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136 results on '"Towne, Meghan C"'

1. Biallelic variants in GTF3C5, a regulator of RNA polymerase III-mediated transcription, cause a multisystem developmental disorder

Author

Iwata-Otsubo, Aiko, Skraban, Cara M., Yoshimura, Atsunori, Sakata, Toyonori, Alves, Cesar Augusto P., Fiordaliso, Sarah K., Kuroda, Yukiko, Vengoechea, Jaime, Grochowsky, Angela, Ernste, Paige, Lulis, Lauren, Nesbitt, Addie, Tayoun, Ahmad Abou, Gray, Christopher, Towne, Meghan C., Radtke, Kelly, Normand, Elizabeth A., Rhodes, Lindsay, Seiler, Christoph, Shirahige, Katsuhiko, and Izumi, Kosuke

Published
2024
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2. Novel variants in KAT6B spectrum of disorders expand our knowledge of clinical manifestations and molecular mechanisms

Author

Yabumoto, Megan, Kianmahd, Jessica, Singh, Meghna, Palafox, Maria F, Wei, Angela, Elliott, Kathryn, Goodloe, Dana H, Dean, S Joy, Gooch, Catherine, Murray, Brianna K, Swartz, Erin, Vergano, Samantha A Schrier, Towne, Meghan C, Nugent, Kimberly, Roeder, Elizabeth R, Kresge, Christina, Pletcher, Beth A, Grand, Katheryn, Graham, John M, Gates, Ryan, Gomez‐Ospina, Natalia, Ramanathan, Subhadra, Clark, Robin Dawn, Glaser, Kimberly, Benke, Paul J, Cohen, Julie S, Fatemi, Ali, Mu, Weiyi, Baranano, Kristin W, Madden, Jill A, Gubbels, Cynthia S, Yu, Timothy W, Agrawal, Pankaj B, Chambers, Mary‐Kathryn, Phornphutkul, Chanika, Pugh, John A, Tauber, Kate A, Azova, Svetlana, Smith, Jessica R, O’Donnell‐Luria, Anne, Medsker, Hannah, Srivastava, Siddharth, Krakow, Deborah, Schweitzer, Daniela N, and Arboleda, Valerie A

Subjects
Biological Sciences, Genetics, Brain Disorders, Congenital Structural Anomalies, Clinical Research, Pediatric, Intellectual and Developmental Disabilities (IDD), Rare Diseases, Genetic Testing, Aetiology, 2.1 Biological and endogenous factors, Congenital, Abnormalities, Multiple, Alleles, Blepharophimosis, Cohort Studies, Congenital Hypothyroidism, Craniofacial Abnormalities, Facies, Genetic Association Studies, Genetic Counseling, Genetic Loci, Genetic Predisposition to Disease, Genotype, Heart Defects, Congenital, Histone Acetyltransferases, Humans, Intellectual Disability, Joint Instability, Kidney, Male, Mutation, Patella, Phenotype, Psychomotor Disorders, Scrotum, Urogenital Abnormalities, CRISPR, Genitopatellar syndrome, KAT6B-related disorders, phenotypic spectrum, Say-Barber-Biesecker-Young-Simpson syndrome, variable expressivity, rare genetic diagnosis, variable expressivity, rare genetic diagnosis, Medicinal and Biomolecular Chemistry, Clinical Sciences, Medicinal and biomolecular chemistry
Abstract

The phenotypic variability associated with pathogenic variants in Lysine Acetyltransferase 6B (KAT6B, a.k.a. MORF, MYST4) results in several interrelated syndromes including Say-Barber-Biesecker-Young-Simpson Syndrome and Genitopatellar Syndrome. Here we present 20 new cases representing 10 novel KAT6B variants. These patients exhibit a range of clinical phenotypes including intellectual disability, mobility and language difficulties, craniofacial dysmorphology, and skeletal anomalies. Given the range of features previously described for KAT6B-related syndromes, we have identified additional phenotypes including concern for keratoconus, sensitivity to light or noise, recurring infections, and fractures in greater numbers than previously reported. We surveyed clinicians to qualitatively assess the ways families engage with genetic counselors upon diagnosis. We found that 56% (10/18) of individuals receive diagnoses before the age of 2 years (median age = 1.96 years), making it challenging to address future complications with limited accessible information and vast phenotypic severity. We used CRISPR to introduce truncating variants into the KAT6B gene in model cell lines and performed chromatin accessibility and transcriptome sequencing to identify key dysregulated pathways. This study expands the clinical spectrum and addresses the challenges to management and genetic counseling for patients with KAT6B-related disorders.

Published
2021

3. The landscape of reported VUS in multi-gene panel and genomic testing: Time for a change

Author

Marshall, Christian, Meng, Linyan, Jobanputra, Vaidehi, Taft, Ryan, Ashley, Euan, Nakouzi, Ghunwa, Shen, Wei, Kingsmore, Stephen, Rehm, Heidi, Rehm, Heidi L., Alaimo, Joseph T., Aradhya, Swaroop, Bayrak-Toydemir, Pinar, Best, Hunter, Brandon, Rhonda, Buchan, Jillian G., Chao, Elizabeth C., Chen, Elaine, Clifford, Jacob, Cohen, Ana S.A., Conlin, Laura K., Das, Soma, Davis, Kyle W., del Gaudio, Daniela, Del Viso, Florencia, DiVincenzo, Christina, Eisenberg, Marcia, Guidugli, Lucia, Hammer, Monia B., Harrison, Steven M., Hatchell, Kathryn E., Dyer, Lindsay Havens, Hoang, Lily U., Holt, James M., Karbassi, Izabela D., Kearney, Hutton M., Kelly, Melissa A., Kelly, Jacob M., Kluge, Michelle L., Komala, Timothy, Kruszka, Paul, Lau, Lynette, Lebo, Matthew S., Marshall, Christian R., McKnight, Dianalee, McWalter, Kirsty, Meng, Yan, Nagan, Narasimhan, Neckelmann, Christian S., Neerman, Nir, Niu, Zhiyv, Paolillo, Vitoria K., Paolucci, Sarah A., Perry, Denise, Pesaran, Tina, Radtke, Kelly, Rasmussen, Kristen J., Retterer, Kyle, Saunders, Carol J., Spiteri, Elizabeth, Stanley, Christine, Szuto, Anna, Taft, Ryan J., Thiffault, Isabelle, Thomas, Brittany C., Thomas-Wilson, Amanda, Thorpe, Erin, Tidwell, Timothy J., Towne, Meghan C., and Zouk, Hana

Published
2023
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4. The Epithelial Sodium Channel Is a Modifier of the Long-Term Nonprogressive Phenotype Associated with F508del CFTR Mutations

Author

Agrawal, Pankaj B, Wang, Ruobing, Li, Hongmei Lisa, Schmitz-Abe, Klaus, Simone-Roach, Chantelle, Chen, Jingxin, Shi, Jiahai, Louie, Tin, Sheng, Shaohu, Towne, Meghan C, Brainson, Christine F, Matthay, Michael A, Kim, Carla F, Bamshad, Michael, Emond, Mary J, Gerard, Norma P, Kleyman, Thomas R, and Gerard, Craig

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Human Genome, Orphan Drug, Cystic Fibrosis, Rare Diseases, Pediatric, Lung, 2.1 Biological and endogenous factors, Aetiology, Congenital, Amino Acid Sequence, Animals, Cystic Fibrosis Transmembrane Conductance Regulator, Epithelial Sodium Channels, Female, Humans, Male, Sequence Deletion, Xenopus, Xenopus laevis, cystic fibrosis, ENaC, epithelial sodium channel, genetic modifier, SCNN1D, Cardiorespiratory Medicine and Haematology, Respiratory System, Biochemistry and cell biology, Cardiovascular medicine and haematology
Abstract

Cystic fibrosis (CF) remains the most lethal genetic disease in the Caucasian population. However, there is great variability in clinical phenotypes and survival times, even among patients harboring the same genotype. We identified five patients with CF and a homozygous F508del mutation in the CFTR gene who were in their fifth or sixth decade of life and had shown minimal changes in lung function over a longitudinal period of more than 20 years. Because of the rarity of this long-term nonprogressive phenotype, we hypothesized these individuals may carry rare genetic variants in modifier genes that ameliorate disease severity. Individuals at the extremes of survival time and lung-function trajectory underwent whole-exome sequencing, and the sequencing data were filtered to include rare missense, stopgain, indel, and splicing variants present with a mean allele frequency of

Published
2017

5. De Novo Mutations in Protein Kinase Genes CAMK2A and CAMK2B Cause Intellectual Disability

Author

Küry, Sébastien, van Woerden, Geeske M, Besnard, Thomas, Onori, Martina Proietti, Latypova, Xénia, Towne, Meghan C, Cho, Megan T, Prescott, Trine E, Ploeg, Melissa A, Sanders, Stephan, Stessman, Holly AF, Pujol, Aurora, Distel, Ben, Robak, Laurie A, Bernstein, Jonathan A, Denommé-Pichon, Anne-Sophie, Lesca, Gaëtan, Sellars, Elizabeth A, Berg, Jonathan, Carré, Wilfrid, Busk, Øyvind Løvold, van Bon, Bregje WM, Waugh, Jeff L, Deardorff, Matthew, Hoganson, George E, Bosanko, Katherine B, Johnson, Diana S, Dabir, Tabib, Holla, Øystein Lunde, Sarkar, Ajoy, Tveten, Kristian, de Bellescize, Julitta, Braathen, Geir J, Terhal, Paulien A, Grange, Dorothy K, van Haeringen, Arie, Lam, Christina, Mirzaa, Ghayda, Burton, Jennifer, Bhoj, Elizabeth J, Douglas, Jessica, Santani, Avni B, Nesbitt, Addie I, Helbig, Katherine L, Andrews, Marisa V, Begtrup, Amber, Tang, Sha, van Gassen, Koen LI, Juusola, Jane, Foss, Kimberly, Enns, Gregory M, Moog, Ute, Hinderhofer, Katrin, Paramasivam, Nagarajan, Lincoln, Sharyn, Kusako, Brandon H, Lindenbaum, Pierre, Charpentier, Eric, Nowak, Catherine B, Cherot, Elouan, Simonet, Thomas, Ruivenkamp, Claudia AL, Hahn, Sihoun, Brownstein, Catherine A, Xia, Fan, Schmitt, Sébastien, Deb, Wallid, Bonneau, Dominique, Nizon, Mathilde, Quinquis, Delphine, Chelly, Jamel, Rudolf, Gabrielle, Sanlaville, Damien, Parent, Philippe, Gilbert-Dussardier, Brigitte, Toutain, Annick, Sutton, Vernon R, Thies, Jenny, Peart-Vissers, Lisenka ELM, Boisseau, Pierre, Vincent, Marie, Grabrucker, Andreas M, Dubourg, Christèle, Network, Undiagnosed Diseases, Tan, Wen-Hann, Verbeek, Nienke E, Granzow, Martin, Santen, Gijs WE, Shendure, Jay, Isidor, Bertrand, Pasquier, Laurent, Redon, Richard, Yang, Yaping, State, Matthew W, Kleefstra, Tjitske, Cogné, Benjamin, HUGO, GEM, Study, Deciphering Developmental Disorders, Petrovski, Slavé, and Retterer, Kyle

