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109 results on '"DiTroia, Stephanie"'

1. Coding and non-coding variants in the ciliopathy gene CFAP410 cause early-onset non-syndromic retinal degeneration

Author: Sangermano, Riccardo, Gupta, Priya, Price, Cherrell, Han, Jinu, Navarro, Julien, Condroyer, Christel, Place, Emily M., Antonio, Aline, Mukai, Shizuo, Zanlonghi, Xavier, Sahel, José-Alain, DiTroia, Stephanie, O’Heir, Emily, Duncan, Jacque L., Pierce, Eric A., Zeitz, Christina, Audo, Isabelle, Huckfeldt, Rachel M., and Bujakowska, Kinga M.
Published: 2024
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2. Critical assessment of variant prioritization methods for rare disease diagnosis within the rare genomes project

Author: Stenton, Sarah L., O’Leary, Melanie C., Lemire, Gabrielle, VanNoy, Grace E., DiTroia, Stephanie, Ganesh, Vijay S., Groopman, Emily, O’Heir, Emily, Mangilog, Brian, Osei-Owusu, Ikeoluwa, Pais, Lynn S., Serrano, Jillian, Singer-Berk, Moriel, Weisburd, Ben, Wilson, Michael W., Austin-Tse, Christina, Abdelhakim, Marwa, Althagafi, Azza, Babbi, Giulia, Bellazzi, Riccardo, Bovo, Samuele, Carta, Maria Giulia, Casadio, Rita, Coenen, Pieter-Jan, De Paoli, Federica, Floris, Matteo, Gajapathy, Manavalan, Hoehndorf, Robert, Jacobsen, Julius O. B., Joseph, Thomas, Kamandula, Akash, Katsonis, Panagiotis, Kint, Cyrielle, Lichtarge, Olivier, Limongelli, Ivan, Lu, Yulan, Magni, Paolo, Mamidi, Tarun Karthik Kumar, Martelli, Pier Luigi, Mulargia, Marta, Nicora, Giovanna, Nykamp, Keith, Pejaver, Vikas, Peng, Yisu, Pham, Thi Hong Cam, Podda, Maurizio S., Rao, Aditya, Rizzo, Ettore, Saipradeep, Vangala G., Savojardo, Castrense, Schols, Peter, Shen, Yang, Sivadasan, Naveen, Smedley, Damian, Soru, Dorian, Srinivasan, Rajgopal, Sun, Yuanfei, Sunderam, Uma, Tan, Wuwei, Tiwari, Naina, Wang, Xiao, Wang, Yaqiong, Williams, Amanda, Worthey, Elizabeth A., Yin, Rujie, You, Yuning, Zeiberg, Daniel, Zucca, Susanna, Bakolitsa, Constantina, Brenner, Steven E., Fullerton, Stephanie M., Radivojac, Predrag, Rehm, Heidi L., and O’Donnell-Luria, Anne
Published: 2024
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3. CIAO1 loss of function causes a neuromuscular disorder with compromise of nucleocytoplasmic Fe-S enzymes

Author: Maio, Nunziata, Orbach, Rotem, Zaharieva, Irina T., Topf, Ana, Donkervoort, Sandra, Munot, Pinki, Mueller, Juliane, Willis, Tracey, Verma, Sumit, Peric, Stojan, Krishnakumar, Deepa, Sudhakar, Sniya, Foley, A. Reghan, Silverstein, Sarah, Douglas, Ganka, Pais, Lynn, DiTroia, Stephanie, Grunseich, Christopher, Hu, Ying, Sewry, Caroline, Sarkozy, Anna, Straub, Volker, Muntoni, Francesco, Rouault, Tracey A., and Bonnemann, Carsten G.
Subjects: Gene mutations -- Research, Cytoplasm -- Genetic aspects -- Health aspects, Medical research, Medicine, Experimental, Neuromuscular diseases -- Causes of -- Genetic aspects, Iron proteins -- Genetic aspects -- Health aspects, Enzymes -- Genetic aspects -- Health aspects, Health care industry
Abstract: Cytoplasmic and nuclear iron-sulfur (Fe-S) enzymes that are essential for genome maintenance and replication depend on the cytoplasmic Fe-S assembly (CIA) machinery for cluster acquisition. The core of the CIA machinery consists of a complex of CIAO1, MMS19 and FAM96B. The physiological consequences of loss of function in the components of the CIA pathway have thus far remained uncharacterized. Our study revealed that patients with biallelic loss of function in CIAO1 developed proximal and axial muscle weakness, fluctuating creatine kinase elevation, and respiratory insufficiency. In addition, they presented with CNS symptoms including learning difficulties and neurobehavioral comorbidities, along with iron deposition in deep brain nuclei, mild normocytic to macrocytic anemia, and gastrointestinal symptoms. Mutational analysis revealed reduced stability of the variants compared with WT CIAO1. Functional assays demonstrated failure of the variants identified in patients to recruit Fe-S recipient proteins, resulting in compromised activities of DNA helicases, polymerases, and repair enzymes that rely on the CIA complex to acquire their Fe-S cofactors. Lentivirus-mediated restoration of CIAO1 expression reversed all patient-derived cellular abnormalities. Our study identifies CIAO1 as a human disease gene and provides insights into the broader implications of the cytosolic Fe-S assembly pathway in human health and disease., Introduction Iron-sulfur (Fe-S) clusters are ancient and evolutionarily conserved prosthetic groups with unique chemical properties that enable the proteins that contain them (Fe-S proteins) to function in several essential cellular [...]
Published: 2024
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4. Considerations for reporting variants in novel candidate genes identified during clinical genomic testing

Author: Abouhala, Siwaar, Albert, Jessica, Almalvez, Miguel, Alvarez, Raquel, Amin, Mutaz, Anderson, Peter, Aradhya, Swaroop, Ashley, Euan, Assimes, Themistocles, Auriga, Light, Austin-Tse, Christina, Bamshad, Mike, Barseghyan, Hayk, Baxter, Samantha, Behera, Sairam, Beheshti, Shaghayegh, Bejerano, Gill, Berger, Seth, Bernstein, Jon, Best, Sabrina, Blankenmeister, Benjamin, Blue, Elizabeth, Boerwinkle, Eric, Bonkowski, Emily, Bonner, Devon, Boone, Philip, Bornhorst, Miriam, Brand, Harrison, Buckingham, Kati, Calame, Daniel, Carter, Jennefer, Casadei, Silvia, Chadwick, Lisa, Chavez, Clarisa, Chen, Ziwei, Chinn, Ivan, Chong, Jessica, Coban-Akdemir, Zeynep, Cohen, Andrea J., Conner, Sarah, Conomos, Matthew, Coveler, Karen, Cui, Ya Allen, Currin, Sara, Daber, Robert, Dardas, Zain, Davis, Colleen, Dawood, Moez, de Dios, Ivan, de Esch, Celine, Delaney, Meghan, Delot, Emmanuele, DiTroia, Stephanie, Doddapaneni, Harsha, Du, Haowei, Duan, Ruizhi, Dugan-Perez, Shannon, Duong, Nhat, Duyzend, Michael, Eichler, Evan, Emami, Sara, Fraser, Jamie, Fusaro, Vincent, Galey, Miranda, Ganesh, Vijay, Garcia, Brandon, Garimella, Kiran, Gibbs, Richard, Gifford, Casey, Ginsburg, Amy, Goddard, Page, Gogarten, Stephanie, Gogate, Nikhita, Gordon, William, Gorzynski, John E., Greenleaf, William, Grochowski, Christopher, Groopman, Emily, Sousa, Rodrigo Guarischi, Gudmundsson, Sanna, Gulati, Ashima, Hall, Stacey, Harvey, William, Hawley, Megan, Heavner, Ben, Horike-Pyne, Martha, Hu, Jianhong, Huang, Yongqing, Hwang, James, Jarvik, Gail, Jensen, Tanner, Jhangiani, Shalini, Jimenez-Morales, David, Jin, Christopher, Saad, Ahmed K., Kahn-Kirby, Amanda, Kain, Jessica, Kaur, Parneet, Keehan, Laura, Knoblach, Susan, Ko, Arthur, Kundaje, Anshul, Kundu, Soumya, Lancaster, Samuel M., Larsson, Katie, Lee, Arthur, Lemire, Gabrielle, Lewis, Richard, Li, Wei, Li, Yidan, Liu, Pengfei, LoTempio, Jonathan, Lupski, James (Jim), Ma, Jialan, MacArthur, Daniel, Mahmoud, Medhat, Malani, Nirav, Mangilog, Brian, Marafi, Dana, Marmolejos, Sofia, Marten, Daniel, Martinez, Eva, Marvin, Colby, Marwaha, Shruti, Mastrorosa, Francesco Kumara, Matalon, Dena, May, Susanne, McGee, Sean, Meador, Lauren, Mefford, Heather, Mendez, Hector Rodrigo, Miller, Alexander, Miller, Danny E., Mitani, Tadahiro, Montgomery, Stephen, Moyses, Mariana, Munderloh, Chloe, Muzny, Donna, Nelson, Sarah, Nguyen, Thuy-mi P., Nguyen, Jonathan, Nussbaum, Robert, Nykamp, Keith, O'Callaghan, William, O'Heir, Emily, O'Leary, Melanie, Olsen, Jeren, Osei-Owusu, Ikeoluwa, O'Donnell-Luria, Anne, Padhi, Evin, Pais, Lynn, Pan, Miao, Panchal, Piyush, Patterson, Karynne, Payne, Sheryl, Pehlivan, Davut, Petrowski, Paul, Pham, Alicia, Pitsava, Georgia, Podesta, Astaria`Sara, Ponce, Sarah, Porter, Elizabeth, Posey, Jennifer, Prosser, Jaime, Quertermous, Thomas, Rai, Archana, Ramani, Arun, Rehm, Heidi, Reuter, Chloe, Reuter, Jason, Richardson, Matthew, Rivera-Munoz, Andres, Rubio, Oriane, Sabo, Aniko, Salani, Monica, Samocha, Kaitlin, Sanchis-Juan, Alba, Savage, Sarah, Scott, Evette, Scott, Stuart, Sedlazeck, Fritz, Shah, Gulalai, Shojaie, Ali, Singh, Mugdha, Smith, Kevin, Smith, Josh, Snow, Hana, Snyder, Michael, Socarras, Kayla, Starita, Lea, Stark, Brigitte, Stenton, Sarah, Stergachis, Andrew, Stilp, Adrienne, Sutton, V. Reid, Tai, Jui-Cheng, Talkowski, Michael (Mike), Tise, Christina, Tong, Catherine (Cat), Tsao, Philip, Ungar, Rachel, VanNoy, Grace, Vilain, Eric, Voutos, Isabella, Walker, Kim, Wei, Chia-Lin, Weisburd, Ben, Weiss, Jeff, Wellington, Chris, Weng, Ziming, Westheimer, Emily, Wheeler, Marsha, Wheeler, Matthew, Wiel, Laurens, Wilson, Michael, Wojcik, Monica, Wong, Quenna, Xiao, Changrui, Yadav, Rachita, Yi, Qian, Yuan, Bo, Zhao, Jianhua, Zhen, Jimmy, Zhou, Harry, Chong, Jessica X., Berger, Seth I., Smith, Erica, Calame, Daniel G., Hawley, Megan H., Rivera-Munoz, E. Andres, Bamshad, Michael J., and Rehm, Heidi L.
Published: 2024
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5. Exome copy number variant detection, analysis, and classification in a large cohort of families with undiagnosed rare genetic disease

Author: Lemire, Gabrielle, Sanchis-Juan, Alba, Russell, Kathryn, Baxter, Samantha, Chao, Katherine R., Singer-Berk, Moriel, Groopman, Emily, Wong, Isaac, England, Eleina, Goodrich, Julia, Pais, Lynn, Austin-Tse, Christina, DiTroia, Stephanie, O’Heir, Emily, Ganesh, Vijay S., Wojcik, Monica H., Evangelista, Emily, Snow, Hana, Osei-Owusu, Ikeoluwa, Fu, Jack, Singh, Mugdha, Mostovoy, Yulia, Huang, Steve, Garimella, Kiran, Kirkham, Samantha L., Neil, Jennifer E., Shao, Diane D., Walsh, Christopher A., Argilli, Emanuela, Le, Carolyn, Sherr, Elliott H., Gleeson, Joseph G., Shril, Shirlee, Schneider, Ronen, Hildebrandt, Friedhelm, Sankaran, Vijay G., Madden, Jill A., Genetti, Casie A., Beggs, Alan H., Agrawal, Pankaj B., Bujakowska, Kinga M., Place, Emily, Pierce, Eric A., Donkervoort, Sandra, Bönnemann, Carsten G., Gallacher, Lyndon, Stark, Zornitza, Tan, Tiong Yang, White, Susan M., Töpf, Ana, Straub, Volker, Fleming, Mark D., Pollak, Martin R., Õunap, Katrin, Pajusalu, Sander, Donald, Kirsten A., Bruwer, Zandre, Ravenscroft, Gianina, Laing, Nigel G., MacArthur, Daniel G., Rehm, Heidi L., Talkowski, Michael E., Brand, Harrison, and O’Donnell-Luria, Anne
Published: 2024
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6. Heterozygous loss-of-function SMC3 variants are associated with variable growth and developmental features

