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2. Lymphatic disorders caused by mosaic, activating KRAS variants respond to MEK inhibition

Author

Sheppard, Sarah E, March, Michael E, Seiler, Christoph, Matsuoka, Leticia S, Kim, Sophia E, Kao, Charlly, Rubin, Adam I, Battig, Mark R, Khalek, Nahla, Schindewolf, Erica, O’Connor, Nora, Pinto, Erin, Priestley, Jessica RC, Sanders, Victoria R, Niazi, Rojeen, Ganguly, Arupa, Hou, Cuiping, Slater, Diana, Frieden, Ilona J, Huynh, Thy, Shieh, Joseph T, Krantz, Ian D, Guerrero, Jessenia C, Surrey, Lea F, Biko, David M, Laje, Pablo, Castelo-Soccio, Leslie, Nakano, Taizo A, Snyder, Kristen, Smith, Christopher L, Li, Dong, Dori, Yoav, and Hakonarson, Hakon

Subjects
Rare Diseases, Pediatric, Animals, Humans, Zebrafish, Proto-Oncogene Proteins p21(ras), Endothelial Cells, Phosphorylation, Mitogen-Activated Protein Kinase Kinases, Zebrafish Proteins, Cardiology, Cardiovascular disease, Genetics, Molecular biology, Molecular genetics
Abstract

Central conducting lymphatic anomaly (CCLA) due to congenital maldevelopment of the lymphatics can result in debilitating and life-threatening disease with limited treatment options. We identified 4 individuals with CCLA, lymphedema, and microcystic lymphatic malformation due to pathogenic, mosaic variants in KRAS. To determine the functional impact of these variants and identify a targeted therapy for these individuals, we used primary human dermal lymphatic endothelial cells (HDLECs) and zebrafish larvae to model the lymphatic dysplasia. Expression of the p.Gly12Asp and p.Gly13Asp variants in HDLECs in a 2‑dimensional (2D) model and 3D organoid model led to increased ERK phosphorylation, demonstrating these variants activate the RAS/MAPK pathway. Expression of activating KRAS variants in the venous and lymphatic endothelium in zebrafish resulted in lymphatic dysplasia and edema similar to the individuals in the study. Treatment with MEK inhibition significantly reduced the phenotypes in both the organoid and the zebrafish model systems. In conclusion, we present the molecular characterization of the observed lymphatic anomalies due to pathogenic, somatic, activating KRAS variants in humans. Our preclinical studies suggest that MEK inhibition should be studied in future clinical trials for CCLA due to activating KRAS pathogenic variants.

Published
2023

4. Gain and loss of function variants in EZH1 disrupt neurogenesis and cause dominant and recessive neurodevelopmental disorders

Author

Gracia-Diaz, Carolina, Zhou, Yijing, Yang, Qian, Maroofian, Reza, Espana-Bonilla, Paula, Lee, Chul-Hwan, Zhang, Shuo, Padilla, Natàlia, Fueyo, Raquel, Waxman, Elisa A., Lei, Sunyimeng, Otrimski, Garrett, Li, Dong, Sheppard, Sarah E., Mark, Paul, Harr, Margaret H., Hakonarson, Hakon, Rodan, Lance, Jackson, Adam, Vasudevan, Pradeep, Powel, Corrina, Mohammed, Shehla, Maddirevula, Sateesh, Alzaidan, Hamad, Faqeih, Eissa A., Efthymiou, Stephanie, Turchetti, Valentina, Rahman, Fatima, Maqbool, Shazia, Salpietro, Vincenzo, Ibrahim, Shahnaz H., di Rosa, Gabriella, Houlden, Henry, Alharbi, Maha Nasser, Al-Sannaa, Nouriya Abbas, Bauer, Peter, Zifarelli, Giovanni, Estaras, Conchi, Hurst, Anna C. E., Thompson, Michelle L., Chassevent, Anna, Smith-Hicks, Constance L., de la Cruz, Xavier, Holtz, Alexander M., Elloumi, Houda Zghal, Hajianpour, M J, Rieubland, Claudine, Braun, Dominique, Banka, Siddharth, French, Deborah L., Heller, Elizabeth A., Saade, Murielle, Song, Hongjun, Ming, Guo-li, Alkuraya, Fowzan S., Agrawal, Pankaj B., Reinberg, Danny, Bhoj, Elizabeth J., Martínez-Balbás, Marian A., and Akizu, Naiara

Published
2023
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5. Central conducting lymphatic anomaly: from bench to bedside

Author

Torales, Luciana Daniela Garlisi, Sempowski, Benjamin A., Krikorian, Georgia L., Woodis, Kristina M., Paulissen, Scott M., Smith, Christopher L., and Sheppard, Sarah E.

Subjects
Tetracycline, Genomics -- Genetic aspects, Tetracyclines, Health care industry
Abstract

Central conducting lymphatic anomaly (CCLA) is a complex lymphatic anomaly characterized by abnormalities of the central lymphatics and may present with nonimmune fetal hydrops, chylothorax, chylous ascites, or lymphedema. CCLA has historically been difficult to diagnose and treat; however, recent advances in imaging, such as dynamic contrast magnetic resonance lymphangiography, and in genomics, such as deep sequencing and utilization of cell-free DNA, have improved diagnosis and refined both genotype and phenotype. Furthermore, in vitro and in vivo models have confirmed genetic causes of CCLA, defined the underlying pathogenesis, and facilitated personalized medicine to improve outcomes. Basic, translational, and clinical science are essential for a bedside-to-bench and back approach for CCLA., Introduction The lymphatic system and its functions. The lymphatic system is a network of vessels and associated organs that play an essential role in human health by maintaining human tissue [...]

Published
2024
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6. Genomic profiling informs diagnoses and treatment in vascular anomalies

Author

Li, Dong, Sheppard, Sarah E., March, Michael E., Battig, Mark R., Surrey, Lea F., Srinivasan, Abhay S., Matsuoka, Leticia S., Tian, Lifeng, Wang, Fengxiang, Seiler, Christoph, Dayneka, Jill, Borst, Alexandra J., Matos, Mary C., Paulissen, Scott M., Krishnamurthy, Ganesh, Nriagu, Bede, Sikder, Tamjeed, Casey, Melissa, Williams, Lydia, Rangu, Sneha, O’Connor, Nora, Thomas, Alexandria, Pinto, Erin, Hou, Cuiping, Nguyen, Kenny, Pellegrino da Silva, Renata, Chehimi, Samar N., Kao, Charlly, Biroc, Lauren, Britt, Allison D., Queenan, Maria, Reid, Janet R., Napoli, Joseph A., Low, David M., Vatsky, Seth, Treat, James, Smith, Christopher L., Cahill, Anne Marie, Snyder, Kristen M., Adams, Denise M., Dori, Yoav, and Hakonarson, Hakon

Published
2023
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8. Expanding the genotypic and phenotypic spectrum in a diverse cohort of 104 individuals with Wiedemann‐Steiner syndrome

Author

Sheppard, Sarah E, Campbell, Ian M, Harr, Margaret H, Gold, Nina, Li, Dong, Bjornsson, Hans T, Cohen, Julie S, Fahrner, Jill A, Fatemi, Ali, Harris, Jacqueline R, Nowak, Catherine, Stevens, Cathy A, Grand, Katheryn, Au, Margaret, Graham, John M, Sanchez‐Lara, Pedro A, Del Campo, Miguel, Jones, Marilyn C, Abdul‐Rahman, Omar, Alkuraya, Fowzan S, Bassetti, Jennifer A, Bergstrom, Katherine, Bhoj, Elizabeth, Dugan, Sarah, Kaplan, Julie D, Derar, Nada, Gripp, Karen W, Hauser, Natalie, Innes, A Micheil, Keena, Beth, Kodra, Neslida, Miller, Rebecca, Nelson, Beverly, Nowaczyk, Malgorzata J, Rahbeeni, Zuhair, Ben‐Shachar, Shay, Shieh, Joseph T, Slavotinek, Anne, Sobering, Andrew K, Abbott, Mary‐Alice, Allain, Dawn C, Amlie‐Wolf, Louise, Au, Ping Yee Billie, Bedoukian, Emma, Beek, Geoffrey, Barry, James, Berg, Janet, Bernstein, Jonathan A, Cytrynbaum, Cheryl, Chung, Brian Hon‐Yin, Donoghue, Sarah, Dorrani, Naghmeh, Eaton, Alison, Flores‐Daboub, Josue A, Dubbs, Holly, Felix, Carolyn A, Fong, Chin‐To, Fung, Jasmine Lee Fong, Gangaram, Balram, Goldstein, Amy, Greenberg, Rotem, Ha, Thoa K, Hersh, Joseph, Izumi, Kosuke, Kallish, Staci, Kravets, Elijah, Kwok, Pui‐Yan, Jobling, Rebekah K, Johnson, Amy E Knight, Kushner, Jessica, Lee, Bo Hoon, Levin, Brooke, Lindstrom, Kristin, Manickam, Kandamurugu, Mardach, Rebecca, McCormick, Elizabeth, McLeod, D Ross, Mentch, Frank D, Minks, Kelly, Muraresku, Colleen, Nelson, Stanley F, Porazzi, Patrizia, Pichurin, Pavel N, Powell‐Hamilton, Nina N, Powis, Zoe, Ritter, Alyssa, Rogers, Caleb, Rohena, Luis, Ronspies, Carey, Schroeder, Audrey, Stark, Zornitza, Starr, Lois, Stoler, Joan, Suwannarat, Pim, Velinov, Milen, Weksberg, Rosanna, Wilnai, Yael, Zadeh, Neda, Zand, Dina J, and Falk, Marni J