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Biomedical and Clinical Sciences, Neurosciences, Brain Disorders, Genetics, Intellectual and Developmental Disabilities (IDD), Pediatric, Underpinning research, 1.1 Normal biological development and functioning, Aetiology, 2.1 Biological and endogenous factors, Neurological, Animals, Brain, Calcium-Calmodulin-Dependent Protein Kinase Type 2, Cell Line, Exome, Female, Glutamic Acid, HEK293 Cells, Humans, Intellectual Disability, Male, Mice, Mice, Inbred C57BL, Mutation, Neurons, Phosphorylation, Signal Transduction, Undiagnosed Diseases Network, GEM HUGO, Deciphering Developmental Disorders Study, AMPAR, CAMK2, CAMK2A, CAMK2B, NMDAR, de novo mutations, intellectual disability, synaptic plasticity, Medical and Health Sciences, Genetics & Heredity, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

Calcium/calmodulin-dependent protein kinase II (CAMK2) is one of the first proteins shown to be essential for normal learning and synaptic plasticity in mice, but its requirement for human brain development has not yet been established. Through a multi-center collaborative study based on a whole-exome sequencing approach, we identified 19 exceedingly rare de novo CAMK2A or CAMK2B variants in 24 unrelated individuals with intellectual disability. Variants were assessed for their effect on CAMK2 function and on neuronal migration. For both CAMK2A and CAMK2B, we identified mutations that decreased or increased CAMK2 auto-phosphorylation at Thr286/Thr287. We further found that all mutations affecting auto-phosphorylation also affected neuronal migration, highlighting the importance of tightly regulated CAMK2 auto-phosphorylation in neuronal function and neurodevelopment. Our data establish the importance of CAMK2A and CAMK2B and their auto-phosphorylation in human brain function and expand the phenotypic spectrum of the disorders caused by variants in key players of the glutamatergic signaling pathway.

Published
2017

7. RNA methyltransferase SPOUT1/CENP-32 links mitotic spindle organization with the neurodevelopmental disorder SpADMiSS

Author

Dharmadhikari, Avinash V, primary, Abad, Maria Alba, additional, Khan, Sheraz, additional, Maroofian, Reza, additional, Sands, Tristan T, additional, Ullah, Farid, additional, Samejima, Itaru, additional, Wear, Martin A, additional, Moore, Kiara E, additional, Kondakova, Elena, additional, Mitina, Natalia, additional, Schaub, Theres, additional, Lee, Grace K, additional, Umandap, Christine H, additional, Berger, Sara M, additional, Iglesias, Alejandro D, additional, Popp, Bernt, additional, Jamra, Rami Abou, additional, Gabriel, Heinz, additional, Rentas, Stefan, additional, Rippert, Alyssa L, additional, Izumi, Kosuke, additional, Conlin, Laura K, additional, Koboldt, Daniel C, additional, Mihalic Mosher, Theresa, additional, Hickey, Scott E, additional, Albert, Dara VF, additional, Norwood, Haley, additional, Lewanda, Amy Feldman, additional, Dai, Hongzheng, additional, Liu, Pengfei, additional, Mitani, Tadahiro, additional, Marafi, Dana, additional, Pehlivan, Davut, additional, Posey, Jennifer E, additional, Lippa, Natalie, additional, Vena, Natalie, additional, Heinzen, Erin L, additional, Goldstein, David B, additional, Mignot, Cyril, additional, Agathe, Jean-Madeleine de Sainte, additional, Al-Sannaa, Nouriya Abbas, additional, Zamani, Mina, additional, Sadeghian, Saeid, additional, Seifia, Tahere, additional, Zaki, Maha S, additional, Abdel-Salam, Ghada MH, additional, Abdel-Hamid, Mohamed, additional, Alabdi, Lama, additional, Alkuraya, Fowzan Sami, additional, Dawoud, Heba, additional, Lofty, Aya, additional, Bauer, Peter, additional, Zifarelli, Giovanni, additional, Afzal, Erum, additional, Zafar, Faisal, additional, Efthymiou, Stephanie, additional, Gossett, Daniel, additional, Towne, Meghan C, additional, Yeneabat, Raey, additional, Wontakal, Sandeep N, additional, Aggarwal, Vimla S, additional, Rosenfeld, Jill A, additional, Tarabykin, Victor, additional, Ohta, Shinya, additional, Lupski, James R, additional, Houlden, Henry, additional, Earnshaw, William C, additional, Davis, Erica E, additional, Jeyaprakash, A Arockia, additional, and Liao, Jun, additional

Published
2024
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8. Beta-Ketothiolase Deficiency Presenting with Metabolic Stroke After a Normal Newborn Screen in Two Individuals

Author

Wojcik, Monica H., Wierenga, Klaas J., Rodan, Lance H., Sahai, Inderneel, Ferdinandusse, Sacha, Genetti, Casie A., Towne, Meghan C., Peake, Roy W. A., James, Philip M., Beggs, Alan H., Brownstein, Catherine A., Berry, Gerard T., Agrawal, Pankaj B., Morava, Eva, editor, Baumgartner, Matthias, editor, Patterson, Marc, editor, Rahman, Shamima, editor, Zschocke, Johannes, editor, and Peters, Verena, editor

Published
2018
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10. How parents of children with ataxia‐telangiectasia use dynamic coping to navigate cyclical uncertainty.

Author

Schiller, Julia, Towne, Meghan C., Epstein, Rachel, Thornton, Jennifer Karlin, and Suslovitch, Victoria

Abstract

Ataxia‐telangiectasia (A‐T) is a rare, childhood‐onset, multi‐systemic, progressive condition. Parents of children with rare diseases like A‐T are emotionally, socially, and psychologically impacted by the diagnosis. To examine the parental perspective of having a child with A‐T, and to better understand how parents cope with an A‐T diagnosis, we conducted 10 semistructured interviews. Thematic analysis using a phenomenological approach resulted in five themes: (1) Parental responsibilities change as the result of an A‐T diagnosis, (2) An A‐T diagnosis brings about shifts in identity for all family members, (3) Parental coping changes over time, (4) A‐T parents experience continuous uncertainty and a lack of stability, and (5) A‐T parents receive support from various people, places, and resources. Many parents fostered resilience by adopting a present‐centered and positive mindset about the impacts of the diagnosis. Parents also became A‐T experts and used their knowledge to advocate for their children and help mentor other parents. Responses from parents indicated a need for providers to incorporate parental mental well‐being check‐ins to pediatric rare disease appointments and welcome parents as respected members of their children's care team. Genetic counselors are in a unique position to help coordinate complex care for children with A‐T (and other rare diseases) and provide support to family members using the framework of family‐centered care. This paper offers suggestions for expanding support and learning to cope with a difficult diagnosis for parents of children with rare diseases, specifically A‐T, based on stories from parents of children with A‐T. [ABSTRACT FROM AUTHOR]

Published
2024
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11. Spliceosome malfunction causes neurodevelopmental disorders with overlapping features

Author

Li, Dong, primary, Wang, Qin, additional, Bayat, Allan, additional, Battig, Mark R., additional, Zhou, Yijing, additional, Bosch, Daniëlle G.M., additional, van Haaften, Gijs, additional, Granger, Leslie, additional, Petersen, Andrea K., additional, Pérez-Jurado, Luis A., additional, Aznar-Laín, Gemma, additional, Aneja, Anushree, additional, Hancarova, Miroslava, additional, Bendova, Sarka, additional, Schwarz, Martin, additional, Kremlíková Pourová, Radka, additional, Sedlacek, Zdenek, additional, Keena, Beth A., additional, March, Michael E., additional, Hou, Cuiping, additional, O'Connor, Nora, additional, Bhoj, Elizabeth J., additional, Harr, Margaret H., additional, Lemire, Gabrielle, additional, Boycott, Kym M., additional, Towne, Meghan C., additional, Li, Megan, additional, Tarnopolsky, Mark, additional, Brady, Lauren, additional, Parker, Michael J., additional, Faghfoury, Hanna, additional, Parsley, Lea Kristin, additional, Agolini, Emanuele, additional, Dentici, Maria Lisa, additional, Novelli, Antonio, additional, Wright, Meredith S., additional, Palmquist, Rachel, additional, Lai, Khanh, additional, Scala, Marcello, additional, Striano, Pasquale, additional, Iacomino, Michele, additional, Zara, Federico, additional, Cooper, Annina, additional, Maarup, Timothy J., additional, Byler, Melissa, additional, Lebel, Robert Roger, additional, Balci, Tugce B., additional, Louie, Raymond J., additional, Lyons, Michael J., additional, Douglas, Jessica, additional, Nowak, Catherine B., additional, Afenjar, Alexandra, additional, Hoyer, Juliane, additional, Keren, Boris, additional, Maas, Saskia M., additional, Motazacker, Mahdi M., additional, Martinez-Agosto, Julian A., additional, Rabani, Ahna M., additional, McCormick, Elizabeth M., additional, Falk, Marni, additional, Ruggiero, Sarah M., additional, Helbig, Ingo, additional, Møller, Rikke S., additional, Tessarollo, Lino, additional, Tomassoni-Ardori, Francesco, additional, Palko, Mary Ellen, additional, Hsieh, Tzung-Chien, additional, Krawitz, Peter M., additional, Ganapathi, Mythily, additional, Gelb, Bruce D., additional, Jobanputra, Vaidehi, additional, Wilson, Ashley, additional, Greally, John, additional, Jacquemont, Sébastien, additional, Jizi, Khadijé, additional, Ange-Line, Bruel, additional, Quelin, Chloé, additional, Misra, Vinod K., additional, Chick, Erika, additional, Romano, Corrado, additional, Greco, Donatella, additional, Arena, Alessia, additional, Morleo, Manuela, additional, Nigro, Vincenzo, additional, Seyama, Rie, additional, Uchiyama, Yuri, additional, Matsumoto, Naomichi, additional, Taira, Ryoji, additional, Tashiro, Katsuya, additional, Sakai, Yasunari, additional, Yigit, Gökhan, additional, Wollnik, Bernd, additional, Wagner, Michael, additional, Kutsche, Barbara, additional, Hurst, Anna C.E., additional, Thompson, Michelle L., additional, Schmidt, Ryan J., additional, Randolph, Linda M., additional, Spillmann, Rebecca C., additional, Shashi, Vandana, additional, Higginbotham, Edward J., additional, Cordeiro, Dawn, additional, Carnevale, Amanda, additional, Costain, Gregory, additional, Khan, Tayyaba, additional, Funalot, Benoît, additional, Tran Mau-Them, Frederic, additional, Fernandez Garcia Moya, Luis, additional, García-Miñaúr, Sixto, additional, Osmond, Matthew, additional, Chad, Lauren, additional, Quercia, Nada, additional, Carrasco, Diana, additional, Li, Chumei, additional, Sanchez-Valle, Amarilis, additional, Kelley, Meghan, additional, Nizon, Mathilde, additional, Jensson, Brynjar O., additional, Sulem, Patrick, additional, Stefansson, Kari, additional, Gorokhova, Svetlana, additional, Busa, Tiffany, additional, Rio, Marlène, additional, Hadj Abdallah, Hamza, additional, Lesieur-Sebellin, Marion, additional, Amiel, Jeanne, additional, Pingault, Véronique, additional, Mercier, Sandra, additional, Vincent, Marie, additional, Philippe, Christophe, additional, Fatus-Fauconnier, Clemence, additional, Friend, Kathryn, additional, Halligan, Rebecca K., additional, Biswas, Sunita, additional, Rosser, Jane M.R., additional, Shoubridge, Cheryl, additional, Corbett, Mark A., additional, Barnett, Christopher, additional, Gecz, Jozef, additional, Leppig, Kathleen A., additional, Slavotinek, Anne, additional, Marcelis, Carlo, additional, Pfundt, Rolph, additional, de Vries, Bert B.A., additional, van Slegtenhorst, Marjon A., additional, Brooks, Alice S., additional, Cogne, Benjamin, additional, Rambaud, Thomas, additional, Tümer, Zeynep, additional, Zackai, Elaine H., additional, Akizu, Naiara, additional, Song, Yuanquan, additional, and Hakonarson, Hakon, additional