Author: Ansari, Morad, Faour, Kamli N.W., Shimamura, Akiko, Grimes, Graeme, Kao, Emeline M., Denhoff, Erica R., Blatnik, Ana, Ben-Isvy, Daniel, Wang, Lily, Helm, Benjamin M., Firth, Helen, Breman, Amy M., Bijlsma, Emilia K., Iwata-Otsubo, Aiko, de Ravel, Thomy J.L., Fusaro, Vincent, Fryer, Alan, Nykamp, Keith, Stühn, Lara G., Haack, Tobias B., Korenke, G. Christoph, Constantinou, Panayiotis, Bujakowska, Kinga M., Low, Karen J., Place, Emily, Humberson, Jennifer, Napier, Melanie P., Hoffman, Jessica, Juusola, Jane, Deardorff, Matthew A., Shao, Wanqing, Rockowitz, Shira, Krantz, Ian, Kaur, Maninder, Raible, Sarah, Dortenzio, Victoria, Kliesch, Sabine, Singer-Berk, Moriel, Groopman, Emily, DiTroia, Stephanie, Ballal, Sonia, Srivastava, Siddharth, Rothfelder, Kathrin, Biskup, Saskia, Rzasa, Jessica, Kerkhof, Jennifer, McConkey, Haley, Sadikovic, Bekim, Hilton, Sarah, Banka, Siddharth, Tüttelmann, Frank, Conrad, Donald F., O’Donnell-Luria, Anne, Talkowski, Michael E., FitzPatrick, David R., and Boone, Philip M.
Published: 2024
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7. Beyond the exome: What’s next in diagnostic testing for Mendelian conditions

Author: Abouhala, Siwaar, Albert, Jessica, Almalvez, Miguel, Alvarez, Raquel, Amin, Mutaz, Anderson, Peter, Aradhya, Swaroop, Ashley, Euan, Assimes, Themistocles, Auriga, Light, Austin-Tse, Christina, Bamshad, Mike, Barseghyan, Hayk, Baxter, Samantha, Behera, Sairam, Beheshti, Shaghayegh, Bejerano, Gill, Berger, Seth, Bernstein, Jon, Best, Sabrina, Blankenmeister, Benjamin, Blue, Elizabeth, Boerwinkle, Eric, Bonkowski, Emily, Bonner, Devon, Boone, Philip, Bornhorst, Miriam, Bozkurt-Yozgatli, Tugce, Brand, Harrison, Buckingham, Kati, Calame, Daniel, Casadei, Silvia, Chadwick, Lisa, Chavez, Clarisa, Chen, Ziwei, Chinn, Ivan, Chong, Jessica, Coban-Akdemir, Zeynep, Cohen, Andrea J., Conner, Sarah, Conomos, Matthew, Coveler, Karen, Cui, Ya Allen, Currin, Sara, Daber, Robert, Dardas, Zain, Davis, Colleen, Dawood, Moez, de Dios, Ivan, de Esch, Celine, Delaney, Meghan, Délot, Emmanuèle, DiTroia, Stephanie, Doddapaneni, Harsha, Du, Haowei, Duan, Ruizhi, Dugan-Perez, Shannon, Duong, Nhat, Duyzend, Michael, Eichler, Evan, Emami, Sara, Fatih, Jawid, Fraser, Jamie, Fusaro, Vincent, Galey, Miranda, Ganesh, Vijay, Garimella, Kiran, Gibbs, Richard, Gifford, Casey, Ginsburg, Amy, Goddard, Pagé, Gogarten, Stephanie, Gogate, Nikhita, Gordon, William, Gorzynski, John E., Greenleaf, William, Grochowski, Christopher, Groopman, Emily, Guarischi Sousa, Rodrigo, Gudmundsson, Sanna, Gulati, Ashima, Guo, Daniel, Hale, Walker, Hall, Stacey, Harvey, William, Hawley, Megan, Heavner, Ben, Herman, Isabella, Horike-Pyne, Martha, Hu, Jianhong, Huang, Yongqing, Hwang, James, Jarvik, Gail, Jensen, Tanner, Jhangiani, Shalini, Jimenez-Morales, David, Jin, Christopher, Saad, Ahmed K., Kahn-Kirby, Amanda, Kain, Jessica, Kaur, Parneet, Keehan, Laura, Knoblach, Susan, Ko, Arthur, Kohler, Jennefer, Kundaje, Anshul, Kundu, Soumya, Lancaster, Samuel M., Larsson, Katie, Lemire, Gabrielle, Lewis, Richard, Li, Wei, Li, Yidan, Liu, Pengfei, LoTempio, Jonathan, Lupski, James, Ma, Jialan, MacArthur, Daniel, Mahmoud, Medhat, Malani, Nirav, Mangilog, Brian, Marafi, Dana, Marmolejos, Sofia, Marten, Daniel, Martinez, Eva, Marvin, Colby, Marwaha, Shruti, Kumara Mastrorosa, Francesco, Matalon, Dena, May, Susanne, McGee, Sean, Meador, Lauren, Mefford, Heather, Rodrigo Mendez, Hector, Miller, Alexander, Miller, Danny E., Mitani, Tadahiro, Montgomery, Stephen, Moussa, Hala Mohamed, Moyses, Mariana, Munderloh, Chloe, Muzny, Donna, Nelson, Sarah, Neu, Matthew B., Nguyen, Jonathan, Nguyen, Thuy-mi P., Nussbaum, Robert, Nykamp, Keith, O'Callaghan, William, O'Heir, Emily, O'Leary, Melanie, Olsen, Jeren, Osei-Owusu, Ikeoluwa, O'Donnell-Luria, Anne, Padhi, Evin, Pais, Lynn, Pan, Miao, Panchal, Piyush, Patterson, Karynne, Payne, Sheryl, Pehlivan, Davut, Petrowski, Paul, Pham, Alicia, Pitsava, Georgia, Podesta, Astaria, Ponce, Sarah, Posey, Jennifer, Prosser, Jaime, Quertermous, Thomas, Rai, Archana, Ramani, Arun, Rehm, Heidi, Reuter, Chloe, Reuter, Jason, Richardson, Matthew, Rivera-Munoz, Andres, Rubio, Oriane, Sabo, Aniko, Salani, Monica, Samocha, Kaitlin, Sanchis-Juan, Alba, Savage, Sarah, Scott, Stuart, Scott, Evette, Sedlazeck, Fritz, Shah, Gulalai, Shojaie, Ali, Singh, Mugdha, Smith, Josh, Smith, Kevin, Snow, Hana, Snyder, Michael, Socarras, Kayla, Starita, Lea, Stark, Brigitte, Stenton, Sarah, Stergachis, Andrew, Stilp, Adrienne, Sundaram, Laksshman, Sutton, V. Reid, Tai, Jui-Cheng, Talkowski, Michael, Tise, Christina, Tong, Catherine, Tsao, Philip, Ungar, Rachel, VanNoy, Grace, Vilain, Eric, Voutos, Isabella, Walker, Kim, Weisburd, Ben, Weiss, Jeff, Wellington, Chris, Weng, Ziming, Westheimer, Emily, Wheeler, Marsha, Wheeler, Matthew, Wiel, Laurens, Wilson, Michael, Wojcik, Monica, Wong, Quenna, Wong, Issac, Xiao, Changrui, Yadav, Rachita, Yi, Qian, Yuan, Bo, Zhao, Jianhua, Zhen, Jimmy, Zhou, Harry, Wojcik, Monica H., Reuter, Chloe M., Duyzend, Michael H., Boone, Philip M., Groopman, Emily E., Délot, Emmanuèle C., Jain, Deepti, Starita, Lea M., Montgomery, Stephen B., Bamshad, Michael J., Chong, Jessica X., Wheeler, Matthew T., Berger, Seth I., and Sedlazeck, Fritz J.
Published: 2023
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8. Genome Sequencing for Diagnosing Rare Diseases

Author: Wojcik, Monica H., primary, Lemire, Gabrielle, additional, Berger, Eva, additional, Zaki, Maha S., additional, Wissmann, Mariel, additional, Win, Wathone, additional, White, Susan M., additional, Weisburd, Ben, additional, Wieczorek, Dagmar, additional, Waddell, Leigh B., additional, Verboon, Jeffrey M., additional, VanNoy, Grace E., additional, Töpf, Ana, additional, Tan, Tiong Yang, additional, Syrbe, Steffen, additional, Strehlow, Vincent, additional, Straub, Volker, additional, Stenton, Sarah L., additional, Snow, Hana, additional, Singer-Berk, Moriel, additional, Silver, Josh, additional, Shril, Shirlee, additional, Seaby, Eleanor G., additional, Schneider, Ronen, additional, Sankaran, Vijay G., additional, Sanchis-Juan, Alba, additional, Russell, Kathryn A., additional, Reinson, Karit, additional, Ravenscroft, Gianina, additional, Radtke, Maximilian, additional, Popp, Denny, additional, Polster, Tilman, additional, Platzer, Konrad, additional, Pierce, Eric A., additional, Place, Emily M., additional, Pajusalu, Sander, additional, Pais, Lynn, additional, Õunap, Katrin, additional, Osei-Owusu, Ikeoluwa, additional, Opperman, Henry, additional, Okur, Volkan, additional, Oja, Kaisa Teele, additional, O’Leary, Melanie, additional, O’Heir, Emily, additional, Morel, Chantal F., additional, Merkenschlager, Andreas, additional, Marchant, Rhett G., additional, Mangilog, Brian E., additional, Madden, Jill A., additional, MacArthur, Daniel, additional, Lovgren, Alysia, additional, Lerner-Ellis, Jordan P., additional, Lin, Jasmine, additional, Laing, Nigel, additional, Hildebrandt, Friedhelm, additional, Hentschel, Julia, additional, Groopman, Emily, additional, Goodrich, Julia, additional, Gleeson, Joseph G., additional, Ghaoui, Roula, additional, Genetti, Casie A., additional, Gburek-Augustat, Janina, additional, Gazda, Hanna T., additional, Ganesh, Vijay S., additional, Ganapathi, Mythily, additional, Gallacher, Lyndon, additional, Fu, Jack M., additional, Evangelista, Emily, additional, England, Eleina, additional, Donkervoort, Sandra, additional, DiTroia, Stephanie, additional, Cooper, Sandra T., additional, Chung, Wendy K., additional, Christodoulou, John, additional, Chao, Katherine R., additional, Cato, Liam D., additional, Bujakowska, Kinga M., additional, Bryen, Samantha J., additional, Brand, Harrison, additional, Bönnemann, Carsten G., additional, Beggs, Alan H., additional, Baxter, Samantha M., additional, Bartolomaeus, Tobias, additional, Agrawal, Pankaj B., additional, Talkowski, Michael, additional, Austin-Tse, Christina, additional, Abou Jamra, Rami, additional, Rehm, Heidi L., additional, and O’Donnell-Luria, Anne, additional
Published: 2024
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9. Maternal vitamin C regulates reprogramming of DNA methylation and germline development

Author: DiTroia, Stephanie P, Percharde, Michelle, Guerquin, Marie-Justine, Wall, Estelle, Collignon, Evelyne, Ebata, Kevin T, Mesh, Kathryn, Mahesula, Swetha, Agathocleous, Michalis, Laird, Diana J, Livera, Gabriel, and Ramalho-Santos, Miguel
Subjects: Reproductive Medicine, Biomedical and Clinical Sciences, Genetics, Biological Sciences, Nutrition, Pediatric, Stem Cell Research, 1.1 Normal biological development and functioning, Underpinning research, Generic health relevance, Reproductive health and childbirth, Animals, Ascorbic Acid, Ascorbic Acid Deficiency, Cell Count, DNA Methylation, DNA-Binding Proteins, Epigenomics, Female, Germ Cells, Loss of Function Mutation, Meiosis, Mice, Models, Animal, Pregnancy, Proto-Oncogene Proteins, Transcriptome, General Science & Technology
Abstract: Development is often assumed to be hardwired in the genome, but several lines of evidence indicate that it is susceptible to environmental modulation with potential long-term consequences, including in mammals1,2. The embryonic germline is of particular interest because of the potential for intergenerational epigenetic effects. The mammalian germline undergoes extensive DNA demethylation3-7 that occurs in large part by passive dilution of methylation over successive cell divisions, accompanied by active DNA demethylation by TET enzymes3,8-10. TET activity has been shown to be modulated by nutrients and metabolites, such as vitamin C11-15. Here we show that maternal vitamin C is required for proper DNA demethylation and the development of female fetal germ cells in a mouse model. Maternal vitamin C deficiency does not affect overall embryonic development but leads to reduced numbers of germ cells, delayed meiosis and reduced fecundity in adult offspring. The transcriptome of germ cells from vitamin-C-deficient embryos is remarkably similar to that of embryos carrying a null mutation in Tet1. Vitamin C deficiency leads to an aberrant DNA methylation profile that includes incomplete demethylation of key regulators of meiosis and transposable elements. These findings reveal that deficiency in vitamin C during gestation partially recapitulates loss of TET1, and provide a potential intergenerational mechanism for adjusting fecundity to environmental conditions.
Published: 2019