Subjects
Congenital Structural Anomalies, Clinical Research, Brain Disorders, Rare Diseases, Pediatric, Aetiology, 2.1 Biological and endogenous factors, Black People, Constipation, Failure to Thrive, Genetic Association Studies, Genetic Predisposition to Disease, Growth Disorders, Histone-Lysine N-Methyltransferase, Humans, Hypertrichosis, Intellectual Disability, Loss of Function Mutation, Myeloid-Lymphoid Leukemia Protein, Retrospective Studies, White People, hypertrichosis, KMT2A, MLL1, syndromic intellectual disability, syndromic short stature, Wiedemann&#8208, Steiner syndrome, Wiedemann-Steiner syndrome, Genetics, Clinical Sciences
Abstract

Wiedemann-Steiner syndrome (WSS) is an autosomal dominant disorder caused by monoallelic variants in KMT2A and characterized by intellectual disability and hypertrichosis. We performed a retrospective, multicenter, observational study of 104 individuals with WSS from five continents to characterize the clinical and molecular spectrum of WSS in diverse populations, to identify physical features that may be more prevalent in White versus Black Indigenous People of Color individuals, to delineate genotype-phenotype correlations, to define developmental milestones, to describe the syndrome through adulthood, and to examine clinicians' differential diagnoses. Sixty-nine of the 82 variants (84%) observed in the study were not previously reported in the literature. Common clinical features identified in the cohort included: developmental delay or intellectual disability (97%), constipation (63.8%), failure to thrive (67.7%), feeding difficulties (66.3%), hypertrichosis cubiti (57%), short stature (57.8%), and vertebral anomalies (46.9%). The median ages at walking and first words were 20 months and 18 months, respectively. Hypotonia was associated with loss of function (LoF) variants, and seizures were associated with non-LoF variants. This study identifies genotype-phenotype correlations as well as race-facial feature associations in an ethnically diverse cohort, and accurately defines developmental trajectories, medical comorbidities, and long-term outcomes in individuals with WSS.

Published
2021

11. Rare variants in KDR, encoding VEGF Receptor 2, are associated with tetralogy of Fallot

Author

Škorić-Milosavljević, Doris, Lahrouchi, Najim, Bosada, Fernanda M., Dombrowsky, Gregor, Williams, Simon G., Lesurf, Robert, Tjong, Fleur V.Y., Walsh, Roddy, El Bouchikhi, Ihssane, Breckpot, Jeroen, Audain, Enrique, Ilgun, Aho, Beekman, Leander, Ratbi, Ilham, Strong, Alanna, Muenke, Maximilian, Heide, Solveig, Muir, Alison M., Hababa, Mariam, Cross, Laura, Zhou, Dihong, Pastinen, Tomi, Hitz, Marc-Phillip, Abdul-Khaliq, Hashim, Berger, Felix, Dähnert, Ingo, Dittrich, Sven, Uebing, Anselm, Stiller, Brigitte, Zackai, Elaine, Atmani, Samir, Ouldim, Karim, Adadi, Najlae, Steindl, Katharina, Rauch, Anita, Brook, David, Wilsdon, Anna, Kuipers, Irene, Blom, Nico A., Mulder, Barbara J., Mefford, Heather C., Keren, Boris, Joset, Pascal, Kruszka, Paul, Thiffault, Isabelle, Sheppard, Sarah E., Roberts, Amy, Lodder, Elisabeth M., Keavney, Bernard D., Clur, Sally-Ann B., Mital, Seema, Hitz, Marc-Philip, Christoffels, Vincent M., Postma, Alex V., and Bezzina, Connie R.

Published
2021
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14. The importance of patient‐specific resources for families dealing with prenatal rare diseases.

Author

Shukla, Dhyanam P., Cutshall, Jennifer Ortiz, van der Heijden, Lex, Schindewolf, Erica, and Sheppard, Sarah E.

Abstract

Rare diseases (RDs) are defined as diseases that affect a low number of the population. Prenatal diagnoses of RDs can add a lot of unique stress for parents. For example, parents who have prenatal diagnoses experience not only grief of expectation, but are forced to become patient advocates with incomplete information as their child is not yet born, and in many cases parents experience a lot of uncertainty. This typically involves seeking support groups and finding pre‐ and postnatal specialists all which come with mental and financial cost. Here we discuss the importance of targeted patient resources for parents to help alleviate some of their stress. Patient advocacy organizations can be incredibly useful for parents to navigate the complex healthcare system and help mitigate feelings of isolation, especially when parents can talk to others in a similar situation. We collaborated with a patient organization to create a prenatal parent support guide to address how parental needs such as mental well‐being and practicing self‐care can be met. We hope that resources such as these can help empower those with a pregnancy affected with a RD diagnosis. [ABSTRACT FROM AUTHOR]

Published
2024
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16. Microcystic lymphatic malformations in Turner syndrome are due to somatic mosaicism of PIK3CA

Author

Nriagu, Bede N., primary, Williams, Lydia S., additional, Brewer, Niambi, additional, Surrey, Lea F., additional, Srinivasan, Abhay S., additional, Li, Dong, additional, Britt, Allison, additional, Treat, James, additional, Crowley, T. Blaine, additional, O'Connor, Nora, additional, Ganguly, Arupa, additional, Low, David, additional, Queenan, Maria, additional, Drivas, Theodore G., additional, Zackai, Elaine H., additional, Adams, Denise M., additional, Hakonarson, Hakon, additional, Snyder, Kristen M., additional, and Sheppard, Sarah E., additional

Published
2023
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18. Microcystic lymphatic malformations in Turner syndrome are due to somatic mosaicism of PIK3CA.

Author

Nriagu, Bede N., Williams, Lydia S., Brewer, Niambi, Surrey, Lea F., Srinivasan, Abhay S., Li, Dong, Britt, Allison, Treat, James, Crowley, T. Blaine, O'Connor, Nora, Ganguly, Arupa, Low, David, Queenan, Maria, Drivas, Theodore G., Zackai, Elaine H., Adams, Denise M., Hakonarson, Hakon, Snyder, Kristen M., and Sheppard, Sarah E.