Published
2023
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14. Inherited bone marrow failure with macrothrombocytopenia due to germline tubulin beta class I (TUBB) variant

Author

Shah, Yash B., primary, Lin, Ping, additional, Chen, Stone, additional, Zheng, Alan, additional, Alcaraz, Wendy, additional, Towne, Meghan C., additional, Gabriel, Courtney, additional, Bhoj, Elizabeth J., additional, Lambert, Michele P., additional, Olson, Timothy S., additional, Frank, Dale M., additional, Ellis, Colin A., additional, and Babushok, Daria V., additional

Published
2022
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15. The landscape of reported VUS in multi-gene panel and genomic testing: Time for a change

Author

Rehm, Heidi L, primary, Alaimo, Joseph T, additional, Aradhya, Swaroop, additional, Bayrak-Toydemir, Pinar, additional, Best, Hunter, additional, Brandon, Rhonda, additional, Buchan, Jillian G, additional, Chao, Elizabeth C, additional, Chen, Elaine, additional, Clifford, Jacob, additional, Cohen, Ana S, additional, Conlin, Laura K, additional, Das, Soma, additional, Davis, Kyle W, additional, Gaudio, Daniela del, additional, Viso, Florencia Del, additional, DiVincenzo, Christina, additional, Eisenberg, Marcia, additional, Guidugli, Lucia, additional, Hammer, Monia B, additional, Harrison, Steven M, additional, Hatchell, Kathryn E, additional, Dyer, Lindsay Havens, additional, Hoang, Lily U, additional, Holt, James M, additional, Jobanputra, Vaidehi, additional, Karbassi, Izabela D, additional, Kearney, Hutton M, additional, Kelly, Melissa A, additional, Kelly, Jacob M, additional, Kluge, Michelle L, additional, Komala, Timothy, additional, Kruszka, Paul, additional, Lau, Lynette, additional, Lebo, Matthew S, additional, Marshall, Christian R, additional, McKnight, Dianalee, additional, McWalter, Kirsty, additional, Meng, Yan, additional, Nagan, Narasimhan, additional, Neckelmann, Christian S, additional, Neerman, Nir, additional, Niu, Zhiyv, additional, Paolillo, Vitoria K, additional, Paolucci, Sarah A, additional, Perry, Denise, additional, Pesaran, Tina, additional, Radtke, Kelly, additional, Rasmussen, Kristen J, additional, Retterer, Kyle, additional, Saunders, Carol J, additional, Spiteri, Elizabeth, additional, Stanley, Christine M, additional, Szuto, Anna, additional, Taft, Ryan J, additional, Thiffault, Isabelle, additional, Thomas, Brittany C, additional, Thomas-Wilson, Amanda, additional, Thorpe, Erin, additional, Tidwell, Timothy J, additional, Towne, Meghan C, additional, and Zouk, Hana, additional

Published
2022
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17. Beta-Ketothiolase Deficiency Presenting with Metabolic Stroke After a Normal Newborn Screen in Two Individuals

Author

Wojcik, Monica H., primary, Wierenga, Klaas J., additional, Rodan, Lance H., additional, Sahai, Inderneel, additional, Ferdinandusse, Sacha, additional, Genetti, Casie A., additional, Towne, Meghan C., additional, Peake, Roy W. A., additional, James, Philip M., additional, Beggs, Alan H., additional, Brownstein, Catherine A., additional, Berry, Gerard T., additional, and Agrawal, Pankaj B., additional

Published
2017
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21. Overlapping 16p13.11 deletion and gain of copies variations associated with childhood onset psychosis include genes with mechanistic implications for autism associated pathways: Two case reports

Author

Brownstein, Catherine A., Kleiman, Robin J., Engle, Elizabeth C., Towne, Meghan C., DʼAngelo, Eugene J., Yu, Timothy W., Beggs, Alan H., Picker, Jonathan, Fogler, Jason M., Carroll, Devon, Schmitt, Rachel C. O., Wolff, Robert R., Shen, Yiping, Lip, Va, Bilguvar, Kaya, Kim, April, Tembulkar, Sahil, OʼDonnell, Kyle, and Gonzalez-Heydrich, Joseph

Published
2016
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22. Inherited bone marrow failure with macrothrombocytopenia due to germline tubulin beta class I (TUBB) variant.

Author

Shah, Yash B., Lin, Ping, Chen, Stone, Zheng, Alan, Alcaraz, Wendy, Towne, Meghan C., Gabriel, Courtney, Bhoj, Elizabeth J., Lambert, Michele P., Olson, Timothy S., Frank, Dale M., Ellis, Colin A., and Babushok, Daria V.

Subjects
BONE marrow, TUBULINS, THROMBOCYTOPENIA, GERM cells, RIBAVIRIN, HEPATITIS C, PANCYTOPENIA
Abstract

Summary: Germline mutations in tubulin beta class I (TUBB), which encodes one of the β‐tubulin isoforms, were previously associated with neurological and cutaneous abnormalities. Here, we describe the first case of inherited bone marrow (BM) failure, including marked thrombocytopenia, morphological abnormalities, and cortical dysplasia, associated with a de novo p.D249V variant in TUBB. Mutant TUBB had abnormal cellular localisation in transfected cells. Following interferon/ribavirin therapy administered for transfusion‐acquired hepatitis C, severe pancytopenia and BM aplasia ensued, which was unresponsive to immunosuppression. Acquired chromosome arm 6p loss of heterozygosity was identified, leading to somatic loss of the mutant TUBB allele. [ABSTRACT FROM AUTHOR]

Published
2023
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25. SPEN haploinsufficiency causes a neurodevelopmental disorder overlapping proximal 1p36 deletion syndrome with an episignature of X chromosomes in females

