31 results on '"Dardas, Zain"'
Search Results
2. Considerations for reporting variants in novel candidate genes identified during clinical genomic testing
- Author
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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.
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- 2024
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3. Investigating the genetic profile of familial atypical cystic fibrosis patients (DeltaF508-CFTR) with neonatal biliary atresia
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Altamimi, Eyad, Rabab’h, Omar, Aburizeg, Dunia, Akasheh, Lynn, Dardas, Zain, Srour, Luma, Awad, Heyam, and Azab, Bilal
- Published
- 2023
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4. Beyond the exome: What’s next in diagnostic testing for Mendelian conditions
- Author
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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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5. Genomic Balancing Act: Deciphering DNA rearrangements in the Complex Chromosomal Aberration involving 5p15.2, 2q31.1 and 18q21.32
- Author
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Lupski, James, primary, Dardas, Zain, additional, Marafi, Dana, additional, Duan, Ruizhi, additional, Fatih, Jawid, additional, El-Rashidy, Omnia, additional, Grochowski, Christopher, additional, Carvalho, Claudia, additional, Jhangiani, Shalini, additional, Bi, Weimin, additional, Du, Haowei, additional, Gibbs, Richard, additional, Posey, Jennifer, additional, Calame, Daniel, additional, and Zaki, Maha, additional
- Published
- 2024
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6. Biallelic variation in the choline and ethanolamine transporter FLVCR1 underlies a pleiotropic disease spectrum from adult neurodegeneration to severe developmental disorders
- Author
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Calame, Daniel G, primary, Wong, Jovi Huixin, additional, Panda, Puravi, additional, Nguyen, Dat Tuan, additional, Leong, Nancy C.P., additional, Sangermano, Riccardo, additional, Patankar, Sohil G, additional, AlAbdi, Lama, additional, Safwat, Sylvia, additional, Flannery, Kyle, additional, Dardas, Zain, additional, Fatih, Jawid M, additional, Murali, Chaya, additional, Kannan, Varun, additional, Lotze, Timothy E, additional, Herman, Isabella, additional, Ammouri, Farrah, additional, Rezich, Brianna, additional, Efthymiou, Stephanie, additional, Alavi, Shahryar, additional, Murphy, David, additional, Firoozfar, Zahra, additional, Nasab, Mahya Ebrahimi, additional, Bahreini, Amir, additional, Ghasemi, Majid, additional, Haridy, Nourelhoda A, additional, Goldouzi, Hamid Reza, additional, Eghbal, Fatemeh, additional, Karimiani, Ehsan Ghayoor, additional, Srinivasan, Varunvenkat M, additional, Gowda, Vykuntaraju K, additional, Du, Haowei, additional, Jhangiani, Shalini N, additional, Coban-Akdemir, Zeynep, additional, Marafi, Dana, additional, Rodan, Lance, additional, Isikay, Sedat, additional, Rosenfeld, Jill A, additional, Ramanathan, Subhadra, additional, Staton, Michael, additional, Oberg, Kerby C, additional, Clark, Robin D, additional, Wenman, Catharina, additional, Loughlin, Sam, additional, Saad, Ramy, additional, Ashraf, Tazeen, additional, Male, Alison, additional, Tadros, Shereen, additional, Boostani, Reza, additional, Abdel-Salam, Ghada H.M., additional, Zaki, Maha, additional, Abdalla, Ebtesam, additional, Manzini, M Chiara, additional, Pehlivan, Davut, additional, Posey, Jennifer E, additional, Gibbs, Richard A, additional, Houlden, Henry, additional, Alkuraya, Fowzan S, additional, Bujakowska, Kinga, additional, Maroofian, Reza, additional, Lupski, James R, additional, and Nguyen, Long Nam, additional
- Published
- 2024
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7. Enteric anendocrinosis attributable to a novel Neurogenin-3 variant
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Azab, Belal, Dardas, Zain, Rabab'h, Omar, Srour, Luma, Telfah, Hussam, Hatmal, Ma'mon M., Mustafa, Lina, Rashdan, Lana, and Altamimi, Eyad