Abstract

Turner syndrome (45,X) is caused by a complete or partial absence of a single X chromosome. Vascular malformations occur due to abnormal development of blood and/or lymphatic vessels. They arise from either somatic or germline pathogenic variants in the genes regulating growth and apoptosis of vascular channels. Aortic abnormalities are a common, known vascular anomaly of Turner syndrome. However, previous studies have described other vascular malformations as a rare feature of Turner syndrome and suggested that vascular abnormalities in individuals with Turner syndrome may be more generalized. In this study, we describe two individuals with co‐occurrence of Turner syndrome and vascular malformations with a lymphatic component. In these individuals, genetic testing of the lesional tissue revealed a somatic pathogenic variant in PIK3CA—a known and common cause of lymphatic malformations. Based on this finding, we conclude that the vascular malformations presented here and likely those previously in the literature are not a rare part of the clinical spectrum of Turner syndrome, but rather a separate clinical entity that may or may not co‐occur in individuals with Turner syndrome. [ABSTRACT FROM AUTHOR]

Published
2024
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19. Pathogenic variants in PIK3CA are associated with clinical phenotypes of kaposiform lymphangiomatosis, generalized lymphatic anomaly, and central conducting lymphatic anomaly

Author

Grenier, Jeremy M., primary, Borst, Alexandra J., additional, Sheppard, Sarah E., additional, Snyder, Kristen M., additional, Li, Dong, additional, Surrey, Lea F., additional, Al‐Ibraheemi, Alyaa, additional, Weber, David R., additional, Treat, James R., additional, Smith, Christopher L., additional, Laje, Pablo, additional, Dori, Yoav, additional, Adams, Denise M., additional, Acord, Michael, additional, and Srinivasan, Abhay S., additional

Published
2023
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21. Clinical decision support with a comprehensive in-EHR patient tracking system improves genetic testing follow up

Author

Campbell, Ian M, primary, Karavite, Dean J, additional, Mcmanus, Morgan L, additional, Cusick, Fred C, additional, Junod, David C, additional, Sheppard, Sarah E, additional, Lourie, Eli M, additional, Shelov, Eric D, additional, Hakonarson, Hakon, additional, Luberti, Anthony A, additional, Muthu, Naveen, additional, and Grundmeier, Robert W, additional

Published
2023
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22. Mechanism of KMT5B haploinsufficiency in neurodevelopment in humans and mice

Author

Sheppard, Sarah E., primary, Bryant, Laura, additional, Wickramasekara, Rochelle N., additional, Vaccaro, Courtney, additional, Robertson, Brynn, additional, Hallgren, Jodi, additional, Hulen, Jason, additional, Watson, Cynthia J., additional, Faundes, Victor, additional, Duffourd, Yannis, additional, Lee, Pearl, additional, Simon, M. Celeste, additional, de la Cruz, Xavier, additional, Padilla, Natália, additional, Flores-Mendez, Marco, additional, Akizu, Naiara, additional, Smiler, Jacqueline, additional, Pellegrino Da Silva, Renata, additional, Li, Dong, additional, March, Michael, additional, Diaz-Rosado, Abdias, additional, Peixoto de Barcelos, Isabella, additional, Choa, Zhao Xiang, additional, Lim, Chin Yan, additional, Dubourg, Christèle, additional, Journel, Hubert, additional, Demurger, Florence, additional, Mulhern, Maureen, additional, Akman, Cigdem, additional, Lippa, Natalie, additional, Andrews, Marisa, additional, Baldridge, Dustin, additional, Constantino, John, additional, van Haeringen, Arie, additional, Snoeck-Streef, Irina, additional, Chow, Penny, additional, Hing, Anne, additional, Graham, John M., additional, Au, Margaret, additional, Faivre, Laurence, additional, Shen, Wei, additional, Mao, Rong, additional, Palumbos, Janice, additional, Viskochil, David, additional, Gahl, William, additional, Tifft, Cynthia, additional, Macnamara, Ellen, additional, Hauser, Natalie, additional, Miller, Rebecca, additional, Maffeo, Jessica, additional, Afenjar, Alexandra, additional, Doummar, Diane, additional, Keren, Boris, additional, Arn, Pamela, additional, Macklin-Mantia, Sarah, additional, Meerschaut, Ilse, additional, Callewaert, Bert, additional, Reis, André, additional, Zweier, Christiane, additional, Brewer, Carole, additional, Saggar, Anand, additional, Smeland, Marie F., additional, Kumar, Ajith, additional, Elmslie, Frances, additional, Deshpande, Charu, additional, Nizon, Mathilde, additional, Cogne, Benjamin, additional, van Ierland, Yvette, additional, Wilke, Martina, additional, van Slegtenhorst, Marjon, additional, Koudijs, Suzanne, additional, Chen, Jin Yun, additional, Dredge, David, additional, Pier, Danielle, additional, Wortmann, Saskia, additional, Kamsteeg, Erik-Jan, additional, Koch, Johannes, additional, Haynes, Devon, additional, Pollack, Lynda, additional, Titheradge, Hannah, additional, Ranguin, Kara, additional, Denommé-Pichon, Anne-Sophie, additional, Weber, Sacha, additional, Pérez de la Fuente, Rubén, additional, Sánchez del Pozo, Jaime, additional, Lezana Rosales, Jose Miguel, additional, Joset, Pascal, additional, Steindl, Katharina, additional, Rauch, Anita, additional, Mei, Davide, additional, Mari, Francesco, additional, Guerrini, Renzo, additional, Lespinasse, James, additional, Tran Mau-Them, Frédéric, additional, Philippe, Christophe, additional, Dauriat, Benjamin, additional, Raymond, Laure, additional, Moutton, Sébastien, additional, Cueto-González, Anna M., additional, Tan, Tiong Yang, additional, Mignot, Cyril, additional, Grotto, Sarah, additional, Renaldo, Florence, additional, Drivas, Theodore G., additional, Hennessy, Laura, additional, Raper, Anna, additional, Parenti, Ilaria, additional, Kaiser, Frank J., additional, Kuechler, Alma, additional, Busk, Øyvind L., additional, Islam, Lily, additional, Siedlik, Jacob A., additional, Henderson, Lindsay B., additional, Juusola, Jane, additional, Person, Richard, additional, Schnur, Rhonda E., additional, Vitobello, Antonio, additional, Banka, Siddharth, additional, Bhoj, Elizabeth J., additional, and Stessman, Holly A. F., additional

Published
2023
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23. Mechanism of KMT5B haploinsufficiency in neurodevelopment in humans and mice

Author

Sheppard, Sarah E., Bryant, Laura, Wickramasekara, Rochelle N., Vaccaro, Courtney, Robertson, Brynn, Hallgren, Jodi, Hulen, Jason, Watson, Cynthia J., Faundes, Victor, Duffourd, Yannis, Lee, Pearl, Celeste Simon, M., de la Cruz, Xavier, Padilla, Natália, Flores-Mendez, Marco, Akizu, Naiara, Smiler, Jacqueline, Da Silva, Renata Pellegrino, Li, Dong, March, Michael, Diaz-Rosado, Abdias, de Barcelos, Isabella Peixoto, Choa, Zhao Xiang, Lim, Chin Yan, Dubourg, Christèle, Journel, Hubert, Demurger, Florence, Mulhern, Maureen, Akman, Cigdem, Lippa, Natalie, Andrews, Marisa, Baldridge, Dustin, Constantino, John, van Haeringen, Arie, Snoeck-Streef, Irina, Chow, Penny, Hing, Anne, Graham, John M., Au, Margaret, Faivre, Laurence, Shen, Wei, Mao, Rong, Palumbos, Janice, Viskochil, David, Gahl, William, Tifft, Cynthia, Macnamara, Ellen, Hauser, Natalie, Miller, Rebecca, Maffeo, Jessica, Afenjar, Alexandra, Doummar, Diane, Keren, Boris, Arn, Pamela, Macklin-Mantia, Sarah, Meerschaut, Ilse, Callewaert, Bert, Reis, André, Zweier, Christiane, Brewer, Carole, Saggar, Anand, Smeland, Marie F., Kumar, Ajith, Elmslie, Frances, Deshpande, Charu, Nizon, Mathilde, Cogne, Benjamin, van Ierland, Yvette, Wilke, Martina, van Slegtenhorst, Marjon, Koudijs, Suzanne, Chen, Jin Yun, Dredge, David, Pier, Danielle, Wortmann, Saskia, Kamsteeg, Erik Jan, Koch, Johannes, Haynes, Devon, Pollack, Lynda, Titheradge, Hannah, Ranguin, Kara, Denommé-Pichon, Anne Sophie, Weber, Sacha, de la Fuente, Rubén Pérez, del Pozo, Jaime Sánchez, Rosales, Jose Miguel Lezana, Joset, Pascal, Steindl, Katharina, Rauch, Anita, Mei, Davide, Mari, Francesco, Guerrini, Renzo, Lespinasse, James, Mau-Them, Frédéric Tran, Philippe, Christophe, Dauriat, Benjamin, Raymond, Laure, Moutton, Sébastien, Cueto-González, Anna M., Tan, Tiong Yang, Mignot, Cyril, Grotto, Sarah, Renaldo, Florence, Drivas, Theodore G., Hennessy, Laura, Raper, Anna, Parenti, Ilaria, Kaiser, Frank J., Kuechler, Alma, Busk, Øyvind L., Islam, Lily, Siedlik, Jacob A., Henderson, Lindsay B., Juusola, Jane, Person, Richard, Schnur, Rhonda E., Vitobello, Antonio, Banka, Siddharth, Bhoj, Elizabeth J., Stessman, Holly A.F., Sheppard, Sarah E., Bryant, Laura, Wickramasekara, Rochelle N., Vaccaro, Courtney, Robertson, Brynn, Hallgren, Jodi, Hulen, Jason, Watson, Cynthia J., Faundes, Victor, Duffourd, Yannis, Lee, Pearl, Celeste Simon, M., de la Cruz, Xavier, Padilla, Natália, Flores-Mendez, Marco, Akizu, Naiara, Smiler, Jacqueline, Da Silva, Renata Pellegrino, Li, Dong, March, Michael, Diaz-Rosado, Abdias, de Barcelos, Isabella Peixoto, Choa, Zhao Xiang, Lim, Chin Yan, Dubourg, Christèle, Journel, Hubert, Demurger, Florence, Mulhern, Maureen, Akman, Cigdem, Lippa, Natalie, Andrews, Marisa, Baldridge, Dustin, Constantino, John, van Haeringen, Arie, Snoeck-Streef, Irina, Chow, Penny, Hing, Anne, Graham, John M., Au, Margaret, Faivre, Laurence, Shen, Wei, Mao, Rong, Palumbos, Janice, Viskochil, David, Gahl, William, Tifft, Cynthia, Macnamara, Ellen, Hauser, Natalie, Miller, Rebecca, Maffeo, Jessica, Afenjar, Alexandra, Doummar, Diane, Keren, Boris, Arn, Pamela, Macklin-Mantia, Sarah, Meerschaut, Ilse, Callewaert, Bert, Reis, André, Zweier, Christiane, Brewer, Carole, Saggar, Anand, Smeland, Marie F., Kumar, Ajith, Elmslie, Frances, Deshpande, Charu, Nizon, Mathilde, Cogne, Benjamin, van Ierland, Yvette, Wilke, Martina, van Slegtenhorst, Marjon, Koudijs, Suzanne, Chen, Jin Yun, Dredge, David, Pier, Danielle, Wortmann, Saskia, Kamsteeg, Erik Jan, Koch, Johannes, Haynes, Devon, Pollack, Lynda, Titheradge, Hannah, Ranguin, Kara, Denommé-Pichon, Anne Sophie, Weber, Sacha, de la Fuente, Rubén Pérez, del Pozo, Jaime Sánchez, Rosales, Jose Miguel Lezana, Joset, Pascal, Steindl, Katharina, Rauch, Anita, Mei, Davide, Mari, Francesco, Guerrini, Renzo, Lespinasse, James, Mau-Them, Frédéric Tran, Philippe, Christophe, Dauriat, Benjamin, Raymond, Laure, Moutton, Sébastien, Cueto-González, Anna M., Tan, Tiong Yang, Mignot, Cyril, Grotto, Sarah, Renaldo, Florence, Drivas, Theodore G., Hennessy, Laura, Raper, Anna, Parenti, Ilaria, Kaiser, Frank J., Kuechler, Alma, Busk, Øyvind L., Islam, Lily, Siedlik, Jacob A., Henderson, Lindsay B., Juusola, Jane, Person, Richard, Schnur, Rhonda E., Vitobello, Antonio, Banka, Siddharth, Bhoj, Elizabeth J., and Stessman, Holly A.F.