Author

Radio, Francesca Clementina, Pang, Kaifang, Ciolfi, Andrea, Levy, Michael A., Hernández-García, Andrés, Pedace, Lucia, Pantaleoni, Francesca, Liu, Zhandong, de Boer, Elke, Jackson, Adam, Bruselles, Alessandro, McConkey, Haley, Stellacci, Emilia, Lo Cicero, Stefania, Motta, Marialetizia, Carrozzo, Rosalba, Dentici, Maria Lisa, McWalter, Kirsty, Desai, Megha, Monaghan, Kristin G., Telegrafi, Aida, Philippe, Christophe, Vitobello, Antonio, Au, Margaret, Grand, Katheryn, Sanchez-Lara, Pedro A., Baez, Joanne, Lindstrom, Kristin, Kulch, Peggy, Sebastian, Jessica, Madan-Khetarpal, Suneeta, Roadhouse, Chelsea, MacKenzie, Jennifer J., Monteleone, Berrin, Saunders, Carol J., Jean Cuevas, July K., Cross, Laura, Zhou, Dihong, Hartley, Taila, Sawyer, Sarah L., Monteiro, Fabíola Paoli, Secches, Tania Vertemati, Kok, Fernando, Schultz-Rogers, Laura E., Macke, Erica L., Morava, Eva, Klee, Eric W., Kemppainen, Jennifer, Iascone, Maria, Selicorni, Angelo, Tenconi, Romano, Amor, David J., Pais, Lynn, Gallacher, Lyndon, Turnpenny, Peter D., Stals, Karen, Ellard, Sian, Cabet, Sara, Lesca, Gaetan, Pascal, Joset, Steindl, Katharina, Ravid, Sarit, Weiss, Karin, Castle, Alison M.R., Carter, Melissa T., Kalsner, Louisa, de Vries, Bert B.A., van Bon, Bregje W., Wevers, Marijke R., Pfundt, Rolph, Stegmann, Alexander P.A., Kerr, Bronwyn, Kingston, Helen M., Chandler, Kate E., Sheehan, Willow, Elias, Abdallah F., Shinde, Deepali N., Towne, Meghan C., Robin, Nathaniel H., Goodloe, Dana, Vanderver, Adeline, Sherbini, Omar, Bluske, Krista, Hagelstrom, R. Tanner, Zanus, Caterina, Faletra, Flavio, Musante, Luciana, Kurtz-Nelson, Evangeline C., Earl, Rachel K., Anderlid, Britt Marie, Morin, Gilles, van Slegtenhorst, Marjon, Diderich, Karin E.M., Brooks, Alice S., Gribnau, Joost, Boers, Ruben G., Finestra, Teresa Robert, Carter, Lauren B., Rauch, Anita, Gasparini, Paolo, Boycott, Kym M., Barakat, Tahsin Stefan, Graham, John M., Faivre, Laurence, Banka, Siddharth, Wang, Tianyun, Eichler, Evan E., Priolo, Manuela, Dallapiccola, Bruno, Vissers, Lisenka E.L.M., Sadikovic, Bekim, Scott, Daryl A., Holder, Jimmy Lloyd, Tartaglia, Marco, Radio, Francesca Clementina, Pang, Kaifang, Ciolfi, Andrea, Levy, Michael A., Hernández-García, Andrés, Pedace, Lucia, Pantaleoni, Francesca, Liu, Zhandong, de Boer, Elke, Jackson, Adam, Bruselles, Alessandro, McConkey, Haley, Stellacci, Emilia, Lo Cicero, Stefania, Motta, Marialetizia, Carrozzo, Rosalba, Dentici, Maria Lisa, McWalter, Kirsty, Desai, Megha, Monaghan, Kristin G., Telegrafi, Aida, Philippe, Christophe, Vitobello, Antonio, Au, Margaret, Grand, Katheryn, Sanchez-Lara, Pedro A., Baez, Joanne, Lindstrom, Kristin, Kulch, Peggy, Sebastian, Jessica, Madan-Khetarpal, Suneeta, Roadhouse, Chelsea, MacKenzie, Jennifer J., Monteleone, Berrin, Saunders, Carol J., Jean Cuevas, July K., Cross, Laura, Zhou, Dihong, Hartley, Taila, Sawyer, Sarah L., Monteiro, Fabíola Paoli, Secches, Tania Vertemati, Kok, Fernando, Schultz-Rogers, Laura E., Macke, Erica L., Morava, Eva, Klee, Eric W., Kemppainen, Jennifer, Iascone, Maria, Selicorni, Angelo, Tenconi, Romano, Amor, David J., Pais, Lynn, Gallacher, Lyndon, Turnpenny, Peter D., Stals, Karen, Ellard, Sian, Cabet, Sara, Lesca, Gaetan, Pascal, Joset, Steindl, Katharina, Ravid, Sarit, Weiss, Karin, Castle, Alison M.R., Carter, Melissa T., Kalsner, Louisa, de Vries, Bert B.A., van Bon, Bregje W., Wevers, Marijke R., Pfundt, Rolph, Stegmann, Alexander P.A., Kerr, Bronwyn, Kingston, Helen M., Chandler, Kate E., Sheehan, Willow, Elias, Abdallah F., Shinde, Deepali N., Towne, Meghan C., Robin, Nathaniel H., Goodloe, Dana, Vanderver, Adeline, Sherbini, Omar, Bluske, Krista, Hagelstrom, R. Tanner, Zanus, Caterina, Faletra, Flavio, Musante, Luciana, Kurtz-Nelson, Evangeline C., Earl, Rachel K., Anderlid, Britt Marie, Morin, Gilles, van Slegtenhorst, Marjon, Diderich, Karin E.M., Brooks, Alice S., Gribnau, Joost, Boers, Ruben G., Finestra, Teresa Robert, Carter, Lauren B., Rauch, Anita, Gasparini, Paolo, Boycott, Kym M., Barakat, Tahsin Stefan, Graham, John M., Faivre, Laurence, Banka, Siddharth, Wang, Tianyun, Eichler, Evan E., Priolo, Manuela, Dallapiccola, Bruno, Vissers, Lisenka E.L.M., Sadikovic, Bekim, Scott, Daryl A., Holder, Jimmy Lloyd, and Tartaglia, Marco

Abstract

Deletion 1p36 (del1p36) syndrome is the most common human disorder resulting from a terminal autosomal deletion. This condition is molecularly and clinically heterogeneous. Deletions involving two non-overlapping regions, known as the distal (telomeric) and proximal (centromeric) critical regions, are sufficient to cause the majority of the recurrent clinical features, although with different facial features and dysmorphisms. SPEN encodes a transcriptional repressor commonly deleted in proximal del1p36 syndrome and is located centromeric to the proximal 1p36 critical region. Here, we used clinical data from 34 individuals with truncating variants in SPEN to define a neurodevelopmental disorder presenting with features that overlap considerably with those of proximal del1p36 syndrome. The clinical profile of this disease includes developmental delay/intellectual disability, autism spectrum disorder, anxiety, aggressive behavior, attention deficit disorder, hypotonia, brain and spine anomalies, congenital heart defects, high/narrow palate, facial dysmorphisms, and obesity/increased BMI, especially in females. SPEN also emerges as a relevant gene for del1p36 syndrome by co-expression analyses. Finally, we show that haploinsufficiency of SPEN is associated with a distinctive DNA methylation episignature of the X chromosome in affected females, providing further evidence of a specific contribution of the protein to the epigenetic control of this chromosome, and a paradigm of an X chromosome-specific episignature that classifies syndromic traits. We conclude that SPEN is required for multiple developmental processes and SPEN haploinsufficiency is a major contributor to a disorder associated with deletions centromeric to the previously established 1p36 critical regions.

Published
2021

26. Misattributed parentage identified through diagnostic exome sequencing: Frequency of detection and reporting practices.

Author

Stefka, Julie, El‐Khechen, Dima, Cain, Taylor, Blanco, Kirsten, Feldmann, Benjamin, Towne, Meghan C., and Hagman, Kelly D. Farwell

Abstract

Access to genetic testing, namely, diagnostic exome sequencing (DES), has significantly improved, subsequently increasing the likelihood of discovering incidental findings, such as misattributed relationships and specifically misattributed parentage (MP). Until the recently published ACMG statement, there had been no consensus for laboratories and clinicians to follow when addressing such findings. Family‐based genomic testing is valuable for accurate variant interpretation but has the potential to uncover misattributed familial relationships. Here, we present the first published data on the frequency of MP identified through DES at a clinical laboratory. We also investigated clinicians' decisions on how to proceed with analysis, reporting, and disclosure. A database of 6,752 families who underwent parent‐proband ('trio') DES was retrospectively reviewed for molecular identification of MP and clinicians' MP disclosure decisions. Among 6,752 trios, 39 cases of MP were detected (0.58%). Non‐paternity was detected in all cases, and in one instance, non‐maternity was also identified. All clinicians decided to proceed by omitting the MP individual from the analysis. Clinicians chose to proceed with duo analysis (87.2%), modify information on the report (74.4%), and communicate MP results to the mother (71.8%), suggesting a trend toward not disclosing to the putative father or proband. The data show that trio DES involves a chance of detecting MP and that clinician disclosure practices do not appear to routinely include direct disclosure to the putative father. MP identified in our parent‐proband trios sent in for DES is lower than the reported frequency of MP in the general population due in part to ascertainment bias as families with known or suspected MP are presumably less likely to pursue trio testing. These data may inform laboratory policies and clinician practices for addressing incidental findings such as MP. [ABSTRACT FROM AUTHOR]

Published
2022
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27. SPEN haploinsufficiency causes a neurodevelopmental disorder overlapping proximal 1p36 deletion syndrome with an episignature of X chromosomes in females

Author

Radio, Francesca Clementina, primary, Pang, Kaifang, additional, Ciolfi, Andrea, additional, Levy, Michael A., additional, Hernández-García, Andrés, additional, Pedace, Lucia, additional, Pantaleoni, Francesca, additional, Liu, Zhandong, additional, de Boer, Elke, additional, Jackson, Adam, additional, Bruselles, Alessandro, additional, McConkey, Haley, additional, Stellacci, Emilia, additional, Lo Cicero, Stefania, additional, Motta, Marialetizia, additional, Carrozzo, Rosalba, additional, Dentici, Maria Lisa, additional, McWalter, Kirsty, additional, Desai, Megha, additional, Monaghan, Kristin G., additional, Telegrafi, Aida, additional, Philippe, Christophe, additional, Vitobello, Antonio, additional, Au, Margaret, additional, Grand, Katheryn, additional, Sanchez-Lara, Pedro A., additional, Baez, Joanne, additional, Lindstrom, Kristin, additional, Kulch, Peggy, additional, Sebastian, Jessica, additional, Madan-Khetarpal, Suneeta, additional, Roadhouse, Chelsea, additional, MacKenzie, Jennifer J., additional, Monteleone, Berrin, additional, Saunders, Carol J., additional, Jean Cuevas, July K., additional, Cross, Laura, additional, Zhou, Dihong, additional, Hartley, Taila, additional, Sawyer, Sarah L., additional, Monteiro, Fabíola Paoli, additional, Secches, Tania Vertemati, additional, Kok, Fernando, additional, Schultz-Rogers, Laura E., additional, Macke, Erica L., additional, Morava, Eva, additional, Klee, Eric W., additional, Kemppainen, Jennifer, additional, Iascone, Maria, additional, Selicorni, Angelo, additional, Tenconi, Romano, additional, Amor, David J., additional, Pais, Lynn, additional, Gallacher, Lyndon, additional, Turnpenny, Peter D., additional, Stals, Karen, additional, Ellard, Sian, additional, Cabet, Sara, additional, Lesca, Gaetan, additional, Pascal, Joset, additional, Steindl, Katharina, additional, Ravid, Sarit, additional, Weiss, Karin, additional, Castle, Alison M.R., additional, Carter, Melissa T., additional, Kalsner, Louisa, additional, de Vries, Bert B.A., additional, van Bon, Bregje W., additional, Wevers, Marijke R., additional, Pfundt, Rolph, additional, Stegmann, Alexander P.A., additional, Kerr, Bronwyn, additional, Kingston, Helen M., additional, Chandler, Kate E., additional, Sheehan, Willow, additional, Elias, Abdallah F., additional, Shinde, Deepali N., additional, Towne, Meghan C., additional, Robin, Nathaniel H., additional, Goodloe, Dana, additional, Vanderver, Adeline, additional, Sherbini, Omar, additional, Bluske, Krista, additional, Hagelstrom, R. Tanner, additional, Zanus, Caterina, additional, Faletra, Flavio, additional, Musante, Luciana, additional, Kurtz-Nelson, Evangeline C., additional, Earl, Rachel K., additional, Anderlid, Britt-Marie, additional, Morin, Gilles, additional, van Slegtenhorst, Marjon, additional, Diderich, Karin E.M., additional, Brooks, Alice S., additional, Gribnau, Joost, additional, Boers, Ruben G., additional, Finestra, Teresa Robert, additional, Carter, Lauren B., additional, Rauch, Anita, additional, Gasparini, Paolo, additional, Boycott, Kym M., additional, Barakat, Tahsin Stefan, additional, Graham, John M., additional, Faivre, Laurence, additional, Banka, Siddharth, additional, Wang, Tianyun, additional, Eichler, Evan E., additional, Priolo, Manuela, additional, Dallapiccola, Bruno, additional, Vissers, Lisenka E.L.M., additional, Sadikovic, Bekim, additional, Scott, Daryl A., additional, Holder, Jimmy Lloyd, additional, and Tartaglia, Marco, additional

Published
2021
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29. Clinical diagnostic exome sequencing in dystonia: Genetic testing challenges for complex conditions

Author

Powis, Zöe, primary, Towne, Meghan C., additional, Hagman, Kelly D.F., additional, Blanco, Kirsten, additional, Palmaer, Erika, additional, Castro, Andrew, additional, Sajan, Samin A., additional, Radtke, Kelly, additional, Feyma, Timothy J., additional, Juliette, Kali, additional, Tang, Sha, additional, and Sidiropoulos, Christos, additional

Published
2019
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31. Clinical diagnostic exome sequencing in dystonia: Genetic testing challenges for complex conditions.

