenosine Triphosphatases, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Translation (biology), Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], 3. Good health, FAMILY, Child, Preschool, Female, RNA Helicases, MODULE, Adolescent, Mutation, Missense, RNA GRANULES, Biology, Article, Cell Line, 03 medical and health sciences, Stress granule, Cell Line, Tumor, medicine, Humans, HELICASE, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], STRESS GRANULES, Helicase, RNA, Correction, medicine.disease, GENE, 030104 developmental biology, HEK293 Cells, biology.protein, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Contains fulltext : 182457.pdf (Publisher’s version ) (Open Access) DHX30 is a member of the family of DExH-box helicases, which use ATP hydrolysis to unwind RNA secondary structures. Here we identified six different de novo missense mutations in DHX30 in twelve unrelated individuals affected by global developmental delay (GDD), intellectual disability (ID), severe speech impairment and gait abnormalities. While four mutations are recurrent, two are unique with one affecting the codon of one recurrent mutation. All amino acid changes are located within highly conserved helicase motifs and were found to either impair ATPase activity or RNA recognition in different in vitro assays. Moreover, protein variants exhibit an increased propensity to trigger stress granule (SG) formation resulting in global translation inhibition. Thus, our findings highlight the prominent role of translation control in development and function of the central nervous system and also provide molecular insight into how DHX30 dysfunction might cause a neurodevelopmental disorder.

Published
2017
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48. New diagnosis of atypical ataxia-telangiectasia in a 17-year-old boy with T-cell acute lymphoblastic leukemia and a novel ATM mutation

Author

Jennifer Levine, Denis G Loredan, Shan Zha, Mahesh M. Mansukhani, Lenore Omesi, Kwame Anyane-Yeboa, Jasmin Roohi, Anya Revah Politi, and Jennifer Crowe

Subjects
Male, 0301 basic medicine, Pediatrics, medicine.medical_specialty, Adolescent, Ataxia Telangiectasia Mutated Proteins, Disease, Biology, Malignancy, Article, Ataxia Telangiectasia, 03 medical and health sciences, Genetics, medicine, Humans, Missense mutation, Child, Telangiectasia, Genetics (clinical), Immunodeficiency, Infant, Karyotype, Precursor Cell Lymphoblastic Leukemia-Lymphoma, medicine.disease, 3. Good health, 030104 developmental biology, Child, Preschool, Mutation, Ataxia-telangiectasia, Immunology, Chromosome breakage, medicine.symptom
Abstract

Ataxia-telangiectasia (A-T) is an autosomal recessive chromosome breakage disorder caused by mutations in the ATM gene. Typically, it presents in early childhood with progressive cerebellar dysfunction along with immunodeficiency and oculocutaneous telangiectasia. An increased risk of malignancy is also associated with the syndrome and, rarely, may be the presenting feature in small children. We describe a 17-year-old boy with slurred speech, mild motor delays and learning disability diagnosed with atypical A-T in the setting of T-cell acute lymphoblastic leukemia. Suspicion for A-T was raised after review of a peripheral blood karyotype demonstrating rearrangements involving chromosomes 7 and/or 14. The diagnosis was confirmed after molecular testing identified a novel homozygous missense variant in ATM (c.5585T>A; p.Leu1862His) that resulted in protein instability and abolished serine/threonine protein kinase activity. To our knowledge, this is the first report of concurrent A-T and lymphoid malignancy diagnoses in an older child or adult with only mild neurological disease. Our experience suggests that screening for the disorder should be considered in any individual with lymphoid malignancy and neurological findings, especially as radiation and certain chemotherapy protocols are contraindicated in A-T.