- Published
- 2020
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8. The impact of exome sequencing on the diagnostic yield of muscular dystrophies in consanguineous families
- Author
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Dardas, Zain, Swedan, Samer, Al-Sheikh Qassem, Ahmad, and Azab, Belal
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- 2020
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9. HMZDupFinder: a robust computational approach for detecting intragenic homozygous duplications from exome sequencing data
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Du, Haowei, primary, Dardas, Zain, additional, Jolly, Angad, additional, Grochowski, Christopher M, additional, Jhangiani, Shalini N, additional, Li, He, additional, Muzny, Donna, additional, Fatih, Jawid M, additional, Yesil, Gozde, additional, Elçioglu, Nursel H, additional, Gezdirici, Alper, additional, Marafi, Dana, additional, Pehlivan, Davut, additional, Calame, Daniel G, additional, Carvalho, Claudia M B, additional, Posey, Jennifer E, additional, Gambin, Tomasz, additional, Coban-Akdemir, Zeynep, additional, and Lupski, James R, additional
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- 2023
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10. The frequency of NOTCH1 variants in T-acute lymphoblastic leukemia/lymphoma and chronic lymphocytic leukemia/small lymphocytic lymphoma among Jordanian patients
- Author
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Abualhaj, Nezeen Z., Dardas, Zain, Azab, Belal, Ali, Dema, Sughayer, Maher A., Aladily, Tariq N., and Ahram, Mamoun
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- 2019
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11. P634: Exonic SVs driven by Alu/Alu-mediated genomic rearrangements contribute on a large scale to alleles underlying human Mendelian rare disease traits
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Duan, Ruizhi, Du, Haowei, Dardas, Zain, and Lupski, James
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- 2024
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12. Genomic Balancing Act: deciphering DNA rearrangements in the complex chromosomal aberration involving 5p15.2, 2q31.1, and 18q21.32
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Dardas, Zain, Marafi, Dana, Duan, Ruizhi, Fatih, Jawid M., El-Rashidy, Omnia F., Grochowski, Christopher M., Carvalho, Claudia M. B., Jhangiani, Shalini N., Bi, Weimin, Du, Haowei, Gibbs, Richard A., Posey, Jennifer E., Calame, Daniel G., Zaki, Maha S., and Lupski, James R.
- Abstract
Despite extensive research into the genetic underpinnings of neurodevelopmental disorders (NDD), many clinical cases remain unresolved. We studied a female proband with a NDD, mildly dysmorphic facial features, and brain stem hypoplasia on neuroimaging. Comprehensive genomic analyses revealed a terminal 5p loss and a terminal 18q gain in the proband while a diploid copy number for chromosomes 5 and 18 in both parents. Genomic investigations in the proband identified an unbalanced translocation t(5;18) with additional genetic material from chromosome 2 (2q31.3) inserted at the breakpoint, pointing to a complex chromosomal rearrangement (CCR) involving 5p15.2, 2q31.3, and 18q21.32. Breakpoint junction analyses enabled by long-read genome sequencing unveiled the presence of four distinct junctions in the father, who is a carrier of a balanced CCR. The proband inherited from the father both the abnormal chromosome 5 resulting in segmental aneusomies of chr5 (loss) and chr18 (gain) and a der(2) homologue. Evidences suggest a chromoplexy mechanism for this CCR derivation, involving double-strand breaks (DSBs) repaired by non-homologous end joining (NHEJ) or alternative end joining (alt-EJ). The complexity of the CCR and the segregation of homologues elucidate the genetic model for this family. This study demonstrates the importance of combining multiple genomic technologies to uncover genetic causes of complex neurodevelopmental syndromes and to better understand genetic disease mechanisms.