Abstract

Pathogenic variants in KMT5B, a lysine methyltransferase, are associated with global developmental delay, macrocephaly, autism, and congenital anomalies (OMIM# 617788). Given the relatively recent discovery of this disorder, it has not been fully characterized. Deep phenotyping of the largest (n = 43) patient cohort to date identified that hypotonia and congenital heart defects are prominent features that were previously not associated with this syndrome. Both missense variants and putative loss-of-function variants resulted in slow growth in patient-derived cell lines. KMT5B homozygous knockout mice were smaller in size than their wild-type littermates but did not have significantly smaller brains, suggesting relative macrocephaly, also noted as a prominent clinical feature. RNA sequencing of patient lymphoblasts and Kmt5b haploinsufficient mouse brains identified differentially expressed pathways associated with nervous system development and function including axon guidance signaling. Overall, we identified additional pathogenic variants and clinical features in KMT5Brelated neurodevelopmental disorder and provide insights into the molecular mechanisms of the disorder using multiple model systems.

Published
2023

24. Gain and loss of function variants in EZH1 disrupt neurogenesis and cause dominant and recessive neurodevelopmental disorders

Author

National Institutes of Health (US), Ministerio de Economía y Competitividad (España), Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), University of Alabama at Birmingham, Ministerio de Ciencia e Innovación (España), Ministerio de Educación y Ciencia (España), Manchester Biomedical Research Centre, European Commission, National Institute for Health Research (UK), Wellcome Trust, Cancer Research UK, Medical Research Council (UK), Wellcome Sanger Institute, Gracia-Díaz, Carolina, Zhou, Yijing, Yang, Qian, Maroofian, Reza, España-Bonilla, Paula, Lee, Chul-Hwan, Zhang, Shuo, Padilla, Natàlia, Fueyo, Raquel, Waxman, Elisa A., Lei, Sunyimeng, Otrimski, Garrett, Li, Dong, Sheppard, Sarah E., Mark, Paul, Harr, Margaret H., Hakonarson, Hakon, Rodan, Lance, Jackson, Adam, Vasudevan, Pradeep, Powel, Corrina, Mohammed, Shehla, Maddirevula, Sateesh, Alzaidan, Hamad, Faqeih, Eissa A., Efthymiou, Stephanie, Turchetti, Valentina, Rahman, Fátima, Maqbool, Shazia, Salpietro, Vincenzo, Ibrahim, Shahnaz H., di Rosa, Gabriella, Houlden, Henry, Alharbi, Maha Nasser, Al-Sannaa, Nouriya Abbas, Bauer, Peter, Zifarelli, Giovanni, Estaras, Conchi, Hurst, Anna C. E., Thompson, Michelle L., Chassevent, Anna, Smith-Hicks, Constance L., Cruz, Xavier de la, Holtz, Alexander M., Elloumi, Houda Zghal, Hajianpour, M. J., Rieubland, Claudine, Braun, Dominique, Banka, Siddharth, French, Deborah L., Heller, Elizabeth A., Saade, Murielle, Song, Hongjun, Ming, Guo-Li, Alkuraya, Fowzan S., Agrawal, Pankaj B., Reinberg, Danny, Bhoj, Elizabeth J., Martínez-Balbás, Marian, Akizu, Naiara, National Institutes of Health (US), Ministerio de Economía y Competitividad (España), Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), University of Alabama at Birmingham, Ministerio de Ciencia e Innovación (España), Ministerio de Educación y Ciencia (España), Manchester Biomedical Research Centre, European Commission, National Institute for Health Research (UK), Wellcome Trust, Cancer Research UK, Medical Research Council (UK), Wellcome Sanger Institute, Gracia-Díaz, Carolina, Zhou, Yijing, Yang, Qian, Maroofian, Reza, España-Bonilla, Paula, Lee, Chul-Hwan, Zhang, Shuo, Padilla, Natàlia, Fueyo, Raquel, Waxman, Elisa A., Lei, Sunyimeng, Otrimski, Garrett, Li, Dong, Sheppard, Sarah E., Mark, Paul, Harr, Margaret H., Hakonarson, Hakon, Rodan, Lance, Jackson, Adam, Vasudevan, Pradeep, Powel, Corrina, Mohammed, Shehla, Maddirevula, Sateesh, Alzaidan, Hamad, Faqeih, Eissa A., Efthymiou, Stephanie, Turchetti, Valentina, Rahman, Fátima, Maqbool, Shazia, Salpietro, Vincenzo, Ibrahim, Shahnaz H., di Rosa, Gabriella, Houlden, Henry, Alharbi, Maha Nasser, Al-Sannaa, Nouriya Abbas, Bauer, Peter, Zifarelli, Giovanni, Estaras, Conchi, Hurst, Anna C. E., Thompson, Michelle L., Chassevent, Anna, Smith-Hicks, Constance L., Cruz, Xavier de la, Holtz, Alexander M., Elloumi, Houda Zghal, Hajianpour, M. J., Rieubland, Claudine, Braun, Dominique, Banka, Siddharth, French, Deborah L., Heller, Elizabeth A., Saade, Murielle, Song, Hongjun, Ming, Guo-Li, Alkuraya, Fowzan S., Agrawal, Pankaj B., Reinberg, Danny, Bhoj, Elizabeth J., Martínez-Balbás, Marian, and Akizu, Naiara

Abstract

Genetic variants in chromatin regulators are frequently found in neurodevelopmental disorders, but their effect in disease etiology is rarely determined. Here, we uncover and functionally define pathogenic variants in the chromatin modifier EZH1 as the cause of dominant and recessive neurodevelopmental disorders in 19 individuals. EZH1 encodes one of the two alternative histone H3 lysine 27 methyltransferases of the PRC2 complex. Unlike the other PRC2 subunits, which are involved in cancers and developmental syndromes, the implication of EZH1 in human development and disease is largely unknown. Using cellular and biochemical studies, we demonstrate that recessive variants impair EZH1 expression causing loss of function effects, while dominant variants are missense mutations that affect evolutionarily conserved aminoacids, likely impacting EZH1 structure or function. Accordingly, we found increased methyltransferase activity leading to gain of function of two EZH1 missense variants. Furthermore, we show that EZH1 is necessary and sufficient for differentiation of neural progenitor cells in the developing chick embryo neural tube. Finally, using human pluripotent stem cell-derived neural cultures and forebrain organoids, we demonstrate that EZH1 variants perturb cortical neuron differentiation. Overall, our work reveals a critical role of EZH1 in neurogenesis regulation and provides molecular diagnosis for previously undefined neurodevelopmental disorders.