Author

Powis, Zöe, Towne, Meghan C., Hagman, Kelly D.F., Blanco, Kirsten, Palmaer, Erika, Castro, Andrew, Sajan, Samin A., Radtke, Kelly, Feyma, Timothy J., Juliette, Kali, Tang, Sha, and Sidiropoulos, Christos

Subjects
*GENETIC testing, *DEVELOPMENTAL delay, *DYSTONIA, *MEDICAL records, *INTELLECTUAL disabilities, *TREATMENT delay (Medicine)
Abstract

Patients with dystonia are particularly appropriate for diagnostic exome sequencing (DES), due to the complex, diverse features and genetic heterogeneity. Personal and family history data were collected from test requisition forms and medical records from 189 patients with reported dystonia and available family members received for clinical DES. Of them, 20.2% patients had a positive genetic finding associated with dystonia. Detection rates for cases with isolated and combined dystonia were 22.4% and 25.0%, respectively. 71.4% of the cohort had co‐occurring non‐movement‐related findings and a detection rate of 24.4%. Patients with childhood‐onset dystonia trended toward higher detection rates (31.8%) compared to infancy (23.6%), adolescence (12.5%), and early‐adulthood onset (16%). Uncharacterized gene findings were found in 6.7% (8/119) of cases that underwent analysis for genes without an established disease relationship. Patients with intellectual disability/developmental delay, seizures/epilepsy and/or multifocal dystonia were more likely to have positive findings (P =.0093,.0397,.0006). Four (2.1%) patients had findings in two genes, and seven (3.7%) had reclassification after the original report due to new literature, new clinical information or reanalysis request. Pediatric patients were more likely to have positive findings (P =.0180). Our observations show utility of family‐based DES in patients with dystonia and illustrate the complexity of testing. [ABSTRACT FROM AUTHOR]

Published
2020
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32. Backpack health reduces data‐sharingbarriers between the medical community and individuals with rare diseases

Author

May, Lauren, Towne, Meghan C., Haynes, Ginger, Dalton, Emily, LaDuca, Holly, Masciale, Eileen, Stephens, Kim J., Hogan, Melissa, Shapiro‐Barr, Michael, Sheedy, Roughan, and Smith, Erin

Abstract

Technology has changed the way we approach medical care: health data is constantly being generated, medical discoveries are progressing more rapidly, and individuals are more connected across the world than ever before. Backpack Health is a global personal health record platform that harnesses the power of technology to connect users to their primary health data sources, the medical community, and researchers. By syncing with existing patient portals, health data can be stored on the Backpack Health platform and easily accessed and controlled by users in one connected interface. Individuals manage and collate their current and past conditions, genetic test results, symptoms, medications, procedures, labs, and other health data. Users are empowered to disseminate their information to clinicians, researchers, foundations, and pharmaceutical and biotechnology companies they connect with through the Backpack Health application. Here, we describe how two rare disease advocacy groups, The Marfan Foundation and Project Alive, utilize Backpack Health to connect with their target populations. Through secure transfer of pseudonymized data, groups can query their members to improve understanding of clinical features and to facilitate meaningful research. Responses to the groups' surveys show strong member engagement with high completion rates and increases in new Backpack Health users when surveys are deployed. Data from these surveys have been published and used to better inform clinical outcomes for treatment trials. By connecting users directly to the foundations, clinicians, researchers, and industry partners working on their condition, Backpack Health is instrumental in fast‐tracking medical discoveries and treatment for rare diseases.

Published
2021
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33. De Novo Mutations in Protein Kinase Genes CAMK2A and CAMK2B Cause Intellectual Disability

Author

Genetica Klinische Genetica, Child Health, Genetica Sectie Genoomdiagnostiek, Küry, Sébastien, van Woerden, Geeske M, Besnard, Thomas, Proietti Onori, Martina, Latypova, Xénia, Towne, Meghan C, Cho, Megan T., Prescott, Trine E, Ploeg, Melissa A, Sanders, Jan-Stephan, Stessman, Holly A F, Pujol, Aurora, Distel, Ben, Robak, Laurie A, Bernstein, Jonathan A, Denommé-Pichon, Anne-Sophie, Lesca, Gaëtan, Sellars, Elizabeth A, Berg, Jonathan, Carré, Wilfrid, Busk, Øyvind Løvold, van Bon, Bregje W M, Waugh, Jeff L, Deardorff, Matthew, Hoganson, George E, Bosanko, Katherine B, Johnson, Diana S, Dabir, Tabib, Holla, Øystein Lunde, Sarkar, Ajoy, Tveten, Kristian, de Bellescize, Julitta, Braathen, Geir J, Terhal, Paulien A, Grange, Dorothy K, van Haeringen, Arie, Lam, Christina, Mirzaa, Ghayda, Burton, Jennifer, Bhoj, Elizabeth J., Douglas, Jessica, Santani, Avni B, Nesbitt, Addie I, Helbig, Katherine L, Andrews, Marisa V, Begtrup, Amber, Tang, Sha, van Gassen, Koen L I, Juusola, Jane, Verbeek, Nienke E, Undiagnosed Diseases Network, Genetica Klinische Genetica, Child Health, Genetica Sectie Genoomdiagnostiek, Küry, Sébastien, van Woerden, Geeske M, Besnard, Thomas, Proietti Onori, Martina, Latypova, Xénia, Towne, Meghan C, Cho, Megan T., Prescott, Trine E, Ploeg, Melissa A, Sanders, Jan-Stephan, Stessman, Holly A F, Pujol, Aurora, Distel, Ben, Robak, Laurie A, Bernstein, Jonathan A, Denommé-Pichon, Anne-Sophie, Lesca, Gaëtan, Sellars, Elizabeth A, Berg, Jonathan, Carré, Wilfrid, Busk, Øyvind Løvold, van Bon, Bregje W M, Waugh, Jeff L, Deardorff, Matthew, Hoganson, George E, Bosanko, Katherine B, Johnson, Diana S, Dabir, Tabib, Holla, Øystein Lunde, Sarkar, Ajoy, Tveten, Kristian, de Bellescize, Julitta, Braathen, Geir J, Terhal, Paulien A, Grange, Dorothy K, van Haeringen, Arie, Lam, Christina, Mirzaa, Ghayda, Burton, Jennifer, Bhoj, Elizabeth J., Douglas, Jessica, Santani, Avni B, Nesbitt, Addie I, Helbig, Katherine L, Andrews, Marisa V, Begtrup, Amber, Tang, Sha, van Gassen, Koen L I, Juusola, Jane, Verbeek, Nienke E, and Undiagnosed Diseases Network

Published
2017

34. Clinical heterogeneity associated with KCNA1 mutations include cataplexy and nonataxic presentations

Author

Massachusetts Institute of Technology. Department of Biology, Shi, Jiahai, Brownstein, Catherine A., Beggs, Alan H., Rodan, Lance, Towne, Meghan C., Pelletier, Renee, Cao, Siqi, Rosenberg, Paul A., Urion, David K., Picker, Jonathan, Tan, Wen-Hann, Agrawal, Pankaj B., Massachusetts Institute of Technology. Department of Biology, Shi, Jiahai, Brownstein, Catherine A., Beggs, Alan H., Rodan, Lance, Towne, Meghan C., Pelletier, Renee, Cao, Siqi, Rosenberg, Paul A., Urion, David K., Picker, Jonathan, Tan, Wen-Hann, and Agrawal, Pankaj B.

Abstract

Mutations in the KCNA1 gene are known to cause episodic ataxia/myokymia syndrome type 1 (EA1). Here, we describe two families with unique presentations who were enrolled in an IRB-approved study, extensively phenotyped, and whole exome sequencing (WES) performed. Family 1 had a diagnosis of isolated cataplexy triggered by sudden physical exertion in multiple affected individuals with heterogeneous neurological findings. All enrolled affected members carried a KCNA1 c.941T>C (p.I314T) mutation. Family 2 had an 8-year-old patient with muscle spasms with rigidity for whom WES revealed a previously reported heterozygous missense mutation in KCNA1 c.677C>G (p.T226R), confirming the diagnosis of EA1 without ataxia. WES identified variants in KCNA1 that explain both phenotypes expanding the phenotypic spectrum of diseases associated with mutations of this gene. KCNA1 mutations should be considered in patients of all ages with episodic neurological phenotypes, even when ataxia is not present. This is an example of the power of genomic approaches to identify pathogenic mutations in unsuspected genes responsible for heterogeneous diseases.

Published
2017

35. Congenital sideroblastic anemia due to mutations in the mitochondrial HSP70 homologue HSPA9

Author

Schmitz-Abe, Klaus, Ciesielski, Szymon J., Schmidt, Paul J., Campagna, Dean R., Rahimov, Fedik, Schilke, Brenda A., Cuijpers, Marloes, Rieneck, Klaus, Lausen, Birgitte, Linenberger, Michael L., Sendamarai, Anoop K., Guo, Chaoshe, Hofmann, Inga, Newburger, Peter E., Matthews, Dana, Shimamura, Akiko, Snijders, Pieter J.L.M., Towne, Meghan C., Niemeyer, Charlotte M., Watson, Henry G., Dziegiel, Morten H., Heeney, Matthew M., May, Alison, Bottomley, Sylvia S., Swinkels, Dorine W., Markianos, Kyriacos, Craig, Elizabeth A., and Fleming, Mark D.