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- 2024
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13. SLC26A4 Phenotypic Variability Influences Intra- and Inter-Familial Diagnosis and Management
- Author
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Tawalbeh, Mohamed, primary, Aburizeg, Dunia, additional, Abu Alragheb, Bayan O., additional, Alaqrabawi, Wala Sami, additional, Dardas, Zain, additional, Srour, Luma, additional, Altarayra, Baraah Hatem, additional, Zayed, Ayman A., additional, El Omari, Zaid, additional, and Azab, Bilal, additional
- Published
- 2022
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14. Investigating the genetic profile of familial atypical cystic fibrosis patients (DeltaF508-CFTR) with neonatal biliary atresia
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Altamimi, Eyad, primary, Rabab’h, Omar, additional, Aburizeg, Dunia, additional, Akasheh, Lynn, additional, Dardas, Zain, additional, Srour, Luma, additional, Awad, Heyam, additional, and Azab, Bilal, additional
- Published
- 2022
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15. Long read sequencing and expression studies ofAHDC1deletions in Xia‐Gibbs syndrome reveal a novel genetic regulatory mechanism
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Chander, Varuna, primary, Mahmoud, Medhat, additional, Hu, Jianhong, additional, Dardas, Zain, additional, Grochowski, Christopher M., additional, Dawood, Moez, additional, Khayat, Michael M., additional, Li, He, additional, Li, Shoudong, additional, Jhangiani, Shalini, additional, Korchina, Viktoriya, additional, Shen, Hua, additional, Weissenberger, George, additional, Meng, Qingchang, additional, Gingras, Marie‐Claude, additional, Muzny, Donna M., additional, Doddapaneni, Harsha, additional, Posey, Jennifer E., additional, Lupski, James R., additional, Sabo, Aniko, additional, Murdock, David R., additional, Sedlazeck, Fritz J., additional, and Gibbs, Richard A., additional
- Published
- 2022
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16. Potential Composite Digenic Contribution of NPC1 and NOD2 Leading to Atypical Lethal Niemann-Pick Type C with Initial Crohn’s Disease-like Presentation: Genotype-Phenotype Correlation Study
- Author
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Azab, Bilal, primary, Rabab’h, Omar, additional, Aburizeg, Dunia, additional, Mohammad, Hashim, additional, Dardas, Zain, additional, Mustafa, Lina, additional, Khasawneh, Ruba A., additional, Awad, Heyam, additional, Hatmal, Ma’mon M., additional, and Altamimi, Eyad, additional
- Published
- 2022
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17. TBX5 variant with the novel phenotype of mixed‑type total anomalous pulmonary venous return in Holt‑Oram Syndrome and variable intrafamilial heart defects
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Azab, Bilal, primary, Aburizeg, Dunia, additional, Ji, Weizhen, additional, Jeffries, Lauren, additional, Isbeih, Nooredeen, additional, Al‑Akily, Amal, additional, Mohammad, Hashim, additional, Osba, Yousef, additional, Shahin, Mohammad, additional, Dardas, Zain, additional, Hatmal, Ma'mon, additional, Al‑Ammouri, Iyad, additional, and Lakhani, Saquib, additional
- Published
- 2022
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18. Centers for Mendelian Genomics: A decade of facilitating gene discovery
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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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19. Effect of Genetic Testing on Diagnosing Gastrointestinal Pediatric Patients with Previously Undiagnosed Diseases
- Author
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Altamimi, Eyad, Khanfar, Mariam, Rabab’h, Omar, Dardas, Zain, Srour, Luma, Mustafa, Lina, and Azab, Bilal
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The Application of Clinical Genetics ,gastrointestinal diseases ,metabolic diseases ,pediatric diseases ,Original Research ,whole exome sequencing - Abstract
Eyad Altamimi,1 Mariam Khanfar,2 Omar Rabab’h,3 Zain Dardas,4,5 Luma Srour,4 Lina Mustafa,4 Bilal Azab4,6 1Department of Pediatrics and Neonatology, Jordan University of Science and Technology, Irbid, Jordan; 2Department of Medical Laboratory Sciences, Jordan University of Science and Technology, Irbid, Jordan; 3Center of Cognition and Neuroethics, University of Michigan-Flint, Flint, MI, USA; 4Department of Pathology, Microbiology and Forensic Medicine, School of Medicine, University of Jordan, Amman, Jordan; 5Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; 6Human and Molecular Genetics, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA, USACorrespondence: Eyad AltamimiDepartment of Pediatrics and Neonatology, Jordan University of Science and Technology, PO Box 3030, Irbid 22110, JordanTel +962 797464254Email emaltamimi@just.edu.joBilal AzabDepartment of Pathology, Microbiology and Forensic Medicine, School of Medicine, University of Jordan, Amman, JordanEmail azabbm@mymail.vcu.eduPurpose: Four consanguineous Jordanian families with affected members of unknown gastrointestinal related diseases were recruited to assess the utility and efficiency of whole exome sequencing (WES) in reaching the definitive diagnosis.Patients and Methods: Members from four consanguineous Jordanian families were recruited in this study. Laboratory and imaging tests were used for initial diagnosis, followed by performing WES to test all affected members for the detection of causative variants. Sanger sequencing was used for validation.Results: We had a 100% success rate identifying each case presented in this study.Conclusion: This is the first study applying a WES testing approach in the diagnosis of pediatric diseases in Jordan. Our results strongly suggest the need to implement WES as an evident diagnostic tool in the clinical setting, as it will subsequently allow for proper disease management and genetic counseling.Keywords: pediatric diseases, whole exome sequencing, gastrointestinal diseases, metabolic diseases
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- 2020
20. Long read sequencing and expression studies of AHDC1 deletions in Xia‐Gibbs syndrome reveal a novel genetic regulatory mechanism.