Published
2023

25. Mechanism of KMT5B haploinsufficiency in neurodevelopment in humans and mice

Author

Sheppard, Sarah E; https://orcid.org/0000-0003-3480-8123, Bryant, Laura; https://orcid.org/0000-0001-8483-8940, Wickramasekara, Rochelle N; https://orcid.org/0000-0003-3090-9357, Vaccaro, Courtney, Robertson, Brynn, Hallgren, Jodi; https://orcid.org/0000-0002-3892-8213, Hulen, Jason, Watson, Cynthia J, Faundes, Victor; https://orcid.org/0000-0002-6746-0103, Duffourd, Yannis, Lee, Pearl; https://orcid.org/0000-0002-1274-2891, Simon, M Celeste; https://orcid.org/0000-0001-9106-447X, de la Cruz, Xavier; https://orcid.org/0000-0002-9738-8472, Padilla, Natália; https://orcid.org/0000-0002-7872-2279, Flores-Mendez, Marco; https://orcid.org/0000-0002-0524-9740, Akizu, Naiara; https://orcid.org/0000-0001-9222-6960, Smiler, Jacqueline; https://orcid.org/0000-0002-3201-228X, Da Silva, Renata Pellegrino, Li, Dong; https://orcid.org/0000-0002-2265-6727, March, Michael; https://orcid.org/0000-0001-9173-6862, Diaz-Rosado, Abdias, de Barcelos, Isabella Peixoto; https://orcid.org/0000-0002-3843-4520, Choa, Zhao Xiang; https://orcid.org/0000-0002-1838-7931, Lim, Chin Yan; https://orcid.org/0000-0002-1585-002X, Dubourg, Christèle; https://orcid.org/0000-0003-1345-4522, Journel, Hubert, Demurger, Florence, Mulhern, Maureen; https://orcid.org/0000-0001-8642-4741, Akman, Cigdem, Lippa, Natalie; https://orcid.org/0000-0002-7316-1476, Joset, Pascal; https://orcid.org/0000-0002-4349-9951, Steindl, Katharina; https://orcid.org/0000-0002-4425-3072, Rauch, Anita; https://orcid.org/0000-0003-2930-3163, et al, Sheppard, Sarah E; https://orcid.org/0000-0003-3480-8123, Bryant, Laura; https://orcid.org/0000-0001-8483-8940, Wickramasekara, Rochelle N; https://orcid.org/0000-0003-3090-9357, Vaccaro, Courtney, Robertson, Brynn, Hallgren, Jodi; https://orcid.org/0000-0002-3892-8213, Hulen, Jason, Watson, Cynthia J, Faundes, Victor; https://orcid.org/0000-0002-6746-0103, Duffourd, Yannis, Lee, Pearl; https://orcid.org/0000-0002-1274-2891, Simon, M Celeste; https://orcid.org/0000-0001-9106-447X, de la Cruz, Xavier; https://orcid.org/0000-0002-9738-8472, Padilla, Natália; https://orcid.org/0000-0002-7872-2279, Flores-Mendez, Marco; https://orcid.org/0000-0002-0524-9740, Akizu, Naiara; https://orcid.org/0000-0001-9222-6960, Smiler, Jacqueline; https://orcid.org/0000-0002-3201-228X, Da Silva, Renata Pellegrino, Li, Dong; https://orcid.org/0000-0002-2265-6727, March, Michael; https://orcid.org/0000-0001-9173-6862, Diaz-Rosado, Abdias, de Barcelos, Isabella Peixoto; https://orcid.org/0000-0002-3843-4520, Choa, Zhao Xiang; https://orcid.org/0000-0002-1838-7931, Lim, Chin Yan; https://orcid.org/0000-0002-1585-002X, Dubourg, Christèle; https://orcid.org/0000-0003-1345-4522, Journel, Hubert, Demurger, Florence, Mulhern, Maureen; https://orcid.org/0000-0001-8642-4741, Akman, Cigdem, Lippa, Natalie; https://orcid.org/0000-0002-7316-1476, Joset, Pascal; https://orcid.org/0000-0002-4349-9951, Steindl, Katharina; https://orcid.org/0000-0002-4425-3072, Rauch, Anita; https://orcid.org/0000-0003-2930-3163, and et al

Abstract

Pathogenic variants in KMT5B, a lysine methyltransferase, are associated with global developmental delay, macrocephaly, autism, and congenital anomalies (OMIM# 617788). Given the relatively recent discovery of this disorder, it has not been fully characterized. Deep phenotyping of the largest (n = 43) patient cohort to date identified that hypotonia and congenital heart defects are prominent features that were previously not associated with this syndrome. Both missense variants and putative loss-of-function variants resulted in slow growth in patient-derived cell lines. KMT5B homozygous knockout mice were smaller in size than their wild-type littermates but did not have significantly smaller brains, suggesting relative macrocephaly, also noted as a prominent clinical feature. RNA sequencing of patient lymphoblasts and Kmt5b haploinsufficient mouse brains identified differentially expressed pathways associated with nervous system development and function including axon guidance signaling. Overall, we identified additional pathogenic variants and clinical features in KMT5B-related neurodevelopmental disorder and provide insights into the molecular mechanisms of the disorder using multiple model systems.

Published
2023

26. Mechanism of KMT5B haploinsufficiency in neurodevelopment in humans and mice

Author

Sheppard, Sarah E, Bryant, Laura, Wickramasekara, Rochelle N, Vaccaro, Courtney, Robertson, Brynn, Hallgren, Jodi, Hulen, Jason, Watson, Cynthia J, Faundes, Victor, Duffourd, Yannis, Lee, Pearl, Simon, M Celeste, de la Cruz, Xavier, Padilla, Natália, Flores-Mendez, Marco, Akizu, Naiara, Smiler, Jacqueline, Da Silva, Renata Pellegrino, Li, Dong, March, Michael, Diaz-Rosado, Abdias, de Barcelos, Isabella Peixoto, Choa, Zhao Xiang, Lim, Chin Yan, Dubourg, Christèle, Journel, Hubert, Demurger, Florence, Mulhern, Maureen, Akman, Cigdem, Lippa, Natalie, Joset, Pascal, Steindl, Katharina, Rauch, Anita, et al, and University of Zurich

Subjects
1000 Multidisciplinary, Methyltransferases / genetics, 10039 Institute of Medical Genetics, Knockout, 610 Medicine & health, Haploinsufficiency, Methyltransferases, Mice, Phenotype, Megalencephaly, 10036 Medical Clinic, Neurodevelopmental Disorders* / genetics, 570 Life sciences, biology, Animals, Humans
Published
2023

27. Genomic profiling informs diagnoses and treatment in vascular anomalies

Author

Li, Dong, Sheppard, Sarah E., March, Michael E., Battig, Mark R., Surrey, Lea F., Srinivasan, Abhay S., Matsuoka, Leticia S., Tian, Lifeng, Wang, Fengxiang, Seiler, Christoph, Dayneka, Jill, Borst, Alexandra J., Matos, Mary C., Paulissen, Scott M., Krishnamurthy, Ganesh, Nriagu, Bede, Sikder, Tamjeed, Casey, Melissa, Williams, Lydia, Rangu, Sneha, O’Connor, Nora, Thomas, Alexandria, Pinto, Erin, Hou, Cuiping, Nguyen, Kenny, Pellegrino da Silva, Renata, Chehimi, Samar N., Kao, Charlly, Biroc, Lauren, Britt, Allison D., Queenan, Maria, Reid, Janet R., Napoli, Joseph A., Low, David M., Vatsky, Seth, Treat, James, Smith, Christopher L., Cahill, Anne Marie, Snyder, Kristen M., Adams, Denise M., Dori, Yoav, and Hakonarson, Hakon