Published
2015
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36. Novel mutation inCNTNAP1results in congenital hypomyelinating neuropathy

Author

Mehta, Paulomi, primary, Küspert, Melanie, additional, Bale, Tejus, additional, Brownstein, Catherine A., additional, Towne, Meghan C., additional, De Girolami, Umberto, additional, Shi, Jiahai, additional, Beggs, Alan H., additional, Darras, Basil T., additional, Wegner, Michael, additional, Piao, Xianhua, additional, and Agrawal, Pankaj B., additional

Published
2017
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37. The landscape of reported VUS in multi-gene panel and genomic testing: Time for a change

Author

Rehm, Heidi L., Alaimo, Joseph T., Aradhya, Swaroop, Bayrak-Toydemir, Pinar, Best, Hunter, Brandon, Rhonda, Buchan, Jillian G., Chao, Elizabeth C., Chen, Elaine, Clifford, Jacob, Cohen, Ana S.A., Conlin, Laura K., Das, Soma, Davis, Kyle W., del Gaudio, Daniela, Del Viso, Florencia, DiVincenzo, Christina, Eisenberg, Marcia, Guidugli, Lucia, Hammer, Monia B., Harrison, Steven M., Hatchell, Kathryn E., Dyer, Lindsay Havens, Hoang, Lily U., Holt, James M., Jobanputra, Vaidehi, Karbassi, Izabela D., Kearney, Hutton M., Kelly, Melissa A., Kelly, Jacob M., Kluge, Michelle L., Komala, Timothy, Kruszka, Paul, Lau, Lynette, Lebo, Matthew S., Marshall, Christian R., McKnight, Dianalee, McWalter, Kirsty, Meng, Yan, Nagan, Narasimhan, Neckelmann, Christian S., Neerman, Nir, Niu, Zhiyv, Paolillo, Vitoria K., Paolucci, Sarah A., Perry, Denise, Pesaran, Tina, Radtke, Kelly, Rasmussen, Kristen J., Retterer, Kyle, Saunders, Carol J., Spiteri, Elizabeth, Stanley, Christine, Szuto, Anna, Taft, Ryan J., Thiffault, Isabelle, Thomas, Brittany C., Thomas-Wilson, Amanda, Thorpe, Erin, Tidwell, Timothy J., Towne, Meghan C., Zouk, Hana, Marshall, Christian, Meng, Linyan, Jobanputra, Vaidehi, Taft, Ryan, Ashley, Euan, Nakouzi, Ghunwa, Shen, Wei, Kingsmore, Stephen, and Rehm, Heidi

Abstract

Variants of uncertain significance (VUS) are a common result of diagnostic genetic testing and can be difficult to manage with potential misinterpretation and downstream costs, including time investment by clinicians. We investigated the rate of VUS reported on diagnostic testing via multi-gene panels (MGPs) and exome and genome sequencing (ES/GS) to measure the magnitude of uncertain results and explore ways to reduce their potentially detrimental impact.

Published
2023
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41. A novel de novo mutation in ATP1A3 and childhood-onset schizophrenia

Author

Smedemark-Margulies, Niklas, primary, Brownstein, Catherine A., additional, Vargas, Sigella, additional, Tembulkar, Sahil K., additional, Towne, Meghan C., additional, Shi, Jiahai, additional, Gonzalez-Cuevas, Elisa, additional, Liu, Kevin X., additional, Bilguvar, Kaya, additional, Kleiman, Robin J., additional, Han, Min-Joon, additional, Torres, Alcy, additional, Berry, Gerard T., additional, Yu, Timothy W., additional, Beggs, Alan H., additional, Agrawal, Pankaj B., additional, and Gonzalez-Heydrich, Joseph, additional

Published
2016
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44. Clinical heterogeneity associated with KCNA1 mutations include cataplexy and nonataxic presentations

Author

Brownstein, Catherine A., primary, Beggs, Alan H., additional, Rodan, Lance, additional, Shi, Jiahai, additional, Towne, Meghan C., additional, Pelletier, Renee, additional, Cao, Siqi, additional, Rosenberg, Paul A., additional, Urion, David K., additional, Picker, Jonathan, additional, Tan, Wen-Hann, additional, and Agrawal, Pankaj B., additional

Published
2015
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46. An international effort towards developing standards for best practices in analysis, interpretation and reporting of clinical genome sequencing results in the CLARITY Challenge

Author

Brownstein, Catherine A., Beggs, Alan H., Homer, Nils, Merriman, Barry, Yu, Timothy W., Flannery, Katherine C., DeChene, Elizabeth T., Towne, Meghan C., Savage, Sarah K., Price, Emily N., Holm, Ingrid A., Luquette, Lovelace J., Lyon, Elaine, Majzoub, Joseph, Neupert, Peter, McCallie, David, Jr., Szolovits, Peter, Willard, Huntington F., Mendelsohn, Nancy J., Temme, Renee, Finkel, Richard S., Yum, Sabrina W., Medne, Livija, Sunyaev, Shamil R., Adzhubey, Ivan, Cassa, Christopher A., de Bakker, Paul I. W., Duzkale, Hatice, Dworzynski, Piotr, Fairbrother, William, Francioli, Laurent, Funke, Birgit H., Giovanni, Monica A., Handsaker, Robert E., Lage, Kasper, Lebo, Matthew S., Lek, Monkol, Leshchiner, Ignaty, MacArthur, Daniel G., McLaughlin, Heather M., Murray, Michael F., Pers, Tune H., Polak, Paz P., Raychaudhuri, Soumya, Rehm, Heidi L., Soemedi, Rachel, Stitziel, Nathan O., Vestecka, Sara, Supper, Jochen, Gugenmus, Claudia, Klocke, Bernward, Hahn, Alexander, Schubach, Max, Menzel, Mortiz, Biskup, Saskia, Freisinger, Peter, Deng, Mario, Braun, Martin, Perner, Sven, Smith, Richard J. H., Andorf, Janeen L., Huang, Jian, Ryckman, Kelli, Sheffield, Val C., Stone, Edwin M., Bair, Thomas, Black-Ziegelbein, E. Ann, Braun, Terry A., Darbro, Benjamin, DeLuca, Adam P., Kolbe, Diana L., Scheetz, Todd E., Shearer, Aiden E., Sompallae, Rama, Wang, Kai, Bassuk, Alexander G., Edens, Erik, Mathews, Katherine, Moore, Steven A., Shchelochkov, Oleg A., Trapane, Pamela, Bossler, Aaron, Campbell, Colleen A., Heusel, Jonathan W., Kwitek, Anne, Maga, Tara, Panzer, Karin, Wassink, Thomas, Van Daele, Douglas, Azaiez, Hela, Booth, Kevin, Meyer, Nic, Segal, Michael M., Williams, Marc S., Tromp, Gerard, White, Peter, Corsmeier, Donald, Fitzgerald-Butt, Sara, Herman, Gail, Lamb-Thrush, Devon, McBride, Kim L., Newsom, David, Pierson, Christopher R., Rakowsky, Alexander T., Maver, Ales, Lovrecic, Luca, Palandacic, Anja, Peterlin, Borut, Torkamani, Ali, Wedell, Anna, Huss, Mikael, Alexeyenko, Andrey, Lindvall, Jessica M., Magnusson, Mans, Nilsson, Daniel, Stranneheim, Henrik, Taylan, Fulya, Gilissen, Christian, Hoischen, Alexander, van Bon, Bregje, Yntema, Helger, Nelen, Marcel, Zhang, Weidong, Sager, Jason, Zhang, Lu, Blair, Kathryn, Kural, Deniz, Cariaso, Michael, Lennon, Greg G., Javed, Asif, Agrawal, Saloni, Ng, Pauline C., Sandhu, Komal S., Krishna, Shuba, Veeramachaneni, Vamsi, Isakov, Ofer, Halperin, Eran, Friedman, Eitan, Shomron, Noam, Glusman, Gustavo, Roach, Jared C., Caballero, Juan, Cox, Hannah C., Mauldin, Denise, Ament, Seth A., Rowen, Lee, Richards, Daniel R., San Lucas, F. Anthony, Gonzalez-Garay, Manuel L., Caskey, C. Thomas, Bai, Yu, Huang, Ying, Fang, Fang, Zhang, Yan, Wang, Zhengyuan, Barrera, Jorge, Garcia-Lobo, Juan M., Gonzalez-Lamuno, Domingo, Llorca, Javier, Rodriguez, Maria C., Varela, Ignacio, Reese, Martin G., De la Vega, Francisco M., Kiruluta, Edward, Cargill, Michele, Hart, Reece K., Sorenson, Jon M., Lyon, Gholson J., Stevenson, David A., Bray, Bruce E., Moore, Barry M., Eilbeck, Karen, Yandell, Mark, Zhao, Hongyu, Hou, Lin, Chen, Xiaowei, Yan, Xiting, Chen, Mengjie, Li, Cong, Yang, Can, Gunel, Murat, Li, Peining, Kong, Yong, Alexander, Austin C., Albertyn, Zayed I., Boycott, Kym M., Bulman, Dennis E., Gordon, Paul M. K., Innes, A. Micheil, Knoppers, Bartha M., Majewski, Jacek, Marshall, Christian R., Parboosingh, Jillian S., Sawyer, Sarah L., Samuels, Mark E., Schwartzentruber, Jeremy, Kohane, Isaac S., Margulies, David M., Brownstein, Catherine A., Beggs, Alan H., Homer, Nils, Merriman, Barry, Yu, Timothy W., Flannery, Katherine C., DeChene, Elizabeth T., Towne, Meghan C., Savage, Sarah K., Price, Emily N., Holm, Ingrid A., Luquette, Lovelace J., Lyon, Elaine, Majzoub, Joseph, Neupert, Peter, McCallie, David, Jr., Szolovits, Peter, Willard, Huntington F., Mendelsohn, Nancy J., Temme, Renee, Finkel, Richard S., Yum, Sabrina W., Medne, Livija, Sunyaev, Shamil R., Adzhubey, Ivan, Cassa, Christopher A., de Bakker, Paul I. W., Duzkale, Hatice, Dworzynski, Piotr, Fairbrother, William, Francioli, Laurent, Funke, Birgit H., Giovanni, Monica A., Handsaker, Robert E., Lage, Kasper, Lebo, Matthew S., Lek, Monkol, Leshchiner, Ignaty, MacArthur, Daniel G., McLaughlin, Heather M., Murray, Michael F., Pers, Tune H., Polak, Paz P., Raychaudhuri, Soumya, Rehm, Heidi L., Soemedi, Rachel, Stitziel, Nathan O., Vestecka, Sara, Supper, Jochen, Gugenmus, Claudia, Klocke, Bernward, Hahn, Alexander, Schubach, Max, Menzel, Mortiz, Biskup, Saskia, Freisinger, Peter, Deng, Mario, Braun, Martin, Perner, Sven, Smith, Richard J. H., Andorf, Janeen L., Huang, Jian, Ryckman, Kelli, Sheffield, Val C., Stone, Edwin M., Bair, Thomas, Black-Ziegelbein, E. Ann, Braun, Terry A., Darbro, Benjamin, DeLuca, Adam P., Kolbe, Diana L., Scheetz, Todd E., Shearer, Aiden E., Sompallae, Rama, Wang, Kai, Bassuk, Alexander G., Edens, Erik, Mathews, Katherine, Moore, Steven A., Shchelochkov, Oleg A., Trapane, Pamela, Bossler, Aaron, Campbell, Colleen A., Heusel, Jonathan W., Kwitek, Anne, Maga, Tara, Panzer, Karin, Wassink, Thomas, Van Daele, Douglas, Azaiez, Hela, Booth, Kevin, Meyer, Nic, Segal, Michael M., Williams, Marc S., Tromp, Gerard, White, Peter, Corsmeier, Donald, Fitzgerald-Butt, Sara, Herman, Gail, Lamb-Thrush, Devon, McBride, Kim L., Newsom, David, Pierson, Christopher R., Rakowsky, Alexander T., Maver, Ales, Lovrecic, Luca, Palandacic, Anja, Peterlin, Borut, Torkamani, Ali, Wedell, Anna, Huss, Mikael, Alexeyenko, Andrey, Lindvall, Jessica M., Magnusson, Mans, Nilsson, Daniel, Stranneheim, Henrik, Taylan, Fulya, Gilissen, Christian, Hoischen, Alexander, van Bon, Bregje, Yntema, Helger, Nelen, Marcel, Zhang, Weidong, Sager, Jason, Zhang, Lu, Blair, Kathryn, Kural, Deniz, Cariaso, Michael, Lennon, Greg G., Javed, Asif, Agrawal, Saloni, Ng, Pauline C., Sandhu, Komal S., Krishna, Shuba, Veeramachaneni, Vamsi, Isakov, Ofer, Halperin, Eran, Friedman, Eitan, Shomron, Noam, Glusman, Gustavo, Roach, Jared C., Caballero, Juan, Cox, Hannah C., Mauldin, Denise, Ament, Seth A., Rowen, Lee, Richards, Daniel R., San Lucas, F. Anthony, Gonzalez-Garay, Manuel L., Caskey, C. Thomas, Bai, Yu, Huang, Ying, Fang, Fang, Zhang, Yan, Wang, Zhengyuan, Barrera, Jorge, Garcia-Lobo, Juan M., Gonzalez-Lamuno, Domingo, Llorca, Javier, Rodriguez, Maria C., Varela, Ignacio, Reese, Martin G., De la Vega, Francisco M., Kiruluta, Edward, Cargill, Michele, Hart, Reece K., Sorenson, Jon M., Lyon, Gholson J., Stevenson, David A., Bray, Bruce E., Moore, Barry M., Eilbeck, Karen, Yandell, Mark, Zhao, Hongyu, Hou, Lin, Chen, Xiaowei, Yan, Xiting, Chen, Mengjie, Li, Cong, Yang, Can, Gunel, Murat, Li, Peining, Kong, Yong, Alexander, Austin C., Albertyn, Zayed I., Boycott, Kym M., Bulman, Dennis E., Gordon, Paul M. K., Innes, A. Micheil, Knoppers, Bartha M., Majewski, Jacek, Marshall, Christian R., Parboosingh, Jillian S., Sawyer, Sarah L., Samuels, Mark E., Schwartzentruber, Jeremy, Kohane, Isaac S., and Margulies, David M.