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Chander, Varuna, Mahmoud, Medhat, Hu, Jianhong, Dardas, Zain, Grochowski, Christopher M., Dawood, Moez, Khayat, Michael M., Li, He, Li, Shoudong, Jhangiani, Shalini, Korchina, Viktoriya, Shen, Hua, Weissenberger, George, Meng, Qingchang, Gingras, Marie‐Claude, Muzny, Donna M., Doddapaneni, Harsha, Posey, Jennifer E., Lupski, James R., and Sabo, Aniko
- Abstract
Xia‐Gibbs syndrome (XGS; MIM# 615829) is a rare mendelian disorder characterized by Development Delay (DD), intellectual disability (ID), and hypotonia. Individuals with XGS typically harbor de novo protein‐truncating mutations in the AT‐Hook DNA binding motif containing 1 (AHDC1) gene, although some missense mutations can also cause XGS. Large de novo heterozygous deletions that encompass the AHDC1 gene have also been ascribed as diagnostic for the disorder, without substantial evidence to support their pathogenicity. We analyzed 19 individuals with large contiguous deletions involving AHDC1, along with other genes. One individual bore the smallest known contiguous AHDC1 deletion (∼350 Kb), encompassing eight other genes within chr1p36.11 (Feline Gardner‐Rasheed, IFI6, FAM76A, STX12, PPP1R8, THEMIS2, RPA2, SMPDL3B) and terminating within the first intron of AHDC1. The breakpoint junctions and phase of the deletion were identified using both short and long read sequencing (Oxford Nanopore). Quantification of RNA expression patterns in whole blood revealed that AHDC1 exhibited a mono‐allelic expression pattern with no deficiency in overall AHDC1 expression levels, in contrast to the other deleted genes, which exhibited a 50% reduction in mRNA expression. These results suggest that AHDC1 expression in this individual is compensated by a novel regulatory mechanism and advances understanding of mutational and regulatory mechanisms in neurodevelopmental disorders. [ABSTRACT FROM AUTHOR]
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- 2022
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21. Unique Variant Spectrum in a Jordanian Cohort with Inherited Retinal Dystrophies
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Azab, Bilal, primary, Dardas, Zain, additional, Aburizeg, Dunia, additional, Al-Bdour, Muawyah, additional, Abu-Ameerh, Mohammed, additional, Saleh, Tareq, additional, Barham, Raghda, additional, Maswadi, Ranad, additional, Ababneh, Nidaa A, additional, Alsalem, Mohammad, additional, Zouk, Hana, additional, Amr, Sami, additional, and Awidi, Abdalla, additional
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- 2021
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22. Extending the spectrum of CLRN1 ‐ and ABCA4 ‐associated inherited retinal dystrophies caused by novel and recurrent variants using exome sequencing
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Abu‐Ameerh, Mohammed, primary, Mohammad, Hashim, additional, Dardas, Zain, additional, Barham, Raghda, additional, Ali, Dema, additional, Bijawi, Maysa, additional, Tawalbeh, Mohamed, additional, Amr, Sami, additional, Hatmal, Ma'mon M., additional, Al‐Bdour, Muawyah, additional, Awidi, Abdalla, additional, and Azab, Belal, additional
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- 2020
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23. Genotoxicity of cisplatin and carboplatin in cultured human lymphocytes: a comparative study
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Azab, Belal, primary, Alassaf, Anood, additional, Abu-Humdan, Abdulrahman, additional, Dardas, Zain, additional, Almousa, Hashem, additional, Alsalem, Mohammad, additional, Khabour, Omar, additional, Hammad, Hana, additional, Saleh, Tareq, additional, and Awidi, Abdalla, additional
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- 2019
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24. HMZDupFinder: a robust computational approach for detecting intragenic homozygous duplications from exome sequencing data.