Abstract

Vascular anomalies are malformations or tumors of the blood or lymphatic vasculature and can be life-threatening. Although molecularly targeted therapies can be life-saving, identification of the molecular etiology is often impeded by lack of accessibility to affected tissue samples, mosaicism or insufficient sequencing depth. In a cohort of 356 participants with vascular anomalies, including 104 with primary complex lymphatic anomalies (pCLAs), DNA from CD31+ cells isolated from lymphatic fluid or cell-free DNA from lymphatic fluid or plasma underwent ultra-deep sequencing thereby uncovering pathogenic somatic variants down to a variant allele fraction of 0.15%. A molecular diagnosis, including previously undescribed genetic causes, was obtained in 41% of participants with pCLAs and 72% of participants with other vascular malformations, leading to a new medical therapy for 63% (43/69) of participants and resulting in improvement in 63% (35/55) of participants on therapy. Taken together, these data support the development of liquid biopsy-based diagnostic techniques to identify previously undescribed genotype–phenotype associations and guide medical therapy in individuals with vascular anomalies.

Published
2024
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28. Clinical Decision Support with a Comprehensive in-EHR Patient Tracking System Improves Genetic Testing Follow Up

Author

Campbell, Ian M., primary, Karavite, Dean J., additional, McManus, Morgan L., additional, Cusick, Fred C., additional, Junod, David C., additional, Sheppard, Sarah E., additional, Lourie, Eli M., additional, Shelov, Eric D., additional, Hakonarson, Hakon, additional, Luberti, Anthony A., additional, Muthu, Naveen, additional, and Grundmeier, Robert W., additional

Published
2023
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30. A clustering of heterozygous missense variants in the crucial chromatin modifier WDR5 defines a new neurodevelopmental disorder

Author

Snijders Blok, Lot, primary, Verseput, Jolijn, additional, Rots, Dmitrijs, additional, Venselaar, Hanka, additional, Innes, A. Micheil, additional, Stumpel, Connie, additional, Õunap, Katrin, additional, Reinson, Karit, additional, Seaby, Eleanor G., additional, McKee, Shane, additional, Burton, Barbara, additional, Kim, Katherine, additional, van Hagen, Johanna M., additional, Waisfisz, Quinten, additional, Joset, Pascal, additional, Steindl, Katharina, additional, Rauch, Anita, additional, Li, Dong, additional, Zackai, Elaine H., additional, Sheppard, Sarah E., additional, Keena, Beth, additional, Hakonarson, Hakon, additional, Roos, Andreas, additional, Kohlschmidt, Nicolai, additional, Cereda, Anna, additional, Iascone, Maria, additional, Rebessi, Erika, additional, Kernohan, Kristin D., additional, Campeau, Philippe M., additional, Millan, Francisca, additional, Taylor, Jesse A., additional, Lochmüller, Hanns, additional, Higgs, Martin R., additional, Goula, Amalia, additional, Bernhard, Birgitta, additional, Velasco, Danita J., additional, Schmanski, Andrew A., additional, Stark, Zornitza, additional, Gallacher, Lyndon, additional, Pais, Lynn, additional, Marcogliese, Paul C., additional, Yamamoto, Shinya, additional, Raun, Nicholas, additional, Jakub, Taryn E., additional, Kramer, Jamie M., additional, den Hoed, Joery, additional, Fisher, Simon E., additional, Brunner, Han G., additional, and Kleefstra, Tjitske, additional

Published
2023
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31. Genomic and phenotypic characterization of 404 individuals with neurodevelopmental disorders caused by CTNNB1 variants

Author

Kayumi, Sayaka, primary, Pérez-Jurado, Luis A., additional, Palomares, María, additional, Rangu, Sneha, additional, Sheppard, Sarah E., additional, Chung, Wendy K., additional, Kruer, Michael C., additional, Kharbanda, Mira, additional, Amor, David J., additional, McGillivray, George, additional, Cohen, Julie S., additional, García-Miñaúr, Sixto, additional, van Eyk, Clare L., additional, Harper, Kelly, additional, Jolly, Lachlan A., additional, Webber, Dani L., additional, Barnett, Christopher P., additional, Santos-Simarro, Fernando, additional, Pacio-Míguez, Marta, additional, Pozo, Angela del, additional, Bakhtiari, Somayeh, additional, Deardorff, Matthew, additional, Dubbs, Holly A., additional, Izumi, Kosuke, additional, Grand, Katheryn, additional, Gray, Christopher, additional, Mark, Paul R., additional, Bhoj, Elizabeth J., additional, Li, Dong, additional, Ortiz-Gonzalez, Xilma R., additional, Keena, Beth, additional, Zackai, Elaine H., additional, Goldberg, Ethan M., additional, Perez de Nanclares, Guiomar, additional, Pereda, Arrate, additional, Llano-Rivas, Isabel, additional, Arroyo, Ignacio, additional, Fernández-Cuesta, María Ángeles, additional, Thauvin-Robinet, Christel, additional, Faivre, Laurence, additional, Garde, Aurore, additional, Mazel, Benoit, additional, Bruel, Ange-Line, additional, Tress, Michael L., additional, Brilstra, Eva, additional, Fine, Amena Smith, additional, Crompton, Kylie E., additional, Stegmann, Alexander P.A., additional, Sinnema, Margje, additional, Stevens, Servi C.J., additional, Nicolai, Joost, additional, Lesca, Gaetan, additional, Lion-François, Laurence, additional, Haye, Damien, additional, Chatron, Nicolas, additional, Piton, Amelie, additional, Nizon, Mathilde, additional, Cogne, Benjamin, additional, Srivastava, Siddharth, additional, Bassetti, Jennifer, additional, Muss, Candace, additional, Gripp, Karen W., additional, Procopio, Rebecca A., additional, Millan, Francisca, additional, Morrow, Michelle M., additional, Assaf, Melissa, additional, Moreno-De-Luca, Andres, additional, Joss, Shelagh, additional, Hamilton, Mark J., additional, Bertoli, Marta, additional, Foulds, Nicola, additional, McKee, Shane, additional, MacLennan, Alastair H., additional, Gecz, Jozef, additional, and Corbett, Mark A., additional

Published
2022
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33. Clinical Effectiveness of Telemedicine-Based Pediatric Genetics Care

Author

Szigety, Katherine M., primary, Crowley, Terrence B., additional, Gaiser, Kimberly B., additional, Chen, Erin Y., additional, Priestley, Jessica R.C., additional, Williams, Lydia S., additional, Rangu, Sneha A., additional, Wright, Christina M., additional, Adusumalli, Priyanka, additional, Ahrens-Nicklas, Rebecca C., additional, Calderon, Brandon, additional, Cuddapah, Sanmati R., additional, Edmondson, Andrew, additional, Ficicioglu, Can, additional, Ganetzky, Rebecca, additional, Kalish, Jennifer M., additional, Krantz, Ian D., additional, McDonald-McGinn, Donna M., additional, Medne, Livija, additional, Muraresku, Colleen, additional, Pyle, Louise C., additional, Zackai, Elaine H., additional, Campbell, Ian M., additional, and Sheppard, Sarah E., additional

Published
2022
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34. Genomic and phenotypic characterization of 404 individuals with neurodevelopmental disorders caused by CTNNB1 variants