10. De novoAHDC1 Deletions Identified by Genome Sequencing in Two Individuals with Xia-Gibbs Syndrome.

Author: Bertrand, Miriam, Shah, Gulalai, Pedersen, Brent S., Schulz, Alexander, Weise, Anja, Liehr, Thomas, Huppke, Peter, DiTroia, Stephanie, Quinlan, Aaron R., Haack, Tobias B., and Husain, Ralf A.
Published: 2024
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11. Biallelic loss-of-function variants in WDR11 are associated with microcephaly and intellectual disability

Author: Haag, Natja, Tan, Ene-Choo, Begemann, Matthias, Buschmann, Lars, Kraft, Florian, Holschbach, Petra, Lai, Angeline H. M., Brett, Maggie, Mochida, Ganeshwaran H., DiTroia, Stephanie, Pais, Lynn, Neil, Jennifer E., Al-Saffar, Muna, Bastaki, Laila, Walsh, Christopher A., Kurth, Ingo, and Knopp, Cordula
Published: 2021
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12. Loss of Function of the Cytoplasmic Fe-S Assembly Protein CIAO1 Causes a Neuromuscular Disorder with Compromise of Nucleocytoplasmic Fe-S Enzymes

Author: Maio, Nunziata, primary, Orbach, Rotem, additional, Zaharieva, Irina, additional, Töpf, Ana, additional, Donkervoort, Sandra, additional, Munot, Pinki, additional, Mueller, Juliane, additional, Willis, Tracey, additional, Verma, Sumit, additional, Peric, Stojan, additional, Krishnakumar, Deepa, additional, Sudhakar, Sniya, additional, Foley, Aileen Reghan, additional, Silverstein, Sarah, additional, Douglas, Ganka, additional, Pais, Lynn, additional, DiTroia, Stephanie, additional, Grunseich, Christopher, additional, Hu, Ying, additional, Sewry, Caroline, additional, Sarkozy, Anna, additional, Straub, Volker, additional, Muntoni, Francesco, additional, Rouault, Tracey, additional, and Bönnemann, Carsten Gerhart, additional
Published: 2023
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13. Exome copy number variant detection, analysis and classification in a large cohort of families with undiagnosed rare genetic disease

Author: Lemire, Gabrielle, primary, Sanchis-Juan, Alba, additional, Russell, Kathryn, additional, Baxter, Samantha, additional, Chao, Katherine R., additional, Singer-Berk, Moriel, additional, Groopman, Emily, additional, Wong, Isaac, additional, England, Eleina, additional, Goodrich, Julia, additional, Pais, Lynn, additional, Austin-Tse, Christina, additional, DiTroia, Stephanie, additional, O’Heir, Emily, additional, Ganesh, Vijay S., additional, Wojcik, Monica H., additional, Evangelista, Emily, additional, Snow, Hana, additional, Osei-Owusu, Ikeoluwa, additional, Fu, Jack, additional, Singh, Mugdha, additional, Mostovoy, Yulia, additional, Huang, Steve, additional, Garimella, Kiran, additional, Kirkham, Samantha L., additional, Neil, Jennifer E., additional, Shao, Diane D., additional, Walsh, Christopher A., additional, Argili, Emanuela, additional, Le, Carolyn, additional, Sherr, Elliott H., additional, Gleeson, Joseph, additional, Shril, Shirlee, additional, Schneider, Ronen, additional, Hildebrandt, Friedhelm, additional, Sankaran, Vijay G., additional, Madden, Jill A., additional, Genetti, Casie A., additional, Beggs, Alan H., additional, Agrawal, Pankaj B., additional, Bujakowska, Kinga M., additional, Place, Emily, additional, Pierce, Eric A., additional, Donkervoort, Sandra, additional, Bönnemann, Carsten G., additional, Gallacher, Lyndon, additional, Stark, Zornitza, additional, Tan, Tiong, additional, White, Susan M., additional, Töpf, Ana, additional, Straub, Volker, additional, Fleming, Mark D., additional, Pollak, Martin R., additional, Õunap, Katrin, additional, Pajusalu, Sander, additional, Donald, Kirsten A., additional, Bruwer, Zandre, additional, Ravenscroft, Gianina, additional, Laing, Nigel G., additional, MacArthur, Daniel G., additional, Rehm, Heidi L., additional, Talkowski, Michael E., additional, Brand, Harrison, additional, and O’Donnell-Luria, Anne, additional
Published: 2023
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14. Heterozygous loss-of-functionSMC3variants are associated with variable and incompletely penetrant growth and developmental features

Author: Ansari, Morad, primary, Faour, Kamli N. W., additional, Shimamura, Akiko, additional, Grimes, Graeme, additional, Kao, Emeline M., additional, Denhoff, Erica R., additional, Blatnik, Ana, additional, Ben-Isvy, Daniel, additional, Wang, Lily, additional, Helm, Benjamin M., additional, Firth, Helen, additional, Breman, Amy M., additional, Bijlsma, Emilia K., additional, Iwata-Otsubo, Aiko, additional, de Ravel, Thomy J.L., additional, Fusaro, Vincent, additional, Fryer, Alan, additional, Nykamp, Keith, additional, Stuhn, Lara G., additional, Haack, Tobias B., additional, Korenke, G. Christoph, additional, Constantinou, Panayiotis, additional, Bujakowska, Kinga M., additional, Low, Karen J., additional, Place, Emily, additional, Humberson, Jennifer, additional, Napier, Melanie P., additional, Hoffman, Jessica, additional, Juusola, Jane, additional, Deardorff, Matthew A., additional, Shao, Wanqing, additional, Rockowitz, Shira, additional, Krantz, Ian, additional, Kaur, Maninder, additional, Raible, Sarah, additional, Kliesch, Sabine, additional, Singer-Berk, Moriel, additional, Groopman, Emily, additional, DiTroia, Stephanie, additional, Ballal, Sonia, additional, Srivastava, Siddharth, additional, Rothfelder, Kathrin, additional, Biskup, Saskia, additional, Rzasa, Jessica, additional, Kerkhof, Jennifer, additional, McConkey, Haley, additional, O'Donnell-Luria, Anne, additional, Sadikovic, Bekim, additional, Hilton, Sarah, additional, Banka, Siddharth, additional, Tuttelmann, Frank, additional, Conrad, Donald F., additional, Talkowski, Michael E., additional, FitzPatrick, David R., additional, and Boone, Philip M., additional
Published: 2023
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15. Unique Capabilities of Genome Sequencing for Rare Disease Diagnosis

Author: Wojcik, Monica H, primary, Lemire, Gabrielle, additional, Zaki, Maha S, additional, Wissmann, Mariel, additional, Win, Wathone, additional, White, Sue, additional, Weisburd, Ben, additional, Waddell, Leigh B, additional, Verboon, Jeffrey M, additional, VanNoy, Grace E, additional, Topf, Ana, additional, Tan, Tiong Yang, additional, Straub, Volker, additional, Stenton, Sarah L, additional, Snow, Hana, additional, Singer-Berk, Moriel, additional, Silver, Josh, additional, Shril, Shirlee, additional, Seaby, Eleanor G, additional, Schneider, Ronen, additional, Sankaran, Vijay G, additional, Sanchis-Juan, Alba, additional, Russell, Kathryn A, additional, Reinson, Karit, additional, Ravenscroft, Gina, additional, Pierce, Eric A, additional, Place, Emily M, additional, Pajusalu, Sander, additional, Pais, Lynn, additional, Ounap, Katrin, additional, Osei-Owusu, Ikeoluwa, additional, Okur, Volkan, additional, Oja, Kaisa Teele, additional, OLeary, Melanie, additional, OHeir, Emily, additional, Morel, Chantal, additional, Marchant, Rhett G, additional, Mangilog, Brian E, additional, Madden, Jill A, additional, MacArthur, Daniel, additional, Lovgren, Alysia, additional, Lerner-Ellis, Jordan P, additional, Lin, Jasmine, additional, Laing, Nigel, additional, Hildebrandt, Friedhelm, additional, Groopman, Emily, additional, Goodrich, Julia, additional, Gleeson, Joseph G, additional, Ghaoui, Roula, additional, Genetti, Casie A, additional, Gazda, Hanna, additional, Ganesh, Vijay S, additional, Ganapathi, Mythily, additional, Gallacher, Lyndon, additional, Fu, Jack, additional, Evangelista, Emily, additional, England, Eleina, additional, Donkervoort, Sandra, additional, DiTroia, Stephanie, additional, Cooper, Sandra T, additional, Chung, Wendy K, additional, Christodoulou, John, additional, Chao, Katherine R, additional, Cato, Liam D, additional, Bujakowska, Kinga M, additional, Bryen, Samantha J, additional, Brand, Harrison, additional, Bonnemann, Carsten, additional, Beggs, Alan H, additional, Baxter, Samantha M, additional, Agrawal, Pankaj B, additional, Talkowski, Michael, additional, Austin-Tse, Christina, additional, Rehm, Heidi L, additional, and ODonnell-Luria, Anne, additional
Published: 2023
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16. Critical assessment of variant prioritization methods for rare disease diagnosis within the Rare Genomes Project

Author: Stenton, Sarah L., primary, O’Leary, Melanie, additional, Lemire, Gabrielle, additional, VanNoy, Grace E., additional, DiTroia, Stephanie, additional, Ganesh, Vijay S., additional, Groopman, Emily, additional, O’Heir, Emily, additional, Mangilog, Brian, additional, Osei-Owusu, Ikeoluwa, additional, Pais, Lynn S., additional, Serrano, Jillian, additional, Singer-Berk, Moriel, additional, Weisburd, Ben, additional, Wilson, Michael, additional, Austin-Tse, Christina, additional, Abdelhakim, Marwa, additional, Althagafi, Azza, additional, Babbi, Giulia, additional, Bellazzi, Riccardo, additional, Bovo, Samuele, additional, Carta, Maria Giulia, additional, Casadio, Rita, additional, Coenen, Pieter-Jan, additional, De Paoli, Federica, additional, Floris, Matteo, additional, Gajapathy, Manavalan, additional, Hoehndorf, Robert, additional, Jacobsen, Julius O.B., additional, Joseph, Thomas, additional, Kamandula, Akash, additional, Katsonis, Panagiotis, additional, Kint, Cyrielle, additional, Lichtarge, Olivier, additional, Limongelli, Ivan, additional, Lu, Yulan, additional, Magni, Paolo, additional, Mamidi, Tarun Karthik Kumar, additional, Martelli, Pier Luigi, additional, Mulargia, Marta, additional, Nicora, Giovanna, additional, Nykamp, Keith, additional, Pejaver, Vikas, additional, Peng, Yisu, additional, Pham, Thi Hong Cam, additional, Podda, Maurizio S., additional, Rao, Aditya, additional, Rizzo, Ettore, additional, Saipradeep, Vangala G, additional, Savojardo, Castrense, additional, Schols, Peter, additional, Shen, Yang, additional, Sivadasan, Naveen, additional, Smedley, Damian, additional, Soru, Dorian, additional, Srinivasan, Rajgopal, additional, Sun, Yuanfei, additional, Sunderam, Uma, additional, Tan, Wuwei, additional, Tiwari, Naina, additional, Wang, Xiao, additional, Wang, Yaqiong, additional, Williams, Amanda, additional, Worthey, Elizabeth A., additional, Yin, Rujie, additional, You, Yuning, additional, Zeiberg, Daniel, additional, Zucca, Susanna, additional, Bakolitsa, Constantina, additional, Brenner, Steven E., additional, Fullerton, Stephanie M, additional, Radivojac, Predrag, additional, Rehm, Heidi L., additional, and O’Donnell-Luria, Anne, additional
Published: 2023
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17. Loss-of-function variants inCUL3cause a syndromic neurodevelopmental disorder