Abstract

Background: There is tremendous potential for genome sequencing to improve clinical diagnosis and care once it becomes routinely accessible, but this will require formalizing research methods into clinical best practices in the areas of sequence data generation, analysis, interpretation and reporting. The CLARITY Challenge was designed to spur convergence in methods for diagnosing genetic disease starting from clinical case history and genome sequencing data. DNA samples were obtained from three families with heritable genetic disorders and genomic sequence data were donated by sequencing platform vendors. The challenge was to analyze and interpret these data with the goals of identifying disease-causing variants and reporting the findings in a clinically useful format. Participating contestant groups were solicited broadly, and an independent panel of judges evaluated their performance. Results: A total of 30 international groups were engaged. The entries reveal a general convergence of practices on most elements of the analysis and interpretation process. However, even given this commonality of approach, only two groups identified the consensus candidate variants in all disease cases, demonstrating a need for consistent fine-tuning of the generally accepted methods. There was greater diversity of the final clinical report content and in the patient consenting process, demonstrating that these areas require additional exploration and standardization. Conclusions: The CLARITY Challenge provides a comprehensive assessment of current practices for using genome sequencing to diagnose and report genetic diseases. There is remarkable convergence in bioinformatic techniques, but medical interpretation and reporting are areas that require further development by many groups., QC 20140819

Published
2014
Full Text
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47. An international effort towards developing standards for best practices in analysis, interpretation and reporting of clinical genome sequencing results in the CLARITY Challenge

Author

Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science, Szolovits, Peter, Brownstein, Catherine A., Beggs, Alan H., Homer, Nils, Merriman, Barry, Yu, Timothy W., Flannery, Katherine C., DeChene, Elizabeth T., Towne, Meghan C., Savage, Sarah K., Price, Emily N., Holm, Ingrid A., Luquette, Lovelace J., Lyon, Elaine, Majzoub, Joseph, Neupert, Peter, McCallie Jr., David, Willard, Huntington F., Mendelsohn, Nancy J., Temme, Renee, Finkel, Richard S., Yum, Sabrina W., Medne, Livija, Sunyaev, Shamil R., Adzhubey, Ivan, Cassa, Christopher A., de Bakker, Paul I. W., Duzkale, Hatice, Dworzyński, Piotr, Fairbrother, William G., Francioli, Laurent, Funke, Birgit H., Giovanni, Monica A., Handsaker, Robert E., Lage, Kasper, Lebo, Matthew S., Lek, Monkol, Leshchiner, Ignaty, MacArthur, Daniel G., McLaughlin, Heather M., Murray, Michael F., Pers, Tune H., Polak, Paz P., Raychaudhuri, Soumya, Rehm, Heidi L., Soemedi, Rachel, Stitziel, Nathan O., Vestecka, Sara, Supper, Jochen, Gugenmus, Claudia, Klocke, Bernward, Hahn, Alexander, Schubach, Max, Menzel, Mortiz, Biskup, Saskia, Freisinger, Peter, Deng, Mario, Braun, Martin, Perner, Sven, Smith, Richard J. H., Andorf, Janeen L., Huang, Jian, Ryckman, Kelli, Sheffield, Val C., Stone, Edwin M., Bair, Thomas, Black-Ziegelbein, E. A., Braun, Terry A., Darbro, Benjamin, DeLuca, Adam P., Kolbe, Diana L., Scheetz, Todd E., Shearer, Aiden E., Sompallae, Rama, Wang, Kai, Bassuk, Alexander G., Edens, Erik, Mathews, Katherine, Moore, Steven A., Shchelochkov, Oleg A., Trapane, Pamela, Bossler, Aaron, Campbell, Colleen A., Heusel, Jonathan W., Kwitek, Anne, Maga, Tara, Panzer, Karin, Wassink, Thomas, Van Daele, Douglas, Azaiez, Hela, Booth, Kevin, Meyer, Nic, Segal, Michael M., Williams, Marc S., Tromp, Gerard, White, Peter, Corsmeier, Donald, Fitzgerald-Butt, Sara, Herman, Gail, Lamb-Thrush, Devon, McBride, Kim L., Newsom, David, Pierson, Christopher R., Rakowsky, Alexander T., Maver, Ales, Lovrečić, Luca, Palandacic, Anja, Peterlin, Borut, Torkamani, Ali, Wedell, Anna, Huss, Mikael, Alexeyenko, Andrey, Lindvall, Jessica M., Magnusson, Mans, Nilsson, Daniel, Stranneheim, Henrik, Taylan, Fulya, Gilissen, Christian, Hoischen, Alexander, van Bon, Bregje, Yntema, Helger, Nelen, Marcel, Zhang, Weidong, Sager, Jason, Zhang, Lu, Blair, Kathryn, Kural, Deniz, Cariaso, Michael, Lennon, Greg G., Javed, Asif, Agrawal, Saloni, Ng, Pauline C., Sandhu, Komal S., Krishna, Shuba, Veeramachaneni, Vamsi, Isakov, Ofer, Halperin, Eran, Friedman, Eitan, Shomron, Noam, Glusman, Gustavo, Roach, Jared C., Caballero, Juan, Cox, Hannah C., Mauldin, Denise, Ament, Seth A., Rowen, Lee, Richards, Daniel R., Lucas, F Anthony S., Gonzalez-Garay, Manuel L., Caskey, C. T., Bai, Yu, Huang, Ying, Fang, Fang, Zhang, Yan, Wang, Zhengyuan, Barrera, Jorge, Garcia-Lobo, Juan M., González-Lamuno, Domingo, Llorca, Javier, Rodriguez, Maria C., Varela, Ignacio, Reese, Martin G., De La Vega, Francisco M., Kiruluta, Edward, Cargill, Michele, Hart, Reece K., Sorenson, Jon M., Lyon, Gholson J., Stevenson, David A., Bray, Bruce E., Moore, Barry M., Eilbeck, Karen, Yandell, Mark, Zhao, Hongyu, Hou, Lin, Chen, Xiaowei, Yan, Xiting, Chen, Mengjie, Li, Cong, Yang, Can, Gunel, Murat, Li, Peining, Kong, Yong, Alexander, Austin C., Albertyn, Zayed I., Boycott, Kym M., Bulman, Dennis E., Gordon, Paul M. K., Innes, A. M., Knoppers, Bartha M., Majewski, Jacek, Marshall, Christian R., Parboosingh, Jillian S., Sawyer, Sarah L., Samuels, Mark E., Schwartzentruber, Jeremy, Kohane, Isaac, Margulies, David M., Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science, Szolovits, Peter, Brownstein, Catherine A., Beggs, Alan H., Homer, Nils, Merriman, Barry, Yu, Timothy W., Flannery, Katherine C., DeChene, Elizabeth T., Towne, Meghan C., Savage, Sarah K., Price, Emily N., Holm, Ingrid A., Luquette, Lovelace J., Lyon, Elaine, Majzoub, Joseph, Neupert, Peter, McCallie Jr., David, Willard, Huntington F., Mendelsohn, Nancy J., Temme, Renee, Finkel, Richard S., Yum, Sabrina W., Medne, Livija, Sunyaev, Shamil R., Adzhubey, Ivan, Cassa, Christopher A., de Bakker, Paul I. W., Duzkale, Hatice, Dworzyński, Piotr, Fairbrother, William G., Francioli, Laurent, Funke, Birgit H., Giovanni, Monica A., Handsaker, Robert E., Lage, Kasper, Lebo, Matthew S., Lek, Monkol, Leshchiner, Ignaty, MacArthur, Daniel G., McLaughlin, Heather M., Murray, Michael F., Pers, Tune H., Polak, Paz P., Raychaudhuri, Soumya, Rehm, Heidi L., Soemedi, Rachel, Stitziel, Nathan O., Vestecka, Sara, Supper, Jochen, Gugenmus, Claudia, Klocke, Bernward, Hahn, Alexander, Schubach, Max, Menzel, Mortiz, Biskup, Saskia, Freisinger, Peter, Deng, Mario, Braun, Martin, Perner, Sven, Smith, Richard J. H., Andorf, Janeen L., Huang, Jian, Ryckman, Kelli, Sheffield, Val C., Stone, Edwin M., Bair, Thomas, Black-Ziegelbein, E. A., Braun, Terry A., Darbro, Benjamin, DeLuca, Adam P., Kolbe, Diana L., Scheetz, Todd E., Shearer, Aiden E., Sompallae, Rama, Wang, Kai, Bassuk, Alexander G., Edens, Erik, Mathews, Katherine, Moore, Steven A., Shchelochkov, Oleg A., Trapane, Pamela, Bossler, Aaron, Campbell, Colleen A., Heusel, Jonathan W., Kwitek, Anne, Maga, Tara, Panzer, Karin, Wassink, Thomas, Van Daele, Douglas, Azaiez, Hela, Booth, Kevin, Meyer, Nic, Segal, Michael M., Williams, Marc S., Tromp, Gerard, White, Peter, Corsmeier, Donald, Fitzgerald-Butt, Sara, Herman, Gail, Lamb-Thrush, Devon, McBride, Kim L., Newsom, David, Pierson, Christopher R., Rakowsky, Alexander T., Maver, Ales, Lovrečić, Luca, Palandacic, Anja, Peterlin, Borut, Torkamani, Ali, Wedell, Anna, Huss, Mikael, Alexeyenko, Andrey, Lindvall, Jessica M., Magnusson, Mans, Nilsson, Daniel, Stranneheim, Henrik, Taylan, Fulya, Gilissen, Christian, Hoischen, Alexander, van Bon, Bregje, Yntema, Helger, Nelen, Marcel, Zhang, Weidong, Sager, Jason, Zhang, Lu, Blair, Kathryn, Kural, Deniz, Cariaso, Michael, Lennon, Greg G., Javed, Asif, Agrawal, Saloni, Ng, Pauline C., Sandhu, Komal S., Krishna, Shuba, Veeramachaneni, Vamsi, Isakov, Ofer, Halperin, Eran, Friedman, Eitan, Shomron, Noam, Glusman, Gustavo, Roach, Jared C., Caballero, Juan, Cox, Hannah C., Mauldin, Denise, Ament, Seth A., Rowen, Lee, Richards, Daniel R., Lucas, F Anthony S., Gonzalez-Garay, Manuel L., Caskey, C. T., Bai, Yu, Huang, Ying, Fang, Fang, Zhang, Yan, Wang, Zhengyuan, Barrera, Jorge, Garcia-Lobo, Juan M., González-Lamuno, Domingo, Llorca, Javier, Rodriguez, Maria C., Varela, Ignacio, Reese, Martin G., De La Vega, Francisco M., Kiruluta, Edward, Cargill, Michele, Hart, Reece K., Sorenson, Jon M., Lyon, Gholson J., Stevenson, David A., Bray, Bruce E., Moore, Barry M., Eilbeck, Karen, Yandell, Mark, Zhao, Hongyu, Hou, Lin, Chen, Xiaowei, Yan, Xiting, Chen, Mengjie, Li, Cong, Yang, Can, Gunel, Murat, Li, Peining, Kong, Yong, Alexander, Austin C., Albertyn, Zayed I., Boycott, Kym M., Bulman, Dennis E., Gordon, Paul M. K., Innes, A. M., Knoppers, Bartha M., Majewski, Jacek, Marshall, Christian R., Parboosingh, Jillian S., Sawyer, Sarah L., Samuels, Mark E., Schwartzentruber, Jeremy, Kohane, Isaac, and Margulies, David M.