Author

Genetica Klinische Genetica, Brain, Kayumi, Sayaka, Pérez-Jurado, Luis A, Palomares, María, Rangu, Sneha, Sheppard, Sarah E, Chung, Wendy K, Kruer, Michael C, Kharbanda, Mira, Amor, David J, McGillivray, George, Cohen, Julie S, García-Miñaúr, Sixto, van Eyk, Clare L, Harper, Kelly, Jolly, Lachlan A, Webber, Dani L, Barnett, Christopher P, Santos-Simarro, Fernando, Pacio-Míguez, Marta, Pozo, Angela Del, Bakhtiari, Somayeh, Deardorff, Matthew, Dubbs, Holly A, Izumi, Kosuke, Grand, Katheryn, Gray, Christopher, Mark, Paul R, Bhoj, Elizabeth J, Li, Dong, Ortiz-Gonzalez, Xilma R, Keena, Beth, Zackai, Elaine H, Goldberg, Ethan M, Perez de Nanclares, Guiomar, Pereda, Arrate, Llano-Rivas, Isabel, Arroyo, Ignacio, Fernández-Cuesta, María Ángeles, Thauvin-Robinet, Christel, Faivre, Laurence, Garde, Aurore, Mazel, Benoit, Bruel, Ange-Line, Tress, Michael L, Brilstra, Eva, Fine, Amena Smith, Crompton, Kylie E, Stegmann, Alexander P A, Sinnema, Margje, Stevens, Servi C J, Nicolai, Joost, Lesca, Gaetan, Lion-François, Laurence, Haye, Damien, Chatron, Nicolas, Piton, Amelie, Nizon, Mathilde, Cogne, Benjamin, Srivastava, Siddharth, Bassetti, Jennifer, Muss, Candace, Gripp, Karen W, Procopio, Rebecca A, Millan, Francisca, Morrow, Michelle M, Assaf, Melissa, Moreno-De-Luca, Andres, Joss, Shelagh, Hamilton, Mark J, Bertoli, Marta, Foulds, Nicola, McKee, Shane, MacLennan, Alastair H, Gecz, Jozef, Corbett, Mark A, Genetica Klinische Genetica, Brain, Kayumi, Sayaka, Pérez-Jurado, Luis A, Palomares, María, Rangu, Sneha, Sheppard, Sarah E, Chung, Wendy K, Kruer, Michael C, Kharbanda, Mira, Amor, David J, McGillivray, George, Cohen, Julie S, García-Miñaúr, Sixto, van Eyk, Clare L, Harper, Kelly, Jolly, Lachlan A, Webber, Dani L, Barnett, Christopher P, Santos-Simarro, Fernando, Pacio-Míguez, Marta, Pozo, Angela Del, Bakhtiari, Somayeh, Deardorff, Matthew, Dubbs, Holly A, Izumi, Kosuke, Grand, Katheryn, Gray, Christopher, Mark, Paul R, Bhoj, Elizabeth J, Li, Dong, Ortiz-Gonzalez, Xilma R, Keena, Beth, Zackai, Elaine H, Goldberg, Ethan M, Perez de Nanclares, Guiomar, Pereda, Arrate, Llano-Rivas, Isabel, Arroyo, Ignacio, Fernández-Cuesta, María Ángeles, Thauvin-Robinet, Christel, Faivre, Laurence, Garde, Aurore, Mazel, Benoit, Bruel, Ange-Line, Tress, Michael L, Brilstra, Eva, Fine, Amena Smith, Crompton, Kylie E, Stegmann, Alexander P A, Sinnema, Margje, Stevens, Servi C J, Nicolai, Joost, Lesca, Gaetan, Lion-François, Laurence, Haye, Damien, Chatron, Nicolas, Piton, Amelie, Nizon, Mathilde, Cogne, Benjamin, Srivastava, Siddharth, Bassetti, Jennifer, Muss, Candace, Gripp, Karen W, Procopio, Rebecca A, Millan, Francisca, Morrow, Michelle M, Assaf, Melissa, Moreno-De-Luca, Andres, Joss, Shelagh, Hamilton, Mark J, Bertoli, Marta, Foulds, Nicola, McKee, Shane, MacLennan, Alastair H, Gecz, Jozef, and Corbett, Mark A

Published
2022

35. Mosaic pathogenic variants in AKT3 cause capillary malformation and undergrowth.

Author

Bolli, Amber, Nriagu, Bede, Britt, Allison D., Toole, Anjali D., Treat, James, Srinivasan, Abhay, and Sheppard, Sarah E.

Abstract

Capillary malformations are slow‐flow vascular malformations that affect the microcirculation including capillaries and post capillary venules and can be associated with growth differences. Specifically, the association of capillary malformations with undergrowth is a vastly understudied vascular syndrome with few reports of genetic causes including PIK3CA, GNAQ, and GNA11. Recently, a somatic pathogenic variant in AKT3 was identified in one child with a cutaneous vascular syndrome similar to cutis marmorata telangiectatica congenita, undergrowth, and no neurodevelopmental features. Here, we present a male patient with a capillary malformation and undergrowth due to a somatic pathogenic variant in AKT3 to confirm this association. It is essential to consider that mosaic pathogenic variants in AKT3 can cause a wide spectrum of disease. There is a need for future studies focusing on capillary malformations with undergrowth to understand the underlying mechanism. [ABSTRACT FROM AUTHOR]

Published
2023
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36. Pathogenic variants in MDFIC cause recessive central conducting lymphatic anomaly with lymphedema

Author

Byrne, Alicia B., primary, Brouillard, Pascal, additional, Sutton, Drew L., additional, Kazenwadel, Jan, additional, Montazaribarforoushi, Saba, additional, Secker, Genevieve A., additional, Oszmiana, Anna, additional, Babic, Milena, additional, Betterman, Kelly L., additional, Brautigan, Peter J., additional, White, Melissa, additional, Piltz, Sandra G., additional, Thomas, Paul Q., additional, Hahn, Christopher N., additional, Rath, Matthias, additional, Felbor, Ute, additional, Korenke, G. Christoph, additional, Smith, Christopher L., additional, Wood, Kathleen H., additional, Sheppard, Sarah E., additional, Adams, Denise M., additional, Kariminejad, Ariana, additional, Helaers, Raphael, additional, Boon, Laurence M., additional, Revencu, Nicole, additional, Moore, Lynette, additional, Barnett, Christopher, additional, Haan, Eric, additional, Arts, Peer, additional, Vikkula, Miikka, additional, Scott, Hamish S., additional, and Harvey, Natasha L., additional

Published
2022
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38. Cerebrofacial vascular metameric syndrome is caused by somatic pathogenic variants in PIK3CA

Author

Sheppard, Sarah E., primary, Sanders, Victoria R., additional, Srinivasan, Abhay, additional, Finn, Laura S., additional, Adams, Denise, additional, Elton, Andrew, additional, Amlie-Lefond, Catherine, additional, Nelson, Zoe, additional, Dmyterko, Victoria, additional, Jensen, Dana, additional, Zenner, Kaitlyn, additional, Perkins, Jonathan, additional, and Bennett, James T., additional

Published
2021
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40. Contributors