Author: Blackburn, Patrick R., primary, Ebstein, Frédéric, additional, Hsieh, Tzung-Chien, additional, Motta, Marialetizia, additional, Radio, Francesca Clementina, additional, Herkert, Johanna C., additional, Rinne, Tuula, additional, Thiffault, Isabelle, additional, Rapp, Michele, additional, Alders, Mariel, additional, Maas, Saskia, additional, Gerard, Bénédicte, additional, Smol, Thomas, additional, Vincent-Delorme, Catherine, additional, Cogné, Benjamin, additional, Isidor, Bertrand, additional, Vincent, Marie, additional, Bachmann-Gagescu, Ruxandra, additional, Rauch, Anita, additional, Joset, Pascal, additional, Ferrero, Giovanni Battista, additional, Ciolfi, Andrea, additional, Husson, Thomas, additional, Guerrot, Anne-Marie, additional, Bacino, Carlos, additional, Macmurdo, Colleen, additional, Thompson, Stephanie S., additional, Rosenfeld, Jill A., additional, Faivre, Laurence, additional, Mau-Them, Frederic Tran, additional, Deb, Wallid, additional, Vignard, Virginie, additional, Agrawal, Pankaj B., additional, Madden, Jill A., additional, Goldenberg, Alice, additional, Lecoquierre, François, additional, Zech, Michael, additional, Prokisch, Holger, additional, Necpál, Ján, additional, Jech, Robert, additional, Winkelmann, Juliane, additional, Koprušáková, Monika Turčanová, additional, Konstantopoulou, Vassiliki, additional, Younce, John R., additional, Shinawi, Marwan, additional, Mighton, Chloe, additional, Fung, Charlotte, additional, Morel, Chantal, additional, Ellis, Jordan Lerner-, additional, DiTroia, Stephanie, additional, Barth, Magalie, additional, Bonneau, Dominique, additional, Krapels, Ingrid, additional, Stegmann, Sander, additional, Schoot, Vyne van der, additional, Brunet, Theresa, additional, Bußmann, Cornelia, additional, Mignot, Cyril, additional, Courtin, Thomas, additional, Ravelli, Claudia, additional, Keren, Boris, additional, Ziegler, Alban, additional, Hasadsri, Linda, additional, Pichurin, Pavel N., additional, Klee, Eric W., additional, Grand, Katheryn, additional, Sanchez-Lara, Pedro A., additional, Krüger, Elke, additional, Bézieau, Stéphane, additional, Klinkhammer, Hannah, additional, Krawitz, Peter Michael, additional, Eichler, Evan E., additional, Tartaglia, Marco, additional, Küry, Sébastien, additional, and Wang, Tianyun, additional
Published: 2023
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18. P575: The Rare Genomes Project: Improving access to genomic sequencing and identifying causes of rare disease*

Author: Austin-Tse, Christina, DiTroia, Stephanie, O'Leary, Melanie, VanNoy, Grace, Mangilog, Brian, Shah, Gulalai, Martinez, Eva, Serrano, Jillian, Pais, Lynn, O'Heir, Emily, Osei-Owusu, Ikeoluwa, Lemire, Gabrielle, Ganesh, Vijay, Stenton, Sarah, Amin, Mutaz, Socarras, Kayla, Singh, Mugdha, Hall, Stacey, Larsson, Katie, Singer-Berk, Moriel, Marten, Daniel, Wilson, Michael, Snow, Hana, Blankenmeister, Benjamin, Ma, Jialan, Weisburd, Ben, Sanchis-Juan, Alba, Brand, Harrison, Groopman, Emily, Lovgren, Alysia, Williamson, Clara, Hollyer, Marissa, England, Eleina, Seaby, Eleanor, Chao, Katherine, Goodrich, Julia, Baxter, Samantha, MacArthur, Daniel, Talkowski, Michael, Wojcik, Monica, O'Donnell-Luria, Anne, and Rehm, Heidi
Published: 2024
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19. Loss-of-function variants in CUL3 cause a syndromic neurodevelopmental disorder

Author: Blackburn, Patrick R., Ebstein, Frédéric, Hsieh, Tzung-Chien, Motta, Marialetizia, Radio, Francesca Clementina, Herkert, Johanna C., Rinne, Tuula, Thiffault, Isabelle, Rapp, Michele, Alders, Mariel, Maas, Saskia, Gerard, Bénédicte, Smol, Thomas, Vincent-Delorme, Catherine, Cogné, Benjamin, Isidor, Bertrand, Vincent, Marie, Bachmann-Gagescu, Ruxandra, Rauch, Anita, Joset, Pascal, Ferrero, Giovanni Battista, Ciolfi, Andrea, Husson, Thomas, Guerrot, Anne-Marie, Bacino, Carlos, Macmurdo, Colleen, Thompson, Stephanie S., Rosenfeld, Jill A., Faivre, Laurence, Mau-Them, Frederic Tran, Deb, Wallid, Vignard, Virginie, Agrawal, Pankaj B., Madden, Jill A., Goldenberg, Alice, Lecoquierre, François, Zech, Michael, Prokisch, Holger, Necpál, Ján, Jech, Robert, Winkelmann, Juliane, Koprušáková, Monika Turčanová, Konstantopoulou, Vassiliki, Younce, John R., Shinawi, Marwan, Mighton, Chloe, Fung, Charlotte, Morel, Chantal, Ellis, Jordan Lerner, DiTroia, Stephanie, Barth, Magalie, Bonneau, Dominique, Krapels, Ingrid, Stegmann, Sander, van der Schoot, Vyne, Brunet, Theresa, Bußmann, Cornelia, Mignot, Cyril, Courtin, Thomas, Ravelli, Claudia, Keren, Boris, Ziegler, Alban, Hasadsri, Linda, Pichurin, Pavel N., Klee, Eric W., Grand, Katheryn, Sanchez-Lara, Pedro A., Krüger, Elke, Bézieau, Stéphane, Klinkhammer, Hannah, Krawitz, Peter Michael, Eichler, Evan E., Tartaglia, Marco, Küry, Sébastien, and Wang, Tianyun
Subjects: Article
Abstract: PURPOSE: De novo variants in CUL3 (Cullin-3 ubiquitin ligase) have been strongly associated with neurodevelopmental disorders (NDDs), but no large case series have been reported so far. Here we aimed to collect sporadic cases carrying rare variants in CUL3, describe the genotype-phenotype correlation, and investigate the underlying pathogenic mechanism. METHODS: Genetic data and detailed clinical records were collected via multi-center collaboration. Dysmorphic facial features were analyzed using GestaltMatcher. Variant effects on CUL3 protein stability were assessed using patient-derived T-cells. RESULTS: We assembled a cohort of 35 individuals with heterozygous CUL3 variants presenting a syndromic NDD characterized by intellectual disability with or without autistic features. Of these, 33 have loss-of-function (LoF) and two have missense variants. CUL3 LoF variants in patients may affect protein stability leading to perturbations in protein homeostasis, as evidenced by decreased ubiquitin-protein conjugates in vitro . Specifically, we show that cyclin E1 (CCNE1) and 4E-BP1 (EIF4EBP1), two prominent substrates of CUL3, fail to be targeted for proteasomal degradation in patient-derived cells. CONCLUSION: Our study further refines the clinical and mutational spectrum of CUL3 -associated NDDs, expands the spectrum of cullin RING E3 ligase-associated neuropsychiatric disorders, and suggests haploinsufficiency via LoF variants is the predominant pathogenic mechanism.
Published: 2023

20. Exome Sequencing and the Identification of New Genes and Shared Mechanisms in Polymicrogyria

Author: Akula, Shyam S.K., Chen, Allen A.Y., Neil, Jennifer J.E., Shao, Diane D.D., Mo, Alisa, Hylton, Norma N.K., DiTroia, Stephanie S.P., Ganesh, Vijay, Smith, Richard R.S., O'Kane, Katherine, Yeh, Rebecca R.C., Marciano, Jack J.H., Kirkham, Samantha, Kenny, Connor C.J., Song, Janet J.H.T., Al Saffar, Muna, Millan, Francisca, Harris, David D.J., Murphy, Andrea A.V., Klemp, Kara K.C., Braddock, Stephen S.R., Brand, Harrison, Wong, Isaac, Talkowski, Michael M.E., O'Donnell-Luria, Anne, Lai, Abbe, Hill, Robert Sean, Mochida, Ganeshwaran G.H., Doan, Ryan R.N., Barkovich, Anthony James, Yang, Edward, Amrom, Dina, Andermann, Eva, Poduri, Annapurna, Walsh, Christopher C.A., Akula, Shyam S.K., Chen, Allen A.Y., Neil, Jennifer J.E., Shao, Diane D.D., Mo, Alisa, Hylton, Norma N.K., DiTroia, Stephanie S.P., Ganesh, Vijay, Smith, Richard R.S., O'Kane, Katherine, Yeh, Rebecca R.C., Marciano, Jack J.H., Kirkham, Samantha, Kenny, Connor C.J., Song, Janet J.H.T., Al Saffar, Muna, Millan, Francisca, Harris, David D.J., Murphy, Andrea A.V., Klemp, Kara K.C., Braddock, Stephen S.R., Brand, Harrison, Wong, Isaac, Talkowski, Michael M.E., O'Donnell-Luria, Anne, Lai, Abbe, Hill, Robert Sean, Mochida, Ganeshwaran G.H., Doan, Ryan R.N., Barkovich, Anthony James, Yang, Edward, Amrom, Dina, Andermann, Eva, Poduri, Annapurna, and Walsh, Christopher C.A.
Abstract: Importance: Polymicrogyria is the most commonly diagnosed cortical malformation and is associated with neurodevelopmental sequelae including epilepsy, motor abnormalities, and cognitive deficits. Polymicrogyria frequently co-occurs with other brain malformations or as part of syndromic diseases. Past studies of polymicrogyria have defined heterogeneous genetic and nongenetic causes but have explained only a small fraction of cases. Objective: To survey germline genetic causes of polymicrogyria in a large cohort and to consider novel polymicrogyria gene associations. Design, Setting, and Participants: This genetic association study analyzed panel sequencing and exome sequencing of accrued DNA samples from a retrospective cohort of families with members with polymicrogyria. Samples were accrued over more than 20 years (1994 to 2020), and sequencing occurred in 2 stages: panel sequencing (June 2015 to January 2016) and whole-exome sequencing (September 2019 to March 2020). Individuals seen at multiple clinical sites for neurological complaints found to have polymicrogyria on neuroimaging, then referred to the research team by evaluating clinicians, were included in the study. Targeted next-generation sequencing and/or exome sequencing were performed on probands (and available parents and siblings) from 284 families with individuals who had isolated polymicrogyria or polymicrogyria as part of a clinical syndrome and no genetic diagnosis at time of referral from clinic, with sequencing from 275 families passing quality control. Main Outcomes and Measures: The number of families in whom genetic sequencing yielded a molecular diagnosis that explained the polymicrogyria in the family. Secondarily, the relative frequency of different genetic causes of polymicrogyria and whether specific genetic causes were associated with co-occurring head size changes were also analyzed. Results: In 32.7% (90 of 275) of polymicrogyria-affected families, genetic variants were identified that, SCOPUS: ar.j, info:eu-repo/semantics/published
Published: 2023

21. De novoAHDC1Deletions Identified by Genome Sequencing in Two Individuals with Xia-Gibbs Syndrome

Author: Bertrand, Miriam, Shah, Gulalai, Pedersen, Brent S., Schulz, Alexander, Weise, Anja, Liehr, Thomas, Huppke, Peter, DiTroia, Stephanie, Quinlan, Aaron R., Haack, Tobias B., and Husain, Ralf A.
Abstract: Introduction:Xia-Gibbs syndrome (XGS) is a rare syndromic disorder characterized by developmental delay with intellectual disability, muscular hypotonia, brain anomalies, and nonspecific dysmorphic features. Different heterozygous variants in AHDC1have been reported as causal for XGS, comprising mainly de novostop-gain and frameshift events, but also missense variants, deletions, and a duplication of the locus. Case Presentation:We hereby report 2 patients with clinical features of XGS. In the first patient, a de novointerstitial deletion in 1p36.11p35.3 encompassing the entire coding region of AHDC1was initially suspected by trio exome sequencing and subsequently confirmed by shallow genome sequencing. In the second patient, a de novodeletion comprising most of the 5′ untranslated region of AHDC1was detected by genome sequencing. Conclusion:We identified the smallest deletion comprising AHDC1reported so far by shallow genome sequencing as well as another small AHDC1deletion by genome sequencing. These methods represent useful techniques for the identification and confirmation of small deletions and structural variants. Furthermore, our data provide additional evidence of AHDC1haploinsufficiency as a disease mechanism in XGS. Clinically, foot deformity, skin and connective tissue abnormalities observed in one of the patients are consistent with other reported cases of XGS. These findings suggest that these manifestations could be considered as more prevalent characteristics, underscoring the importance of in-depth phenotyping. The neurodevelopmental disorder Xia-Gibbs syndrome is associated with symptoms of various organ systems. It is due to changes in the AHDC1gene. Using sophisticated genetic testing procedures, two different deletions as a particularly rare genetic cause were identified in 2 patients. Here, we provide a summary of their individual characteristics in comparison to those of other patients with similar deletions that have been reported in the literature or public databases.
Published: 2024
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22. Exome Sequencing and the Identification of New Genes and Shared Mechanisms in Polymicrogyria.