Abstract

Background: There is tremendous potential for genome sequencing to improve clinical diagnosis and care once it becomes routinely accessible, but this will require formalizing research methods into clinical best practices in the areas of sequence data generation, analysis, interpretation and reporting. The CLARITY Challenge was designed to spur convergence in methods for diagnosing genetic disease starting from clinical case history and genome sequencing data. DNA samples were obtained from three families with heritable genetic disorders and genomic sequence data were donated by sequencing platform vendors. The challenge was to analyze and interpret these data with the goals of identifying disease-causing variants and reporting the findings in a clinically useful format. Participating contestant groups were solicited broadly, and an independent panel of judges evaluated their performance. Results: A total of 30 international groups were engaged. The entries reveal a general convergence of practices on most elements of the analysis and interpretation process. However, even given this commonality of approach, only two groups identified the consensus candidate variants in all disease cases, demonstrating a need for consistent fine-tuning of the generally accepted methods. There was greater diversity of the final clinical report content and in the patient consenting process, demonstrating that these areas require additional exploration and standardization. Conclusions: The CLARITY Challenge provides a comprehensive assessment of current practices for using genome sequencing to diagnose and report genetic diseases. There is remarkable convergence in bioinformatic techniques, but medical interpretation and reporting are areas that require further development by many groups., Boston Children's Hospital (Manton Center for Orphan Disease Research), Harvard Medical School (Center for Biomedical Infomatics)

Published
2014

48. An international effort towards developing standards for best practices in analysis, interpretation and reporting of clinical genome sequencing results in the CLARITY Challenge

Author

Brownstein, Catherine A, Beggs, Alan H, Homer, Nils, Merriman, Barry, Yu, Timothy W, Flannery, Katherine C, DeChene, Elizabeth T, Towne, Meghan C, Savage, Sarah K, Price, Emily N, Dworzynski, Piotr, Brownstein, Catherine A, Beggs, Alan H, Homer, Nils, Merriman, Barry, Yu, Timothy W, Flannery, Katherine C, DeChene, Elizabeth T, Towne, Meghan C, Savage, Sarah K, Price, Emily N, and Dworzynski, Piotr

Abstract

Background: There is tremendous potential for genome sequencing to improve clinical diagnosis and care once it becomes routinely accessible, but this will require formalizing research methods into clinical best practices in the areas of sequence data generation, analysis, interpretation and reporting. The CLARITY Challenge was designed to spur convergence in methods for diagnosing genetic disease starting from clinical case history and genome sequencing data. DNA samples were obtained from three families with heritable genetic disorders and genomic sequence data were donated by sequencing platform vendors. The challenge was to analyze and interpret these data with the goals of identifying disease-causing variants and reporting the findings in a clinically useful format. Participating contestant groups were solicited broadly, and an independent panel of judges evaluated their performance. Results: A total of 30 international groups were engaged. The entries reveal a general convergence of practices on most elements of the analysis and interpretation process. However, even given this commonality of approach, only two groups identified the consensus candidate variants in all disease cases, demonstrating a need for consistent fine-tuning of the generally accepted methods. There was greater diversity of the final clinical report content and in the patient consenting process, demonstrating that these areas require additional exploration and standardization. Conclusions: The CLARITY Challenge provides a comprehensive assessment of current practices for using genome sequencing to diagnose and report genetic diseases. There is remarkable convergence in bioinformatic techniques, but medical interpretation and reporting are areas that require further development by many groups.

Published
2014

49. Novel mutation in CNTNAP1 results in congenital hypomyelinating neuropathy.

Author

Mehta, Paulomi, Küspert, Melanie, Bale, Tejus, Brownstein, Catherine A., Towne, Meghan C., Girolami, Umberto, Shi, Jiahai, Beggs, Alan H., Darras, Basil T., Wegner, Michael, Piao, Xianhua, Agrawal, Pankaj B., Küspert, Melanie, and De Girolami, Umberto

Subjects
MOTOR neurons, ACTION potentials, CHARCOT-Marie-Tooth disease, DISEASE complications, ELECTROMYOGRAPHY, GLYCOPROTEINS, GENETIC mutation, NEURAL conduction, RESEARCH funding, TREATMENT effectiveness, PHYSIOLOGY
Abstract

Introduction: Congenital hypomyelinating neuropathy (CHN) is a rare congenital neuropathy that presents in the neonatal period and has been linked previously to mutations in several genes associated with myelination. A recent study has linked 4 homozygous frameshift mutations in the contactin-associated protein 1 (CNTNAP1) gene with this condition.Methods: We report a neonate with CHN who was found to have absent sensory nerve and compound muscle action potentials and hypomyelination on nerve biopsy.Results: On whole exome sequencing, we identified a novel CNTNAP1 homozygous missense mutation (p.Arg388Pro) in the proband, and both parents were carriers. Molecular modeling suggests that this variant disrupts a β-strand to cause an unstable structure and likely significant changes in protein function.Conclusions: This report links a missense CNTNAP1 variant to the disease phenotype previously associated only with frameshift mutations. Muscle Nerve 55: 761-765, 2017. [ABSTRACT FROM AUTHOR]

Published
2017
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50. Long-Gap Esophageal Atresia Is a Unique Entity within the Esophageal Atresia Defect Spectrum.

Author

Bairdain, Sigrid, Zurakowski, David, Vargas, Sara O., Stenquist, Nicole, McDonald, Molly, Towne, Meghan C., Miller, David T., Jennings, Russell W., Kantor, David B., and agrawal, Pankaj B.

Subjects
ESOPHAGEAL atresia, ESOPHAGEAL abnormalities, MOLECULAR genetics
Abstract

Background: Long-gap esophageal atresia (LGEA) may have clinical and syndromic presentations different from those of esophageal atresia (EA) that affects shorter segments of the esophagus (non-LGEA). This may suggest unique underlying developmental mechanisms. Objectives: We sought to characterize clinical differences between LGEA and non-LGEA by carefully phenotyping a cohort of EA patients, and furthermore to assess molecular genetic findings in a subset of them. Methods: This is a retrospective cohort study to systematically evaluate clinical and genetic findings in EA infants who presented at our institution over a period of 10 years (2005-2015). Results: Two hundred twenty-nine EA patients were identified, 69 (30%) of whom had LGEA. Tracheoesophageal fistula was present in most non-LGEA patients (158 of 160) but in only 30% of LGEA patients. The VACTERL association was more commonly seen with non-LGEA compared to LGEA (70 vs. 25%; p < 0.001). Further, tri-somy 21 was more common in LGEA than in non-LGEA. 25% of LGEA patients had an isolated EA diagnosis without other anomalies, compared to <1% for non-LGEA. Chromosomal microarray analysis showed copy number variations (CNV) in 4 of 39 non-LGEA patients and 0 of 3 LGEA patients. A review of the ClinGen database showed that none of those CNV have been previously described with EA. Conclusions: LGEA represents a unique type of EA. Compared to non-LGEA, it is more likely to be an isolated defect and associated with trisomy 21. Further, it is less commonly seen with VACTERL anomalies. Our findings suggest the involvement of unique pathways that may be distinct from those causing non-LGEA. [ABSTRACT FROM AUTHOR]

Published
2017
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