Author

Abman, Steven H., Ali, Noorjahan, Allegaert, Karel, Anderson, Jamie E., Ansah, Deidra A., Arya, Bhawna, Askenazi, David, Aucott, Susan W., Back, Stephen A., Baer, Gerri R., Baldwin, H. Scott, Ballas, Jerasimos, Batra, Maneesh, Bayart, Cheryl, Bellus, Gary A., Benjamin, John T., Berry, Gerard T., Billimoria, Zeenia C., Binenbaum, Gil, Blessing, Matthew S., Boos, Markus D., Bosse, Brad, Bouchard, Maryse L., Brandling-Bennett, Heather A., Brown, Colleen, Brown, Erin G., Campbell, Katherine H., Carlberg, Katie, Carter, Brian S., Chabra, Shilpi, Chang, Irene J., Cheng, Edith Y., Chiang, Kai-wen, Christensen, Robert D., Chun, Terrence, Clyman, Ronald I., Cortezzo, Donna, Maria E., Cotten, C.M., Courtney, Sherry E., Davis, Jonathan M., de Alba Campomanes, Alejandra G., Dean, Benjamin, Dees, Ellen, De, Mauro, Sara B., Denne, Scott C., Deschmann, Emöke, Di Blasi, Carolina Cecilia, Di, Vall, Sara A., Doherty, Dan, Durand, David J., Dyess, Nicolle Fernández, Eichenwald, Eric C., Eitel, Kelsey B., Engen, Rachel M., Evans, Kelly N., Farmer, Diana L., Fay, Emily, Fechner, Patricia Y., Fleishman, Rachel, Fleiss, Bobbi, Flynn, Joseph, Jr., Flynn-O’Brien, Katherine T., Kyle Fulton, G., Gallagher, Renata C., Gauda, Estelle B., Christopher Golden, W., Gontasz, Michelle M., Estévez, Natasha González, Gospe, Sidney M., Jr., Gressens, Pierre, Gupta, Deepti, Hingorani, Sangeeta, Hinson, Ashley P., Hintz, Susan R., Alan Hodson, W., Hoppe, Kara K., Huang, Alyssa, Huang, Benjamin, Huen, Kathy, Huff, Katie A., Ionita, Cristian, Craig Jackson, J., Jackson, Jordan E., Jaksic, Tom, Javid, Patrick J., Johnson, Julia, Josephson, Cassandra D., Jungheim, Emily S., Juul, Sandra E., Kabbany, Mohammad Nasser, Karpen, Heidi, Keefe, Gregory, Keene, Jennifer C., Keiser, Amaris M., Keller, Roberta L., Kelly, Thomas F., Khorsand, Kate, Kim, Grace, Kinsella, John P., Komorowski, Allison S., Koves, Ildiko H., Lagatta, Joanne M., Lakshminrusimha, Satyan, Lam, Christina, Lantos, John D., Law, Janessa B., Lee, Su Yeon, Levy, Ofer, Lewis, David B., Lin, Philana Ling, Lorch, Scott A., Lucas, Tiffany L., Maheshwari, Akhil, Maltepe, Emin, Mandell, Erica, Manimtim, Winston M., Martin, Richard J., Mayock, Dennis E., Mc, Aleer, Irene, McQuillen, Patrick, Melvin, Ann J., Merguerian, Paul A., Merjaneh, Lina, Lawrence Merritt, J., Mezger, Valerie, Michaels, Marian G., Mietzsch, Ulrike, Miller, Steven P., Moore, Thomas R., Murray, Karen F., Nandi-Munshi, Debika, Natarajan, Niranjana, Ness, Kathryn D., Neu, Josef, Noori, Shahab, O’Shea, Thomas Michael, Jr., Oatts, Julius T., Paneth, Nigel, Parker, Thomas A., Patel, Ravi Mangal, Patel, Simran, Penn, Anna A., Pettker, Christian M., Peyvandi, Shabnam, Pihoker, Catherine, Plosa, Erin, Poindexter, Brenda, Posencheg, Michael A., Puia-Dumitrescu, Mihai, Cardona, Vilmaris Quiñones, Rice-Townsend, Samuel E., Riddle, Art, Robbins, Elizabeth, Rollins, Mark D., Rosen, Mark A., Rowe, Courtney K., Sahai, Inderneel, Saitta, Sulagna C., Salehi, Parisa, Sanchez, Pablo J., Sawyer, Taylor, Saxonhouse, Matthew A., Schroeder, Katherine M., Selewski, David T., Niroshi Senaratne, T., Seri, Istvan, Sharpe, Emily E., Sheppard, Sarah E., Shnorhavorian, Margarett, Sidbury, Robert, Simmons, La, Vone, Simmons, Rebecca A., Singh, Rachana, Sola-Visner, Martha C., Srinivasan, Lakshmi, Steflik, Heidi J., Steinhorn, Robin H., Stokes, Caleb, Stolp, Helen, Sucre, Jennifer, Sun, Angela, Taha, Dalal K., Tenney, Jessica, Thomas, Janet A., Tiller, George E., Torres, Benjamin A., Truog, William E., Upadhyay, Kirtikumar, Valentine, Gregory C., van den Anker, John N., Vohr, Betty, Wallen, Linda D., Wang, Peter (Zhan Tao), Warady, Bradley A., Ward, Robert M., Watchko, Jon F., Wehbi, Elias, Weitkamp, Joern-Hendrik, Werny, David, White, Klane K., Taylor Wild, K., Wiley, Susan, Willig, Laurel, Woodward, George A., Wright, Clyde J., Yonekawa, Karyn, Yu, Elizabeth, and Zackai, Elaine H.

Published
2024
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41. Elucidating the clinical spectrum and molecular basis of HYAL2 deficiency

Author

Fasham, James, primary, Lin, Siying, additional, Ghosh, Promita, additional, Radio, Francesca Clementina, additional, Farrow, Emily G., additional, Thiffault, Isabelle, additional, Kussman, Jennifer, additional, Zhou, Dihong, additional, Hemming, Rick, additional, Zahka, Kenneth, additional, Chioza, Barry A., additional, Rawlins, Lettie E., additional, Wenger, Olivia K., additional, Gunning, Adam C., additional, Pizzi, Simone, additional, Onesimo, Roberta, additional, Zampino, Giuseppe, additional, Barker, Emily, additional, Osawa, Natasha, additional, Rodriguez, Megan Christine, additional, Neuhann, Teresa M., additional, Zackai, Elaine H., additional, Keena, Beth, additional, Capasso, Jenina, additional, Levin, Alex V., additional, Bhoj, Elizabeth, additional, Li, Dong, additional, Hakonarson, Hakon, additional, Wentzensen, Ingrid M., additional, Jackson, Adam, additional, Chandler, Kate E., additional, Coban-Akdemir, Zeynep H., additional, Posey, Jennifer E., additional, Banka, Siddharth, additional, Lupski, James R., additional, Sheppard, Sarah E., additional, Tartaglia, Marco, additional, Triggs-Raine, Barbara, additional, Crosby, Andrew H., additional, and Baple, Emma L., additional

Published
2021
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42. Correction to: Rare variants in KDR, encoding VEGF Receptor 2, are associated with tetralogy of Fallot

Author

Škorić-Milosavljević, Doris, primary, Lahrouchi, Najim, additional, Bosada, Fernanda M., additional, Dombrowsky, Gregor, additional, Williams, Simon G., additional, Lesurf, Robert, additional, Tjong, Fleur V.Y., additional, Walsh, Roddy, additional, El Bouchikhi, Ihssane, additional, Breckpot, Jeroen, additional, Audain, Enrique, additional, Ilgun, Aho, additional, Beekman, Leander, additional, Ratbi, Ilham, additional, Strong, Alanna, additional, Muenke, Maximilian, additional, Heide, Solveig, additional, Muir, Alison M., additional, Hababa, Mariam, additional, Cross, Laura, additional, Zhou, Dihong, additional, Pastinen, Tomi, additional, Hitz, Marc-Phillip, additional, Abdul-Khaliq, Hashim, additional, Berger, Felix, additional, Dähnert, Ingo, additional, Dittrich, Sven, additional, Uebing, Anselm, additional, Stiller, Brigitte, additional, Zackai, Elaine, additional, Atmani, Samir, additional, Ouldim, Karim, additional, Adadi, Najlae, additional, Steindl, Katharina, additional, Rauch, Anita, additional, Brook, David, additional, Wilsdon, Anna, additional, Kuipers, Irene, additional, Blom, Nico A., additional, Mulder, Barbara J., additional, Mefford, Heather C., additional, Keren, Boris, additional, Joset, Pascal, additional, Kruszka, Paul, additional, Thiffault, Isabelle, additional, Sheppard, Sarah E., additional, Roberts, Amy, additional, Lodder, Elisabeth M., additional, Keavney, Bernard D., additional, Clur, Sally-Ann B., additional, Mital, Seema, additional, Hitz, Marc-Philip, additional, Christoffels, Vincent M., additional, Postma, Alex V., additional, and Bezzina, Connie R., additional

Published
2021
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47. Heterozygous Recurrent HNF4A variant p.Arg85Trp Causes Fanconi Renotubular Syndrome 4 with Maturity Onset Diabetes of the Young, an Autosomal Dominant Phenocopy of Fanconi Bickel Syndrome with Colobomas

Author

Sheppard, Sarah E., Barrett, Brett, Muraresku, Colleen, McKnight, Heather, De Leon, Diva D., Lord, Katherine, and Ganetzky, Rebecca

Subjects
Article
Abstract

Heterozygous pathogenic variants in HNF4A cause hyperinsulinism, maturity onset diabetes of the young type 1, and more rarely Fanconi renotubular syndrome. Specifically, the recurrent point pathogenic variant c.253C >T (p.Arg85Trp) has been associated with a syndromic form of hyperinsulinism with additional features of macrosomia, renal tubular nephropathy, hypophosphatemic rickets, and liver involvement. We present an affected mother, who had been previously diagnosed clinically with Fanconi Bickel Syndrome, and her affected son. The son’s presentation expands the clinical phenotype to include multiple congenital anomalies, including penile chordee with hypospadias and coloboma. This specific pathogenic variant should be considered in the differential diagnosis of Fanconi Bickel Syndrome when genetics are negative or the family history is suggestive of autosomal dominant inheritance. The inclusion of HI and MODY changes the management of this syndrome and the recurrence risk is distinct. Additionally, this family also emphasizes the importance of genetic confirmation of clinical diagnoses, especially in adults who grew up in the pre-molecular era that are now coming to childbearing age. Finally, the expansion of the phenotype to include multiple congenital anomalies suggests that the full spectrum of HNF4A is likely unknown.

Published
2020

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