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Du, Haowei, Dardas, Zain, Jolly, Angad, Grochowski, Christopher M, Jhangiani, Shalini N, Li, He, Muzny, Donna, Fatih, Jawid M, Yesil, Gozde, Elçioglu, Nursel H, Gezdirici, Alper, Marafi, Dana, Pehlivan, Davut, Calame, Daniel G, Carvalho, Claudia M B, Posey, Jennifer E, Gambin, Tomasz, Coban-Akdemir, Zeynep, and Lupski, James R
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- 2024
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25. Novel CERKL variant in consanguineous Jordanian pedigrees with inherited retinal dystrophies
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Azab, Belal, primary, Barham, Raghda, additional, Ali, Dema, additional, Dardas, Zain, additional, Rashdan, Lana, additional, Bijawi, Maysa, additional, Maswadi, Ranad, additional, Awidi, Abdelhalim, additional, Jafar, Hanan, additional, Abu-Ameerh, Mohammed, additional, Al-Bdour, Muawyah, additional, Amr, Sami, additional, and Awidi, Abdalla, additional
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- 2019
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26. Considerations for reporting variants in novel candidate genes identified during clinical genomic testing
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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 (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.
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- 2024
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27. Clinical heterogeneity in retinitis pigmentosa caused by variants in RP1 and RLBP1 in five extended consanguineous pedigrees.
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Al-Bdour, Muawyah, Pauleck, Svenja, Dardas, Zain, Barham, Raghda, Ali, Dema, Amr, Sami, Mustafa, Lina, Abu-Ameerh, Mohammed, Maswadi, Ranad, Azab, Belal, and Awidi, Abdalla
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- 2020
28. Novel frameshift variant in the IDUA gene underlies Mucopolysaccharidoses type I in a consanguineous Yemeni pedigree
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Azab, Belal, primary, Dardas, Zain, additional, Hamarsheh, Mohannad, additional, Alsalem, Mohammad, additional, Kilani, Zaid, additional, Kilani, Farah, additional, Awidi, Abdalla, additional, Jafar, Hanan, additional, and Amr, Sami, additional
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- 2017
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29. Novel frameshift variant in the IDUA gene underlies Mucopolysaccharidoses type I in a consanguineous Yemeni pedigree
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Azab, Belal, Dardas, Zain, Hamarsheh, Mohannad, Alsalem, Mohammad, Kilani, Zaid, Kilani, Farah, Awidi, Abdalla, Jafar, Hanan, and Amr, Sami
- Abstract
Mucopolysaccharidosis type I (MPS I) is an autosomal recessive storage disorder that result as a consequence of a deficiency in the lysosomal hydrolase, a-L-iduronidase enzyme encoded by IDUA gene. Over a hundred causative variants in IDUA have been identified, which result in a progressive multi-systemic disease with a broad range of severity and disease progression reported across affected individuals. The aim of this study was the detection and interpretation of IDUA mutation in a family with two children affected with lethal MPS I. The IDUA gene was sequenced in the parents of two deceased children who had a clinical diagnosis of MPS I, to assess their carrier status and to help inform on risk in future children. The sequencing analysis was performed by PCR and bidirectional Sanger sequencing of the coding region and exon-intron splice junctions at Labor MVZ Westmecklenburg molecular diagnostics laboratory. A heterozygous c.657delA variant in exon 6 was identified in each parent, which is the most likely explanation for disease in their children. This report represents the first Yemeni family to have a molecular diagnosis for MPS I.
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- 2017
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30. Genomic Balancing Act: Deciphering DNA rearrangements in the Complex Chromosomal Aberration involving 5p15.2, 2q31.1 and 18q21.32.
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Lupski J, Dardas Z, Marafi D, Duan R, Fatih J, El-Rashidy O, Grochowski C, Carvalho C, Jhangiani S, Bi W, Du H, Gibbs R, Posey J, Calame D, and Zaki M
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Despite extensive research into the genetic underpinnings of neurodevelopmental disorders (NDD), many clinical cases remain unresolved. We studied a female proband with a NDD, mildly dysmorphic facial features, and brain stem hypoplasia on neuroimaging. Comprehensive genomic analyses revealed a terminal 5p loss and terminal 18q gain in the proband while a diploid copy number for chromosomes 5 and 18 in both parents. Genomic investigations in the proband identified an unbalanced translocation t(5;18) with additional genetic material from chromosome 2 (2q31.3) inserted at the breakpoint, pointing to a complex chromosomal rearrangement (CCR) involving 5p15.2, 2q31.3, and 18q21.32. Breakpoint junction analyses enabled by long read genome sequencing unveiled the presence of four distinct junctions in the father, who is carrier of a balanced CCR. The proband inherited from the father both the abnormal chromosome 5 resulting in segmental aneusomies of chr5 (loss) and chr18 (gain) and a der(2) homologue. Evidences suggest a chromoplexy mechanism for this CCR derivation, involving double-strand breaks (DSBs) repaired by non-homologous end joining (NHEJ) or alternative end joining (alt-EJ). The complexity of the CCR and the segregation of homologues elucidate the genetic model for this family. This study demonstrates the importance of combining multiple genomic technologies to uncover genetic causes of complex neurodevelopmental syndrome and to better understand genetic disease mechanisms., Competing Interests: Additional Declarations: J.R.L. has stock ownership in 23andMe, is a paid consultant for Genome International, and is a co-inventor on multiple U.S. and European patents related to molecular diagnostics for inherited neuropathies, genomic disorders, eye diseases, and bacterial genomic fingerprinting. The Department of Molecular and Human Genetics at Baylor College of Medicine derives revenue from the chromosomal microarray analysis and clinical genomic sequencing (both ES and GS) offered in the Baylor Genetics Laboratory (http://bmgl.com). J.R.L. serves on the Scientific Advisory Board of BG.
