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1. Systematic evaluation of genome sequencing for the diagnostic assessment of autism spectrum disorder and fetal structural anomalies.

Author: Lowther, Chelsea, Valkanas, Elise, Giordano, Jessica, Wang, Harold, Currall, Benjamin, OKeefe, Kathryn, Pierce-Hoffman, Emma, Kurtas, Nehir, Whelan, Christopher, Hao, Stephanie, Weisburd, Ben, Jalili, Vahid, Fu, Jack, Wong, Isaac, Collins, Ryan, Zhao, Xuefang, Austin-Tse, Christina, Evangelista, Emily, Lemire, Gabrielle, Aggarwal, Vimla, Lucente, Diane, Gauthier, Laura, Tolonen, Charlotte, Sahakian, Nareh, Stevens, Christine, An, Joon-Yong, Dong, Shan, MacKenzie, Tippi, Devlin, Bernie, Gilmore, Kelly, Powell, Bradford, Brandt, Alicia, Vetrini, Francesco, DiVito, Michelle, MacArthur, Daniel, Hodge, Jennelle, ODonnell-Luria, Anne, Rehm, Heidi, Vora, Neeta, Levy, Brynn, Brand, Harrison, Wapner, Ronald, Talkowski, Michael, Norton, Mary, and Sanders, Stephan
Subjects: genome sequencing, karyotype, microarray, exome sequencing, structural variant, autism spectrum disorder, structural anomaly, prenatal, first-tier, diagnostic, Female, Pregnancy, Humans, Autism Spectrum Disorder, Pregnancy Trimester, First, Ultrasonography, Prenatal, Chromosome Mapping, Exome
Abstract: Short-read genome sequencing (GS) holds the promise of becoming the primary diagnostic approach for the assessment of autism spectrum disorder (ASD) and fetal structural anomalies (FSAs). However, few studies have comprehensively evaluated its performance against current standard-of-care diagnostic tests: karyotype, chromosomal microarray (CMA), and exome sequencing (ES). To assess the clinical utility of GS, we compared its diagnostic yield against these three tests in 1,612 quartet families including an individual with ASD and in 295 prenatal families. Our GS analytic framework identified a diagnostic variant in 7.8% of ASD probands, almost 2-fold more than CMA (4.3%) and 3-fold more than ES (2.7%). However, when we systematically captured copy-number variants (CNVs) from the exome data, the diagnostic yield of ES (7.4%) was brought much closer to, but did not surpass, GS. Similarly, we estimated that GS could achieve an overall diagnostic yield of 46.1% in unselected FSAs, representing a 17.2% increased yield over karyotype, 14.1% over CMA, and 4.1% over ES with CNV calling or 36.1% increase without CNV discovery. Overall, GS provided an added diagnostic yield of 0.4% and 0.8% beyond the combination of all three standard-of-care tests in ASD and FSAs, respectively. This corresponded to nine GS unique diagnostic variants, including sequence variants in exons not captured by ES, structural variants (SVs) inaccessible to existing standard-of-care tests, and SVs where the resolution of GS changed variant classification. Overall, this large-scale evaluation demonstrated that GS significantly outperforms each individual standard-of-care test while also outperforming the combination of all three tests, thus warranting consideration as the first-tier diagnostic approach for the assessment of ASD and FSAs.
Published: 2023