Author: Akula, Shyam K., Chen, Allen Y., Neil, Jennifer E., Shao, Diane D., Mo, Alisa, Hylton, Norma K., DiTroia, Stephanie, Ganesh, Vijay S., Smith, Richard S., O'Kane, Katherine, Yeh, Rebecca C., Marciano, Jack H., Kirkham, Samantha, Kenny, Connor J., Song, Janet H. T., Al Saffar, Muna, Millan, Francisca, Harris, David J., Murphy, Andrea V., and Klemp, Kara C.
Published: 2023
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23. Author Correction: Maternal vitamin C regulates reprogramming of DNA methylation and germline development

Author: DiTroia, Stephanie P., Percharde, Michelle, Guerquin, Marie-Justine, Wall, Estelle, Collignon, Evelyne, Ebata, Kevin T., Mesh, Kathryn, Mahesula, Swetha, Agathocleous, Michalis, Laird, Diana J., Livera, Gabriel, and Ramalho-Santos, Miguel
Published: 2019
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24. GGPS1‐associated muscular dystrophy with and without hearing loss

Author: Kaiyrzhanov, Rauan, primary, Perry, Luke, additional, Rocca, Clarissa, additional, Zaki, Maha S., additional, Hosny, Heba, additional, Araujo Martins Moreno, Cristiane, additional, Phadke, Rahul, additional, Zaharieva, Irina, additional, Camelo Gontijo, Clara, additional, Beetz, Christian, additional, Pini, Veronica, additional, Movahedinia, Mojtaba, additional, Zanoteli, Edmar, additional, DiTroia, Stephanie, additional, Vuillaumier‐Barrot, Sandrine, additional, Isapof, Arnaud, additional, Mehrjardi, Mohammad Yahya Vahidi, additional, Ghasemi, Nasrin, additional, Sarkozy, Anna, additional, Muntoni, Francesco, additional, Whalen, Sandra, additional, Vona, Barbara, additional, Houlden, Henry, additional, and Maroofian, Reza, additional
Published: 2022
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25. Considerations for reporting variants in novel candidate genes identified during clinical genomic testing

Author: Chong, Jessica X., Berger, Seth I., Baxter, Samantha, Smith, Erica, Xiao, Changrui, Calame, Daniel G., Hawley, Megan H., Rivera-Munoz, E. Andres, DiTroia, Stephanie, Abouhala, Siwaar, Albert, Jessica, Almalvez, Miguel, Alvarez, Raquel, Amin, Mutaz, Anderson, Peter, Aradhya, Swaroop, Ashley, Euan, Assimes, Themistocles, Auriga, Light, Austin-Tse, Christina, Bamshad, Mike, Barseghyan, Hayk, Baxter, Samantha, Behera, Sairam, Beheshti, Shaghayegh, Bejerano, Gill, Berger, Seth, Bernstein, Jon, Best, Sabrina, Blankenmeister, Benjamin, Blue, Elizabeth, Boerwinkle, Eric, Bonkowski, Emily, Bonner, Devon, Boone, Philip, Bornhorst, Miriam, Brand, Harrison, Buckingham, Kati, Calame, Daniel, Carter, Jennefer, Casadei, Silvia, Chadwick, Lisa, Chavez, Clarisa, Chen, Ziwei, Chinn, Ivan, Chong, Jessica, Coban-Akdemir, Zeynep, Cohen, Andrea J., Conner, Sarah, Conomos, Matthew, Coveler, Karen, Cui, Ya Allen, Currin, Sara, Daber, Robert, Dardas, Zain, Davis, Colleen, Dawood, Moez, de Dios, Ivan, de Esch, Celine, Delaney, Meghan, Delot, Emmanuele, DiTroia, Stephanie, Doddapaneni, Harsha, Du, Haowei, Duan, Ruizhi, Dugan-Perez, Shannon, Duong, Nhat, Duyzend, Michael, Eichler, Evan, Emami, Sara, Fraser, Jamie, Fusaro, Vincent, Galey, Miranda, Ganesh, Vijay, Garcia, Brandon, Garimella, Kiran, Gibbs, Richard, Gifford, Casey, Ginsburg, Amy, Goddard, Page, Gogarten, Stephanie, Gogate, Nikhita, Gordon, William, Gorzynski, John E., Greenleaf, William, Grochowski, Christopher, Groopman, Emily, Sousa, Rodrigo Guarischi, Gudmundsson, Sanna, Gulati, Ashima, Hall, Stacey, Harvey, William, Hawley, Megan, Heavner, Ben, Horike-Pyne, Martha, Hu, Jianhong, Huang, Yongqing, Hwang, James, Jarvik, Gail, Jensen, Tanner, Jhangiani, Shalini, Jimenez-Morales, David, Jin, Christopher, Saad, Ahmed K., Kahn-Kirby, Amanda, Kain, Jessica, Kaur, Parneet, Keehan, Laura, Knoblach, Susan, Ko, Arthur, Kundaje, Anshul, Kundu, Soumya, Lancaster, Samuel M., Larsson, Katie, Lee, Arthur, Lemire, Gabrielle, Lewis, Richard, Li, Wei, Li, Yidan, Liu, Pengfei, LoTempio, Jonathan, Lupski, James (Jim), Ma, Jialan, MacArthur, Daniel, Mahmoud, Medhat, Malani, Nirav, Mangilog, Brian, Marafi, Dana, Marmolejos, Sofia, Marten, Daniel, Martinez, Eva, Marvin, Colby, Marwaha, Shruti, Mastrorosa, Francesco Kumara, Matalon, Dena, May, Susanne, McGee, Sean, Meador, Lauren, Mefford, Heather, Mendez, Hector Rodrigo, Miller, Alexander, Miller, Danny E., Mitani, Tadahiro, Montgomery, Stephen, Moyses, Mariana, Munderloh, Chloe, Muzny, Donna, Nelson, Sarah, Nguyen, Thuy-mi P., Nguyen, Jonathan, Nussbaum, Robert, Nykamp, Keith, O'Callaghan, William, O'Heir, Emily, O'Leary, Melanie, Olsen, Jeren, Osei-Owusu, Ikeoluwa, O'Donnell-Luria, Anne, Padhi, Evin, Pais, Lynn, Pan, Miao, Panchal, Piyush, Patterson, Karynne, Payne, Sheryl, Pehlivan, Davut, Petrowski, Paul, Pham, Alicia, Pitsava, Georgia, Podesta, Astaria`Sara, Ponce, Sarah, Porter, Elizabeth, Posey, Jennifer, Prosser, Jaime, Quertermous, Thomas, Rai, Archana, Ramani, Arun, Rehm, Heidi, Reuter, Chloe, Reuter, Jason, Richardson, Matthew, Rivera-Munoz, Andres, Rubio, Oriane, Sabo, Aniko, Salani, Monica, Samocha, Kaitlin, Sanchis-Juan, Alba, Savage, Sarah, Scott, Evette, Scott, Stuart, Sedlazeck, Fritz, Shah, Gulalai, Shojaie, Ali, Singh, Mugdha, Smith, Kevin, Smith, Josh, Snow, Hana, Snyder, Michael, Socarras, Kayla, Starita, Lea, Stark, Brigitte, Stenton, Sarah, Stergachis, Andrew, Stilp, Adrienne, Sutton, V. Reid, Tai, Jui-Cheng, Talkowski, Michael (Mike), Tise, Christina, Tong, Catherine (Cat), Tsao, Philip, Ungar, Rachel, VanNoy, Grace, Vilain, Eric, Voutos, Isabella, Walker, Kim, Wei, Chia-Lin, Weisburd, Ben, Weiss, Jeff, Wellington, Chris, Weng, Ziming, Westheimer, Emily, Wheeler, Marsha, Wheeler, Matthew, Wiel, Laurens, Wilson, Michael, Wojcik, Monica, Wong, Quenna, Xiao, Changrui, Yadav, Rachita, Yi, Qian, Yuan, Bo, Zhao, Jianhua, Zhen, Jimmy, Zhou, Harry, Bamshad, Michael J., and Rehm, Heidi L.
Abstract: Since the first novel gene discovery for a Mendelian condition was made via exome sequencing, the rapid increase in the number of genes known to underlie Mendelian conditions coupled with the adoption of exome (and more recently, genome) sequencing by diagnostic testing labs has changed the landscape of genomic testing for rare diseases. Specifically, many individuals suspected to have a Mendelian condition are now routinely offered clinical ES. This commonly results in a precise genetic diagnosis but frequently overlooks the identification of novel candidate genes. Such candidates are also less likely to be identified in the absence of large-scale gene discovery research programs. Accordingly, clinical laboratories have both the opportunity, and some might argue a responsibility, to contribute to novel gene discovery, which should, in turn, increase the diagnostic yield for many conditions. However, clinical diagnostic laboratories must necessarily balance priorities for throughput, turnaround time, cost efficiency, clinician preferences, and regulatory constraints and often do not have the infrastructure or resources to effectively participate in either clinical translational or basic genome science research efforts. For these and other reasons, many laboratories have historically refrained from broadly sharing potentially pathogenic variants in novel genes via networks such as Matchmaker Exchange, much less reporting such results to ordering providers. Efforts to report such results are further complicated by a lack of guidelines for clinical reporting and interpretation of variants in novel candidate genes. Nevertheless, there are myriad benefits for many stakeholders, including patients/families, clinicians, and researchers, if clinical laboratories systematically and routinely identify, share, and report novel candidate genes. To facilitate this change in practice, we developed criteria for triaging, sharing, and reporting novel candidate genes that are most likely to be promptly validated as underlying a Mendelian condition and translated to use in clinical settings.
Published: 2024
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26. Germline GATA1s-generating mutations predispose to leukemia with acquired trisomy 21 and Down syndrome-like phenotype

Author: Hasle, Henrik, Kline, Ronald M., Kjeldsen, Eigil, Nik-Abdul-Rashid, Nik F., Bhojwani, Deepa, Verboon, Jeffrey M., DiTroia, Stephanie P., Chao, Katherine R., Raaschou-Jensen, Klas, Palle, Josefine, Zwaan, C. Michel, Nyvold, Charlotte Guldborg, Sankaran, Vijay G., Cantor, Alan B., Hasle, Henrik, Kline, Ronald M., Kjeldsen, Eigil, Nik-Abdul-Rashid, Nik F., Bhojwani, Deepa, Verboon, Jeffrey M., DiTroia, Stephanie P., Chao, Katherine R., Raaschou-Jensen, Klas, Palle, Josefine, Zwaan, C. Michel, Nyvold, Charlotte Guldborg, Sankaran, Vijay G., and Cantor, Alan B.
Abstract: Individuals with Down syndrome are at increased risk of myeloid leukemia in early childhood, which is associated with acquisition of GATA1 mutations that generate a short GATA1 isoform called GATA1s. Germline GATA1s-generating mutations result in congenital anemia in males. We report on 2 unrelated families that harbor germline GATA1s-generating mutations in which several members developed acute megakaryoblastic leukemia in early childhood. All evaluable leukemias had acquired trisomy 21 or tetrasomy 21. The leukemia characteristics overlapped with those of myeloid leukemia associated with Down syndrome, including age of onset at younger than 4 years, unique immunophenotype, complex karyotype, gene expression patterns, and drug sensitivity. These findings demonstrate that the combination of trisomy 21 and GATA1s-generating mutations results in a unique myeloid leukemia independent of whether the GATA1 mutation or trisomy 21 is the primary or secondary event and suggest that there is a unique functional cooperation between GATA1s and trisomy 21 in leukemogenesis. The family histories also indicate that germline GATA1s-generating mutations should be included among those associated with familial predisposition for myelodysplastic syndrome and leukemia.
Published: 2022
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27. Germline GATA1s-generating mutations predispose to leukemia with acquired trisomy 21 and Down syndrome-like phenotype

Author: Hasle, Henrik, primary, Kline, Ronald M., additional, Kjeldsen, Eigil, additional, Nik-Abdul-Rashid, Nik F., additional, Bhojwani, Deepa, additional, Verboon, Jeffrey M., additional, DiTroia, Stephanie P., additional, Chao, Katherine R., additional, Raaschou-Jensen, Klas, additional, Palle, Josefine, additional, Zwaan, C. Michel, additional, Nyvold, Charlotte Guldborg, additional, Sankaran, Vijay G., additional, and Cantor, Alan B., additional
Published: 2022
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28. Centers for Mendelian Genomics: A decade of facilitating gene discovery