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- 2024
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31. Biallelic variation in the choline and ethanolamine transporter FLVCR1 underlies a pleiotropic disease spectrum from adult neurodegeneration to severe developmental disorders.
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Calame DG, Wong JH, Panda P, Nguyen DT, Leong NCP, Sangermano R, Patankar SG, Abdel-Hamid M, AlAbdi L, Safwat S, Flannery KP, Dardas Z, Fatih JM, Murali C, Kannan V, Lotze TE, Herman I, Ammouri F, Rezich B, Efthymiou S, Alavi S, Murphy D, Firoozfar Z, Nasab ME, Bahreini A, Ghasemi M, Haridy NA, Goldouzi HR, Eghbal F, Karimiani EG, Srinivasan VM, Gowda VK, Du H, Jhangiani SN, Coban-Akdemir Z, Marafi D, Rodan L, Isikay S, Rosenfeld JA, Ramanathan S, Staton M, Kerby C Oberg, Clark RD, Wenman C, Loughlin S, Saad R, Ashraf T, Male A, Tadros S, Boostani R, Abdel-Salam GMH, Zaki M, Abdalla E, Manzini MC, Pehlivan D, Posey JE, Gibbs RA, Houlden H, Alkuraya FS, Bujakowska K, Maroofian R, Lupski JR, and Nguyen LN
- Abstract
FLVCR1 encodes Feline leukemia virus subgroup C receptor 1 (FLVCR1), a solute carrier (SLC) transporter within the Major Facilitator Superfamily. FLVCR1 is a widely expressed transmembrane protein with plasma membrane and mitochondrial isoforms implicated in heme, choline, and ethanolamine transport. While Flvcr1 knockout mice die in utero with skeletal malformations and defective erythropoiesis reminiscent of Diamond-Blackfan anemia, rare biallelic pathogenic FLVCR1 variants are linked to childhood or adult-onset neurodegeneration of the retina, spinal cord, and peripheral nervous system. We ascertained from research and clinical exome sequencing 27 individuals from 20 unrelated families with biallelic ultra-rare missense and predicted loss-of-function (pLoF) FLVCR1 variant alleles. We characterize an expansive FLVCR1 phenotypic spectrum ranging from adult-onset retinitis pigmentosa to severe developmental disorders with microcephaly, reduced brain volume, epilepsy, spasticity, and premature death. The most severely affected individuals, including three individuals with homozygous pLoF variants, share traits with Flvcr1 knockout mice and Diamond-Blackfan anemia including macrocytic anemia and congenital skeletal malformations. Pathogenic FLVCR1 missense variants primarily lie within transmembrane domains and reduce choline and ethanolamine transport activity compared with wild-type FLVCR1 with minimal impact on FLVCR1 stability or subcellular localization. Several variants disrupt splicing in a mini-gene assay which may contribute to genotype-phenotype correlations. Taken together, these data support an allele-specific gene dosage model in which phenotypic severity reflects residual FLVCR1 activity. This study expands our understanding of Mendelian disorders of choline and ethanolamine transport and demonstrates the importance of choline and ethanolamine in neurodevelopment and neuronal homeostasis., Competing Interests: Potential Conflict of Interest J.R.L. has stock ownership in 23andMe, is a paid consultant for Genome International, and is a co-inventor on multiple United States and European patents related to molecular diagnostics for inherited neuropathies, eye diseases, genomic disorders, and bacterial genomic fingerprinting. The Department of Molecular and Human Genetics at Baylor College of Medicine receives revenue from clinical genetic testing conducted at Baylor Genetics (BG) Laboratories. Other authors have no potential conflicts to disclose.
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- 2024
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