Published
2017
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49. The Epilepsy Genetics Initiative: a final summary

Author

Natalie Lippa, Anna Alkelai, Nan Jiang, Joseph Hostyk, Louise Bier, Avinash V. Dharmadhikari, Tristan T. Sands, Halie May, Erin Heinzen-Cox, Vimla Aggarwal, Samuel F. Berkovic, Natalie Vena, Evan H. Baugh, David Goldstein, Daniel H. Lowenstein, Sulagna Kushary, and Anya Revah-Politi

Subjects
medicine.medical_specialty, Epilepsy, Endocrinology, business.industry, Endocrinology, Diabetes and Metabolism, Genetics, medicine, Psychiatry, medicine.disease, business, Molecular Biology, Biochemistry
Published
2021
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50. The Epilepsy Genetics Initiative: Systematic reanalysis of diagnostic exomes increases yield

Author

Berkovic, SF, Goldstein, DB, Heinzen, EL, Laughlin, BL, Lowenstein, DH, Lubbers, L, Stewart, R, Whittemore, V, Angione, K, Bazil, CW, Bier, L, Bluvstein, J, Brimble, E, Campbell, C, Cavalleri, G, Chambers, C, Choi, H, Cilio, MR, Ciliberto, M, Cornes, S, Delanty, N, Demarest, S, Devinsky, O, Dlugos, D, Dubbs, H, Dugan, P, Ernst, ME, Gibbons, M, Goodkin, HP, Helbig, I, Jansen, L, Johnson, K, Joshi, C, Lippa, NC, Marsh, E, Martinez, A, Millichap, J, Mulhern, MS, Numis, A, Park, K, Pippucci, T, Poduri, A, Porter, B, Regan, B, Sands, TT, Scheffer, IE, Schreiber, JM, Sheidley, B, Singhal, N, Smith, L, Sullivan, J, Taylor, A, Tolete, P, Afgani, TM, Aggarwal, V, Burgess, R, Dixon-Salazar, T, Hemati, P, Milder, J, Petrovski, S, Revah-Politi, A, Stong, N, Berkovic, SF, Goldstein, DB, Heinzen, EL, Laughlin, BL, Lowenstein, DH, Lubbers, L, Stewart, R, Whittemore, V, Angione, K, Bazil, CW, Bier, L, Bluvstein, J, Brimble, E, Campbell, C, Cavalleri, G, Chambers, C, Choi, H, Cilio, MR, Ciliberto, M, Cornes, S, Delanty, N, Demarest, S, Devinsky, O, Dlugos, D, Dubbs, H, Dugan, P, Ernst, ME, Gibbons, M, Goodkin, HP, Helbig, I, Jansen, L, Johnson, K, Joshi, C, Lippa, NC, Marsh, E, Martinez, A, Millichap, J, Mulhern, MS, Numis, A, Park, K, Pippucci, T, Poduri, A, Porter, B, Regan, B, Sands, TT, Scheffer, IE, Schreiber, JM, Sheidley, B, Singhal, N, Smith, L, Sullivan, J, Taylor, A, Tolete, P, Afgani, TM, Aggarwal, V, Burgess, R, Dixon-Salazar, T, Hemati, P, Milder, J, Petrovski, S, Revah-Politi, A, and Stong, N

Abstract

OBJECTIVE: The Epilepsy Genetics Initiative (EGI) was formed in 2014 to create a centrally managed database of clinically generated exome sequence data. EGI performs systematic research-based reanalysis to identify new molecular diagnoses that were not possible at the time of initial sequencing and to aid in novel gene discovery. Herein we report on the efficacy of this approach 3 years after inception. METHODS: One hundred sixty-six individuals with epilepsy who underwent diagnostic whole exome sequencing (WES) were enrolled, including 139 who had not received a genetic diagnosis. Sequence data were transferred to the EGI and periodically reevaluated on a research basis. RESULTS: Eight new diagnoses were made as a result of updated annotations or the discovery of novel epilepsy genes after the initial diagnostic analysis was performed. In five additional cases, we provided new evidence to support or contradict the likelihood of variant pathogenicity reported by the laboratory. One novel epilepsy gene was discovered through dual interrogation of research and clinically generated WES. SIGNIFICANCE: EGI's diagnosis rate of 5.8% represents a considerable increase in diagnostic yield and demonstrates the value of periodic reinterrogation of whole exome data. The initiative's contributions to gene discovery underscore the importance of data sharing and the value of collaborative enterprises.

Published
2019

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