Author: Baxter, Samantha M., primary, Posey, Jennifer E., additional, Lake, Nicole J., additional, Sobreira, Nara, additional, Chong, Jessica X., additional, Buyske, Steven, additional, Blue, Elizabeth E., additional, Chadwick, Lisa H., additional, Coban-Akdemir, Zeynep H., additional, Doheny, Kimberly F., additional, Davis, Colleen P., additional, Lek, Monkol, additional, Wellington, Christopher, additional, Jhangiani, Shalini N., additional, Gerstein, Mark, additional, Gibbs, Richard A., additional, Lifton, Richard P., additional, MacArthur, Daniel G., additional, Matise, Tara C., additional, Lupski, James R., additional, Valle, David, additional, Bamshad, Michael J., additional, Hamosh, Ada, additional, Mane, Shrikant, additional, Nickerson, Deborah A., additional, Rehm, Heidi L., additional, O’Donnell-Luria, Anne, additional, Adams, Marcia, additional, Aguet, François, additional, Akay, Gulsen, additional, Anderson, Peter, additional, Antonescu, Corina, additional, Arachchi, Harindra M., additional, Atik, Mehmed M., additional, Austin-Tse, Christina A., additional, Babb, Larry, additional, Bacus, Tamara J., additional, Bahrambeigi, Vahid, additional, Balasubramanian, Suganthi, additional, Bayram, Yavuz, additional, Beaudet, Arthur L., additional, Beck, Christine R., additional, Belmont, John W., additional, Below, Jennifer E., additional, Bilguvar, Kaya, additional, Boehm, Corinne D., additional, Boerwinkle, Eric, additional, Boone, Philip M., additional, Bowne, Sara J., additional, Brand, Harrison, additional, Buckingham, Kati J., additional, Byrne, Alicia B., additional, Calame, Daniel, additional, Campbell, Ian M., additional, Cao, Xiaolong, additional, Carvalho, Claudia, additional, Chander, Varuna, additional, Chang, Jaime, additional, Chao, Katherine R., additional, Chinn, Ivan K., additional, Clarke, Declan, additional, Collins, Ryan L., additional, Cummings, Beryl, additional, Dardas, Zain, additional, Dawood, Moez, additional, Delano, Kayla, additional, DiTroia, Stephanie P., additional, Doddapaneni, Harshavardhan, additional, Du, Haowei, additional, Du, Renqian, additional, Duan, Ruizhi, additional, Eldomery, Mohammad, additional, Eng, Christine M., additional, England, Eleina, additional, Evangelista, Emily, additional, Everett, Selin, additional, Fatih, Jawid, additional, Felsenfeld, Adam, additional, Francioli, Laurent C., additional, Frazar, Christian D., additional, Fu, Jack, additional, Gamarra, Emmanuel, additional, Gambin, Tomasz, additional, Gan, Weiniu, additional, Gandhi, Mira, additional, Ganesh, Vijay S., additional, Garimella, Kiran V., additional, Gauthier, Laura D., additional, Giroux, Danielle, additional, Gonzaga-Jauregui, Claudia, additional, Goodrich, Julia K., additional, Gordon, William W., additional, Griffith, Sean, additional, Grochowski, Christopher M., additional, Gu, Shen, additional, Gudmundsson, Sanna, additional, Hall, Stacey J., additional, Hansen, Adam, additional, Harel, Tamar, additional, Harmanci, Arif O., additional, Herman, Isabella, additional, Hetrick, Kurt, additional, Hijazi, Hadia, additional, Horike-Pyne, Martha, additional, Hsu, Elvin, additional, Hu, Jianhong, additional, Huang, Yongqing, additional, Hurless, Jameson R., additional, Jahl, Steve, additional, Jarvik, Gail P., additional, Jiang, Yunyun, additional, Johanson, Eric, additional, Jolly, Angad, additional, Karaca, Ender, additional, Khayat, Michael, additional, Knight, James, additional, Kolar, J. Thomas, additional, Kumar, Sushant, additional, Lalani, Seema, additional, Laricchia, Kristen M., additional, Larkin, Kathryn E., additional, Leal, Suzanne M., additional, Lemire, Gabrielle, additional, Lewis, Richard A., additional, Li, He, additional, Ling, Hua, additional, Lipson, Rachel B., additional, Liu, Pengfei, additional, Lovgren, Alysia Kern, additional, López-Giráldez, Francesc, additional, MacMillan, Melissa P., additional, Mangilog, Brian E., additional, Mano, Stacy, additional, Marafi, Dana, additional, Marosy, Beth, additional, Marshall, Jamie L., additional, Martin, Renan, additional, Marvin, Colby T., additional, Mawhinney, Michelle, additional, McGee, Sean, additional, McGoldrick, Daniel J., additional, Mehaffey, Michelle, additional, Mekonnen, Betselote, additional, Meng, Xiaolu, additional, Mitani, Tadahiro, additional, Miyake, Christina Y., additional, Mohr, David, additional, Morris, Shaine, additional, Mullen, Thomas E., additional, Murdock, David R., additional, Murugan, Mullai, additional, Muzny, Donna M., additional, Myers, Ben, additional, Neira, Juanita, additional, Nguyen, Kevin K., additional, Nielsen, Patrick M., additional, Nudelman, Natalie, additional, O’Heir, Emily, additional, O’Leary, Melanie C., additional, Ongaco, Chrissie, additional, Orange, Jordan, additional, Osei-Owusu, Ikeoluwa A., additional, Paine, Ingrid S., additional, Pais, Lynn S., additional, Paschall, Justin, additional, Patterson, Karynne, additional, Pehlivan, Davut, additional, Pelle, Benjamin, additional, Penney, Samantha, additional, Perez de Acha Chavez, Jorge, additional, Pierce-Hoffman, Emma, additional, Poli, Cecilia M., additional, Punetha, Jaya, additional, Radhakrishnan, Aparna, additional, Richardson, Matthew A., additional, Rodrigues, Eliete, additional, Roote, Gwendolin T., additional, Rosenfeld, Jill A., additional, Ryke, Erica L., additional, Sabo, Aniko, additional, Sanchez, Alice, additional, Schrauwen, Isabelle, additional, Scott, Daryl A., additional, Sedlazeck, Fritz, additional, Serrano, Jillian, additional, Shaw, Chad A., additional, Shelford, Tameka, additional, Shively, Kathryn M., additional, Singer-Berk, Moriel, additional, Smith, Joshua D., additional, Snow, Hana, additional, Snyder, Grace, additional, Solomonson, Matthew, additional, Son, Rachel G., additional, Song, Xiaofei, additional, Stankiewicz, Pawel, additional, Stephan, Taylorlyn, additional, Sutton, V. Reid, additional, Sveden, Abigail, additional, Sánchez, Diana Cornejo, additional, Tackett, Monica, additional, Talkowski, Michael, additional, Threlkeld, Machiko S., additional, Tiao, Grace, additional, Udler, Miriam S., additional, Vail, Laura, additional, Valivullah, Zaheer, additional, Valkanas, Elise, additional, VanNoy, Grace E., additional, Wang, Qingbo S., additional, Wang, Gao, additional, Wang, Lu, additional, Wangler, Michael F., additional, Watts, Nicholas A., additional, Weisburd, Ben, additional, Weiss, Jeffrey M., additional, Wheeler, Marsha M., additional, White, Janson J., additional, Williamson, Clara E., additional, Wilson, Michael W., additional, Wiszniewski, Wojciech, additional, Withers, Marjorie A., additional, Witmer, Dane, additional, Witzgall, Lauren, additional, Wohler, Elizabeth, additional, Wojcik, Monica H., additional, Wong, Isaac, additional, Wood, Jordan C., additional, Wu, Nan, additional, Xing, Jinchuan, additional, Yang, Yaping, additional, Yi, Qian, additional, Yuan, Bo, additional, Zeiger, Jordan E., additional, Zhang, Chaofan, additional, Zhang, Peng, additional, Zhang, Yan, additional, Zhang, Xiaohong, additional, Zhang, Yeting, additional, Zhang, Shifa, additional, Zoghbi, Huda, additional, and van den Veyver, Igna, additional
Published: 2022
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29. seqr : A web‐based analysis and collaboration tool for rare disease genomics

Author: Pais, Lynn S., primary, Snow, Hana, additional, Weisburd, Ben, additional, Zhang, Shifa, additional, Baxter, Samantha M., additional, DiTroia, Stephanie, additional, O'Heir, Emily, additional, England, Eleina, additional, Chao, Katherine R., additional, Lemire, Gabrielle, additional, Osei‐Owusu, Ikeoluwa, additional, VanNoy, Grace E., additional, Wilson, Michael, additional, Nguyen, Kevin, additional, Arachchi, Harindra, additional, Phu, William, additional, Solomonson, Matthew, additional, Mano, Stacy, additional, O'Leary, Melanie, additional, Lovgren, Alysia, additional, Babb, Lawrence, additional, Austin‐Tse, Christina A., additional, Rehm, Heidi L., additional, MacArthur, Daniel G., additional, and O'Donnell‐Luria, Anne, additional
Published: 2022
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30. Recessive variants in COL25A1 gene as novel cause of arthrogryposis multiplex congenita with ocular congenital cranial dysinnervation disorder

Author: Natera‐de Benito, Daniel, primary, Jurgens, Julie A., additional, Yeung, Alison, additional, Zaharieva, Irina T., additional, Manzur, Adnan, additional, DiTroia, Stephanie P., additional, Di Gioia, Silvio Alessandro, additional, Pais, Lynn, additional, Pini, Veronica, additional, Barry, Brenda J., additional, Chan, Wai‐Man, additional, Elder, James E., additional, Christodoulou, John, additional, Hay, Eleanor, additional, England, Eleina M., additional, Munot, Pinki, additional, Hunter, David G., additional, Feng, Lucy, additional, Ledoux, Danielle, additional, O'Donnell‐Luria, Anne, additional, Phadke, Rahul, additional, Engle, Elizabeth C., additional, Sarkozy, Anna, additional, and Muntoni, Francesco, additional
Published: 2022
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31. The importance of automation in genetic diagnosis: Lessons from analyzing an inherited retinal degeneration cohort with the Mendelian Analysis Toolkit (MATK)

Author: Zampaglione, Erin, primary, Maher, Matthew, additional, Place, Emily M., additional, Wagner, Naomi E., additional, DiTroia, Stephanie, additional, Chao, Katherine R., additional, England, Eleina, additional, CMG, Broad, additional, Catomeris, Andrew, additional, Nassiri, Sherwin, additional, Himes, Seraphim, additional, Pagliarulo, Joey, additional, Ferguson, Charles, additional, Galdikaité-Braziené, Eglé, additional, Cole, Brian, additional, Pierce, Eric A., additional, and Bujakowska, Kinga M., additional
Published: 2022
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32. Delineation of a novel neurodevelopmental syndrome associated with PAX5 haploinsufficiency

Author: Gofin, Yoel, primary, Wang, Tianyun, additional, Gillentine, Madelyn A., additional, Scott, Tiana M., additional, Berry, Aliska M., additional, Azamian, Mahshid S., additional, Genetti, Casie, additional, Agrawal, Pankaj B., additional, Picker, Jonathan, additional, Wojcik, Monica H., additional, Delgado, Mauricio R., additional, Lynch, Sally A., additional, Scherer, Stephen W., additional, Howe, Jennifer L., additional, Bacino, Carlos A., additional, DiTroia, Stephanie, additional, VanNoy, Grace E., additional, O'Donnell‐Luria, Anne, additional, Lalani, Seema R., additional, Graf, William D., additional, Rosenfeld, Jill A., additional, Eichler, Evan E., additional, Earl, Rachel K., additional, and Scott, Daryl A., additional
Published: 2022
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33. seqr : a web-based analysis and collaboration tool for rare disease genomics

Author: Pais, Lynn S., primary, Snow, Hana, additional, Weisburd, Ben, additional, Zhang, Shifa, additional, Baxter, Samantha, additional, DiTroia, Stephanie, additional, O’Heir, Emily, additional, England, Eleina, additional, Chao, Katherine, additional, Lemire, Gabrielle, additional, Osei-Owusu, Ikeoluwa, additional, VanNoy, Grace E., additional, Wilson, Michael, additional, Nguyen, Kevin, additional, Arachchi, Harindra, additional, Phu, William, additional, Solomonson, Matthew, additional, Mano, Stacy, additional, O’Leary, Melanie, additional, Lovgren, Alysia, additional, Babb, Lawrence, additional, Austin-Tse, Christina, additional, Rehm, Heidi L., additional, MacArthur, Daniel G., additional, and O’Donnell-Luria, Anne, additional
Published: 2021
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34. KCND2 variants associated with global developmental delay differentially impair Kv4.2 channel gating

Author: Zhang, Yongqiang, primary, Tachtsidis, Georgios, additional, Schob, Claudia, additional, Koko, Mahmoud, additional, Hedrich, Ulrike B S, additional, Lerche, Holger, additional, Lemke, Johannes R, additional, van Haeringen, Arie, additional, Ruivenkamp, Claudia, additional, Prescott, Trine, additional, Tveten, Kristian, additional, Gerstner, Thorsten, additional, Pruniski, Brianna, additional, DiTroia, Stephanie, additional, VanNoy, Grace E, additional, Rehm, Heidi L, additional, McLaughlin, Heather, additional, Bolz, Hanno J, additional, Zechner, Ulrich, additional, Bryant, Emily, additional, McDonough, Tiffani, additional, Kindler, Stefan, additional, and Bähring, Robert, additional
Published: 2021
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35. KCND2 variants associated with global developmental delay differentially impair Kv4.2 channel gating

Author: Zhang, Yongqiang, Tachtsidis, Georgios, Schob, Claudia, Koko, Mahmoud, Hedrich, Ulrike B. S., Lerche, Holger, Lemke, Johannes R., van Haeringen, Arie, Ruivenkamp, Claudia, Prescott, Trine, Tveten, Kristian, Gerstner, Thorsten, Pruniski, Brianna, DiTroia, Stephanie, VanNoy, Grace E., Rehm, Heidi L., McLaughlin, Heather, Bolz, Hanno J., Zechner, Ulrich, Bryant, Emily, McDonough, Tiffani, Kindler, Stefan, Baehring, Robert, Zhang, Yongqiang, Tachtsidis, Georgios, Schob, Claudia, Koko, Mahmoud, Hedrich, Ulrike B. S., Lerche, Holger, Lemke, Johannes R., van Haeringen, Arie, Ruivenkamp, Claudia, Prescott, Trine, Tveten, Kristian, Gerstner, Thorsten, Pruniski, Brianna, DiTroia, Stephanie, VanNoy, Grace E., Rehm, Heidi L., McLaughlin, Heather, Bolz, Hanno J., Zechner, Ulrich, Bryant, Emily, McDonough, Tiffani, Kindler, Stefan, and Baehring, Robert
Abstract: Here, we report on six unrelated individuals, all presenting with early-onset global developmental delay, associated with impaired motor, speech and cognitive development, partly with developmental epileptic encephalopathy and physical dysmorphisms. All individuals carry heterozygous missense variants of KCND2, which encodes the voltage-gated potassium (Kv) channel alpha-subunit Kv4.2. The amino acid substitutions associated with the variants, p.(Glu323Lys) (E323K), p.(Pro403Ala) (P403A), p.(Val404Leu) (V404L) and p.(Val404Met) (V404M), affect sites known to be critical for channel gating. To unravel their likely pathogenicity, recombinant mutant channels were studied in the absence and presence of auxiliary beta-subunits under two-electrode voltage clamp in Xenopus oocytes. All channel mutants exhibited slowed and incomplete macroscopic inactivation, and the P403A variant in addition slowed activation. Co-expression of KChIP2 or DPP6 augmented the functional expression of both wild-type and mutant channels; however, the auxiliary beta-subunit-mediated gating modifications differed from wild type and among mutants. To simulate the putative setting in the affected individuals, heteromeric Kv4.2 channels (wild type + mutant) were studied as ternary complexes (containing both KChIP2 and DPP6). In the heteromeric ternary configuration, the E323K variant exhibited only marginal functional alterations compared to homomeric wild-type ternary, compatible with mild loss-of-function. By contrast, the P403A, V404L and V404M variants displayed strong gating impairment in the heteromeric ternary configuration, compatible with loss-of-function or gain-of-function. Our results support the etiological involvement of Kv4.2 channel gating impairment in early-onset monogenic global developmental delay. In addition, they suggest that gain-of-function mechanisms associated with a substitution of V404 increase epileptic seizure susceptibility.
Published: 2021

36. Familial thrombocytopenia due to a complex structural variant resulting in a WAC-ANKRD26 fusion transcript

Author: Wahlster, Lara, primary, Verboon, Jeffrey M., additional, Ludwig, Leif S., additional, Black, Susan C., additional, Luo, Wendy, additional, Garg, Kopal, additional, Voit, Richard A., additional, Collins, Ryan L., additional, Garimella, Kiran, additional, Costello, Maura, additional, Chao, Katherine R., additional, Goodrich, Julia K., additional, DiTroia, Stephanie P., additional, O’Donnell-Luria, Anne, additional, Talkowski, Michael E., additional, Michelson, Alan D., additional, Cantor, Alan B., additional, and Sankaran, Vijay G., additional
Published: 2021
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37. More than a fancy exome: unique capabilities of genome sequencing for pediatric rare disease diagnosis

Author: Wojcik, Monica, primary, Chao, Katherine, additional, Goodrich, Julia, additional, Pais, Lynn, additional, DiTroia, Stephanie, additional, O’Heir, Emily, additional, Ganesh, Vijay, additional, Weisburd, Ben, additional, Beggs, Alan, additional, Baxter, Samantha, additional, Agrawal, Pankaj, additional, Pajusalu, Sander, additional, Ounap, Katrin, additional, MacArthur, Daniel, additional, Rehm, Heidi, additional, and O’Donnell-Luria, Anne, additional
Published: 2021
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38. Germline mutation in POLR2A: a heterogeneous, multi-systemic developmental disorder characterized by transcriptional dysregulation

Author: Hansen, Adam W., primary, Arora, Payal, additional, Khayat, Michael M., additional, Smith, Leah J., additional, Lewis, Andrea M., additional, Rossetti, Linda Z., additional, Jayaseelan, Joy, additional, Cristian, Ingrid, additional, Haynes, Devon, additional, DiTroia, Stephanie, additional, Meeks, Naomi, additional, Delgado, Mauricio R., additional, Rosenfeld, Jill A., additional, Pais, Lynn, additional, White, Susan M., additional, Meng, Qingchang, additional, Pehlivan, Davut, additional, Liu, Pengfei, additional, Gingras, Marie-Claude, additional, Wangler, Michael F., additional, Muzny, Donna M., additional, Lupski, James R., additional, Kaplan, Craig D., additional, and Gibbs, Richard A., additional
Published: 2021
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39. Exome and genome sequencing in adults with undiagnosed disease: a prospective cohort study

Author: Shickh, Salma, primary, Gutierrez Salazar, Mariana, additional, Zakoor, Kathleen-Rose, additional, Lázaro, Conxi, additional, Gu, Jessica, additional, Goltz, Jamie, additional, Kleinman, Dakota, additional, Noor, Abdul, additional, Khalouei, Sam, additional, Mighton, Chloe, additional, Reble, Emma, additional, Kodida, Rita, additional, Bombard, Yvonne, additional, DiTroia, Stephanie, additional, Baxter, Samantha, additional, Watkins, Nicholas, additional, Care, Melanie, additional, Adler, Arnon, additional, Horsburgh, Sheri, additional, Morar, Oana, additional, Murphy, Jillian, additional, Nevay, Dayna-Lynn, additional, Szybowska, Marta, additional, Aronson, Melyssa, additional, Panchal, Seema, additional, Godoy, Ruth, additional, Holter, Spring, additional, Randall Armel, Susan, additional, Semotiuk, Kara, additional, Elser, Christine, additional, Kim, Raymond H, additional, Chitayat, David, additional, So, Joyce, additional, Faghfoury, Hanna, additional, Silver, Josh, additional, Morel, Chantal F, additional, and Lerner-Ellis, Jordan, additional
Published: 2020
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40. Expanding the phenotypic spectrum in RDH12-associated retinal disease

Author: Scott, Hilary A., primary, Place, Emily M., additional, Ferenchak, Kevin, additional, Zampaglione, Erin, additional, Wagner, Naomi E., additional, Chao, Katherine R., additional, DiTroia, Stephanie P., additional, Navarro-Gomez, Daniel, additional, Mukai, Shizuo, additional, Huckfeldt, Rachel M., additional, Pierce, Eric A., additional, and Bujakowska, Kinga M., additional
Published: 2020
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41. Maternal vitamin C regulates reprogramming of DNA methylation and germline development

Author: DiTroia, Stephanie S.P., Percharde, Michelle, Guerquin, Marie Justine, Wall, Estelle, Collignon, Evelyne, Ebata, Kevin K.T., Mesh, Kathryn, Mahesula, Swetha, Agathocleous, Michalis, Laird, Diana D.J., Livera, Gabriel, Ramalho-Santos, Miguel, DiTroia, Stephanie S.P., Percharde, Michelle, Guerquin, Marie Justine, Wall, Estelle, Collignon, Evelyne, Ebata, Kevin K.T., Mesh, Kathryn, Mahesula, Swetha, Agathocleous, Michalis, Laird, Diana D.J., Livera, Gabriel, and Ramalho-Santos, Miguel
Abstract: Development is often assumed to be hardwired in the genome, but several lines of evidence indicate that it is susceptible to environmental modulation with potential long-term consequences, including in mammals1,2. The embryonic germline is of particular interest because of the potential for intergenerational epigenetic effects. The mammalian germline undergoes extensive DNA demethylation3–7 that occurs in large part by passive dilution of methylation over successive cell divisions, accompanied by active DNA demethylation by TET enzymes3,8–10. TET activity has been shown to be modulated by nutrients and metabolites, such as vitamin C11–15. Here we show that maternal vitamin C is required for proper DNA demethylation and the development of female fetal germ cells in a mouse model. Maternal vitamin C deficiency does not affect overall embryonic development but leads to reduced numbers of germ cells, delayed meiosis and reduced fecundity in adult offspring. The transcriptome of germ cells from vitamin-C-deficient embryos is remarkably similar to that of embryos carrying a null mutation in Tet1. Vitamin C deficiency leads to an aberrant DNA methylation profile that includes incomplete demethylation of key regulators of meiosis and transposable elements. These findings reveal that deficiency in vitamin C during gestation partially recapitulates loss of TET1, and provide a potential intergenerational mechanism for adjusting fecundity to environmental conditions., SCOPUS: ar.j, info:eu-repo/semantics/published
Published: 2019

42. Exome and genome sequencing in adults with undiagnosed disease: a prospective cohort study.

Author: Shickh, Salma, Salazar, Mariana Gutierrez, Zakoor, Kathleen-Rose, Lázaro, Conxi, Gu, Jessica, Goltz, Jamie, Kleinman, Dakota, Noor, Abdul, Khalouei, Sam, Mighton, Chloe, Reble, Emma, Kodida, Rita, Bombard, Yvonne, DiTroia, Stephanie, Baxter, Samantha, Watkins, Nicholas, Care, Melanie, Adler, Arnon, Horsburgh, Sheri, and Morar, Oana
Abstract: Background: Exome and genome sequencing have been demonstrated to increase diagnostic yield in paediatric populations, improving treatment options and providing risk information for relatives. There are limited studies examining the clinical utility of these tests in adults, who currently have limited access to this technology. Methods: Patients from adult and cancer genetics clinics across Toronto, Ontario, Canada were recruited into a prospective cohort study evaluating the diagnostic utility of exome and genome sequencing in adults. Eligible patients were =18 years of age and suspected of having a hereditary disorder but had received previous uninformative genetic test results. In total, we examined the diagnostic utility of exome and genome sequencing in 47 probands and 34 of their relatives who consented to participate and underwent exome or genome sequencing. Results: Overall, 17% (8/47) of probands had a pathogenic or likely pathogenic variant identified in a gene associated with their primary indication for testing. The diagnostic yield for patients with a cancer history was similar to the yield for patients with a non-cancer history (4/18 (22%) vs 4/29 (14%)). An additional 24 probands (51%) had an inconclusive result. Secondary findings were identified in 10 patients (21%); three had medically actionable results. Conclusions: This study lends evidence to the diagnostic utility of exome or genome sequencing in an undiagnosed adult population. The significant increase in diagnostic yield warrants the use of this technology. The identification and communication of secondary findings may provide added value when using this testing modality as a first-line test. [ABSTRACT FROM AUTHOR]
Published: 2021
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43. Biallelic loss-of-function variants in WDR11are associated with microcephaly and intellectual disability

Author: Haag, Natja, Tan, Ene-Choo, Begemann, Matthias, Buschmann, Lars, Kraft, Florian, Holschbach, Petra, Lai, Angeline H. M., Brett, Maggie, Mochida, Ganeshwaran H., DiTroia, Stephanie, Pais, Lynn, Neil, Jennifer E., Al-Saffar, Muna, Bastaki, Laila, Walsh, Christopher A., Kurth, Ingo, and Knopp, Cordula
Abstract: Heterozygous missense variants in the WD repeat domain 11(WDR11) gene are associated with hypogonadotropic hypogonadism in humans. In contrast, knockout of both alleles of Wdr11in mice results in a more severe phenotype with growth and developmental delay, features of holoprosencephaly, heart defects and reproductive disorders. Similar developmental defects known to be associated with aberrant hedgehog signaling and ciliogenesis have been found in zebrafish after Wdr11knockdown. We here report biallelic loss-of-function variants in the WDR11gene in six patients from three independent families with intellectual disability, microcephaly and short stature. The findings suggest that biallelic WDR11variants in humans result in an overlapping but milder phenotype compared to Wdr11-deficient animals. However, the observed human phenotype differs significantly from dominantly inherited variants leading to hypogonadotropic hypogonadism, suggesting that recessive WDR11variants result in a clinically distinct entity.
Published: 2021
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44. Germline GATA1s generating mutations predispose to leukemia with acquired trisomy 21 and Down syndrome-like phenotype

Author: Hasle, Henrik, Kline, Ronald M., Kjeldsen, Eigil, Nik-Abdul-Rashid, Nik F., Bhojwani, Deepa, Verboon, Jeffrey M., DiTroia, Stephanie P., Chao, Katherine R., Raaschou-Jensen, Klas, Palle, Josefine, Zwaan, C. Michel, Nyvold, Charlotte Guldborg, Sankaran, Vijay G., and Cantor, Alan B.
Abstract: Individuals with Down syndrome are at increased risk of myeloid leukemia in early childhood associated with acquisition of GATA1mutations that generate a short GATA1 isoform called GATA1s. Germline GATA1s generating mutations result in congenital anemia in males. We report on two unrelated families harboring germline GATA1s generating mutations in which several members developed acute megakaryoblastic leukemia in early childhood. All evaluable leukemias had acquired trisomy or tetrasomy 21. The leukemia characteristics overlapped those of myeloid leukemia of Down syndrome including age of onset of less than 4 years, unique immunophenotype, complex karyotype, gene expression pattern, and drug sensitivity. These findings demonstrate that the combination of trisomy 21 and GATA1s generating mutations results in a unique myeloid leukemia independent of whether the GATA1mutation or trisomy 21 is the primary or secondary event and suggest that there is unique functional cooperatively between GATA1s and trisomy 21 in leukemogenesis. The family histories also indicate that germline GATA1s generatingmutations should be included among those associated with familial myelodysplastic syndrome and leukemia predisposition.
Published: 2021
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45. eP132 - More than a fancy exome: unique capabilities of genome sequencing for pediatric rare disease diagnosis.

Author: Wojcik, Monica, Chao, Katherine, Goodrich, Julia, Pais, Lynn, DiTroia, Stephanie, O'Heir, Emily, Ganesh, Vijay, Weisburd, Ben, Beggs, Alan, Baxter, Samantha, Agrawal, Pankaj, Pajusalu, Sander, Ounap, Katrin, MacArthur, Daniel, Rehm, Heidi, and O'Donnell-Luria, Anne
Subjects: *RARE diseases, *DIAGNOSIS, *EXOMES
Published: 2021
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46. De novo AHDC1 Deletions Identified by Genome Sequencing in Two Individuals with Xia-Gibbs Syndrome.

Author: Bertrand M, Shah G, Pedersen BS, Schulz A, Weise A, Liehr T, Huppke P, DiTroia S, Quinlan AR, Haack TB, and Husain RA
Abstract: Introduction: Xia-Gibbs syndrome (XGS) is a rare syndromic disorder characterized by developmental delay with intellectual disability, muscular hypotonia, brain anomalies, and nonspecific dysmorphic features. Different heterozygous variants in AHDC1 have been reported as causal for XGS, comprising mainly de novo stop-gain and frameshift events, but also missense variants, deletions, and a duplication of the locus., Case Presentation: We hereby report 2 patients with clinical features of XGS. In the first patient, a de novo interstitial deletion in 1p36.11p35.3 encompassing the entire coding region of AHDC1 was initially suspected by trio exome sequencing and subsequently confirmed by shallow genome sequencing. In the second patient, a de novo deletion comprising most of the 5' untranslated region of AHDC1 was detected by genome sequencing., Conclusion: We identified the smallest deletion comprising AHDC1 reported so far by shallow genome sequencing as well as another small AHDC1 deletion by genome sequencing. These methods represent useful techniques for the identification and confirmation of small deletions and structural variants. Furthermore, our data provide additional evidence of AHDC1 haploinsufficiency as a disease mechanism in XGS. Clinically, foot deformity, skin and connective tissue abnormalities observed in one of the patients are consistent with other reported cases of XGS. These findings suggest that these manifestations could be considered as more prevalent characteristics, underscoring the importance of in-depth phenotyping., Competing Interests: The authors have no conflicts of interest to declare., (© 2024 S. Karger AG, Basel.)
Published: 2024
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47. Loss-of-Function Variants in CUL3 Cause a Syndromic Neurodevelopmental Disorder.

Author: Blackburn PR, Ebstein F, Hsieh TC, Motta M, Radio FC, Herkert JC, Rinne T, Thiffault I, Rapp M, Alders M, Maas S, Gerard B, Smol T, Vincent-Delorme C, Cogné B, Isidor B, Vincent M, Bachmann-Gagescu R, Rauch A, Joset P, Ferrero GB, Ciolfi A, Husson T, Guerrot AM, Bacino C, Macmurdo C, Thompson SS, Rosenfeld JA, Faivre L, Mau-Them FT, Deb W, Vignard V, Agrawal PB, Madden JA, Goldenberg A, Lecoquierre F, Zech M, Prokisch H, Necpál J, Jech R, Winkelmann J, Koprušáková MT, Konstantopoulou V, Younce JR, Shinawi M, Mighton C, Fung C, Morel CF, Lerner-Ellis J, DiTroia S, Barth M, Bonneau D, Krapels I, Stegmann APA, van der Schoot V, Brunet T, Bußmann C, Mignot C, Zampino G, Wortmann SB, Mayr JA, Feichtinger RG, Courtin T, Ravelli C, Keren B, Ziegler A, Hasadsri L, Pichurin PN, Klee EW, Grand K, Sanchez-Lara PA, Krüger E, Bézieau S, Klinkhammer H, Krawitz PM, Eichler EE, Tartaglia M, Küry S, and Wang T
Abstract: Objective: De novo variants in cullin-3 ubiquitin ligase (CUL3) have been strongly associated with neurodevelopmental disorders (NDDs), but no large case series have been reported so far. Here, we aimed to collect sporadic cases carrying rare variants in CUL3, describe the genotype-phenotype correlation, and investigate the underlying pathogenic mechanism., Methods: Genetic data and detailed clinical records were collected via multicenter collaboration. Dysmorphic facial features were analyzed using GestaltMatcher. Variant effects on CUL3 protein stability were assessed using patient-derived T-cells., Results: We assembled a cohort of 37 individuals with heterozygous CUL3 variants presenting a syndromic NDD characterized by intellectual disability with or without autistic features. Of these, 35 have loss-of-function (LoF) and 2 have missense variants. CUL3 LoF variants in patients may affect protein stability leading to perturbations in protein homeostasis, as evidenced by decreased ubiquitin-protein conjugates in vitro. Notably, we show that 4E-BP1 (EIF4EBP1), a prominent substrate of CUL3, fails to be targeted for proteasomal degradation in patient-derived cells., Interpretation: Our study further refines the clinical and mutational spectrum of CUL3-associated NDDs, expands the spectrum of cullin RING E3 ligase-associated neuropsychiatric disorders, and suggests haploinsufficiency via LoF variants is the predominant pathogenic mechanism. ANN NEUROL 2024., (© 2024 American Neurological Association.)
Published: 2024
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48. Considerations for reporting variants in novel candidate genes identified during clinical genomic testing.

Author: Chong JX, Berger SI, Baxter S, Smith E, Xiao C, Calame DG, Hawley MH, Rivera-Munoz EA, DiTroia S, Bamshad MJ, and Rehm HL
Abstract: Since the first novel gene discovery for a Mendelian condition was made via exome sequencing (ES), the rapid increase in the number of genes known to underlie Mendelian conditions coupled with the adoption of exome (and more recently, genome) sequencing by diagnostic testing labs has changed the landscape of genomic testing for rare disease. Specifically, many individuals suspected to have a Mendelian condition are now routinely offered clinical ES. This commonly results in a precise genetic diagnosis but frequently overlooks the identification of novel candidate genes. Such candidates are also less likely to be identified in the absence of large-scale gene discovery research programs. Accordingly, clinical laboratories have both the opportunity, and some might argue a responsibility, to contribute to novel gene discovery which should in turn increase the diagnostic yield for many conditions. However, clinical diagnostic laboratories must necessarily balance priorities for throughput, turnaround time, cost efficiency, clinician preferences, and regulatory constraints, and often do not have the infrastructure or resources to effectively participate in either clinical translational or basic genome science research efforts. For these and other reasons, many laboratories have historically refrained from broadly sharing potentially pathogenic variants in novel genes via networks like Matchmaker Exchange, much less reporting such results to ordering providers. Efforts to report such results are further complicated by a lack of guidelines for clinical reporting and interpretation of variants in novel candidate genes. Nevertheless, there are myriad benefits for many stakeholders, including patients/families, clinicians, researchers, if clinical laboratories systematically and routinely identify, share, and report novel candidate genes. To facilitate this change in practice, we developed criteria for triaging, sharing, and reporting novel candidate genes that are most likely to be promptly validated as underlying a Mendelian condition and translated to use in clinical settings.
Published: 2024
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49. Loss of Function of the Cytoplasmic Fe-S Assembly Protein CIAO1 Causes a Neuromuscular Disorder with Compromise of Nucleocytoplasmic Fe-S Enzymes.

Author: Maio N, Orbach R, Zaharieva I, Töpf A, Donkervoort S, Munot P, Mueller J, Willis T, Verma S, Peric S, Krishnakumar D, Sudhakar S, Foley AR, Silverstein S, Douglas G, Pais L, DiTroia S, Grunseich C, Hu Y, Sewry C, Sarkozy A, Straub V, Muntoni F, Rouault T, and Bönnemann CG
Abstract: Cytoplasmic and nuclear iron-sulfur enzymes that are essential for genome maintenance and replication depend on the cytoplasmic iron-sulfur assembly (CIA) machinery for cluster acquisition. Here we report that patients with biallelic loss of function in CIAO1 , a key CIA component, develop proximal and axial muscle weakness, fluctuating creatine kinase elevation and respiratory insufficiency. In addition, they present with CNS symptoms including learning difficulties and neurobehavioral comorbidities, along with iron deposition in deep brain nuclei, macrocytic anemia and gastrointestinal symptoms. Mutational analysis and functional assays revealed reduced stability of the variants compared to wild-type CIAO1. Loss of CIAO1 impaired DNA helicases, polymerases and repair enzymes which rely on the CIA complex to acquire their Fe-S cofactors, with lentiviral restoration reversing all patient-derived cellular abnormalities. Our study identifies CIAO1 as a novel human disease gene and provides insights into the broader implications of the iron-sulfur assembly pathway in human health and disease.
Published: 2023
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50. Exome copy number variant detection, analysis and classification in a large cohort of families with undiagnosed rare genetic disease.

Author: Lemire G, Sanchis-Juan A, Russell K, Baxter S, Chao KR, Singer-Berk M, Groopman E, Wong I, England E, Goodrich J, Pais L, Austin-Tse C, DiTroia S, O'Heir E, Ganesh VS, Wojcik MH, Evangelista E, Snow H, Osei-Owusu I, Fu J, Singh M, Mostovoy Y, Huang S, Garimella K, Kirkham SL, Neil JE, Shao DD, Walsh CA, Argili E, Le C, Sherr EH, Gleeson J, Shril S, Schneider R, Hildebrandt F, Sankaran VG, Madden JA, Genetti CA, Beggs AH, Agrawal PB, Bujakowska KM, Place E, Pierce EA, Donkervoort S, Bönnemann CG, Gallacher L, Stark Z, Tan T, White SM, Töpf A, Straub V, Fleming MD, Pollak MR, Õunap K, Pajusalu S, Donald KA, Bruwer Z, Ravenscroft G, Laing NG, MacArthur DG, Rehm HL, Talkowski ME, Brand H, and O'Donnell-Luria A
Abstract: Copy number variants (CNVs) are significant contributors to the pathogenicity of rare genetic diseases and with new innovative methods can now reliably be identified from exome sequencing. Challenges still remain in accurate classification of CNV pathogenicity. CNV calling using GATK-gCNV was performed on exomes from a cohort of 6,633 families (15,759 individuals) with heterogeneous phenotypes and variable prior genetic testing collected at the Broad Institute Center for Mendelian Genomics of the GREGoR consortium. Each family's CNV data was analyzed using the seqr platform and candidate CNVs classified using the 2020 ACMG/ClinGen CNV interpretation standards. We developed additional evidence criteria to address situations not covered by the current standards. The addition of CNV calling to exome analysis identified causal CNVs for 173 families (2.6%). The estimated sizes of CNVs ranged from 293 bp to 80 Mb with estimates that 44% would not have been detected by standard chromosomal microarrays. The causal CNVs consisted of 141 deletions, 15 duplications, 4 suspected complex structural variants (SVs), 3 insertions and 10 complex SVs, the latter two groups being identified by orthogonal validation methods. We interpreted 153 CNVs as likely pathogenic/pathogenic and 20 CNVs as high interest variants of uncertain significance. Calling CNVs from existing exome data increases the diagnostic yield for individuals undiagnosed after standard testing approaches, providing a higher resolution alternative to arrays at a fraction of the cost of genome sequencing. Our improvements to the classification approach advances the systematic framework to assess the pathogenicity of CNVs., Competing Interests: Declaration of interests H.L.R. has received support from Illumina and Microsoft to support rare disease gene discovery and diagnosis. A.O-D.L. has consulted for Tome Biosciences and Ono Pharma USA Inc. D.G.M is a paid advisor to GlaxoSmithKline, Insitro, Variant Bio and Overtone Therapeutics, and has received research support from AbbVie, Astellas, Biogen, BioMarin, Eisai, Google, Merck, Microsoft, Pfizer, and Sanofi-Genzyme. C.A.W. is a paid advisor to Maze Therapeutics. M.E.T. receives research funding from Microsoft Inc, Illumina Inc and Levo Therapeutics. The remaining authors declare no competing interests.
Published: 2023
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