2. Genome-wide structural variant analysis identifies risk loci for non-Alzheimer’s dementias

Author: Kaivola, Karri, Chia, Ruth, Ding, Jinhui, Rasheed, Memoona, Fujita, Masashi, Menon, Vilas, Walton, Ronald L, Collins, Ryan L, Billingsley, Kimberley, Brand, Harrison, Talkowski, Michael, Zhao, Xuefang, Dewan, Ramita, Stark, Ali, Ray, Anindita, Solaiman, Jerez, Pilar Alvarez, Malik, Laksh, Dawson, Ted M, Rosenthal, Liana S, Albert, Marilyn S, Pletnikova, Olga, Troncoso, Juan C, Masellis, Mario, Keith, Julia, Black, Sandra E, Ferrucci, Luigi, Resnick, Susan M, Tanaka, Toshiko, Soltis, Anthony R, Viollet, Coralie, Sukumar, Gauthaman, Alba, Camille, Lott, Nathaniel, Martinez, Elisa McGrath, Tuck, Meila, Singh, Jatinder, Bacikova, Dagmar, Zhang, Xijun, Hupalo, Daniel N, Adeleye, Adelani, Wilkerson, Matthew D, Pollard, Harvey B, Dalgard, Clifton L, Gan-Or, Ziv, Rogaeva, Ekaterina, Brice, Alexis, Lesage, Suzanne, Xiromerisiou, Georgia, Calvo, Andrea, Canosa, Antonio, Chio, Adriano, Logroscino, Giancarlo, Mora, Gabriele, Krüger, Reijko, May, Patrick, Alcolea, Daniel, Clarimon, Jordi, Fortea, Juan, Gonzalez-Aramburu, Isabel, Infante, Jon, Lage, Carmen, Lleó, Alberto, Pastor, Pau, Sanchez-Juan, Pascual, Brett, Francesca, Aarsland, Dag, Al-Sarraj, Safa, Attems, Johannes, Gentleman, Steve, Hardy, John A, Hodges, Angela K, Love, Seth, McKeith, Ian G, Morris, Christopher M, Morris, Huw R, Palmer, Laura, Pickering-Brown, Stuart, Ryten, Mina, Thomas, Alan J, Troakes, Claire, Barrett, Matthew J, Beach, Thomas G, Bekris, Lynn M, Bennett, David A, Boeve, Bradley F, Dickson, Dennis W, Faber, Kelley, Ferman, Tanis, Flanagan, Margaret E, Foroud, Tatiana M, Ghetti, Bernardino, and Gibbs, J Raphael
Subjects: Biological Sciences, Genetics, Brain Disorders, Dementia, ALS, Rare Diseases, Neurodegenerative, Neurosciences, Human Genome, Frontotemporal Dementia (FTD), Alzheimer's Disease, Alzheimer's Disease Related Dementias (ADRD), Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Acquired Cognitive Impairment, Aging, Aetiology, 2.1 Biological and endogenous factors, Neurological, American Genome Center, International LBD Genomics Consortium, International ALS/FTD Consortium, PROSPECT Consortium, Lewy body dementia, amyotrophic lateral sclerosis, case-control study, frontotemporal dementia, genome-wide association study, non–Alzheimer's dementia, resource, structural variant
Abstract: We characterized the role of structural variants, a largely unexplored type of genetic variation, in two non-Alzheimer's dementias, namely Lewy body dementia (LBD) and frontotemporal dementia (FTD)/amyotrophic lateral sclerosis (ALS). To do this, we applied an advanced structural variant calling pipeline (GATK-SV) to short-read whole-genome sequence data from 5,213 European-ancestry cases and 4,132 controls. We discovered, replicated, and validated a deletion in TPCN1 as a novel risk locus for LBD and detected the known structural variants at the C9orf72 and MAPT loci as associated with FTD/ALS. We also identified rare pathogenic structural variants in both LBD and FTD/ALS. Finally, we assembled a catalog of structural variants that can be mined for new insights into the pathogenesis of these understudied forms of dementia.
Published: 2023

3. Rare coding variation provides insight into the genetic architecture and phenotypic context of autism

Author: Fu, Jack M, Satterstrom, F Kyle, Peng, Minshi, Brand, Harrison, Collins, Ryan L, Dong, Shan, Wamsley, Brie, Klei, Lambertus, Wang, Lily, Hao, Stephanie P, Stevens, Christine R, Cusick, Caroline, Babadi, Mehrtash, Banks, Eric, Collins, Brett, Dodge, Sheila, Gabriel, Stacey B, Gauthier, Laura, Lee, Samuel K, Liang, Lindsay, Ljungdahl, Alicia, Mahjani, Behrang, Sloofman, Laura, Smirnov, Andrey N, Barbosa, Mafalda, Betancur, Catalina, Brusco, Alfredo, Chung, Brian HY, Cook, Edwin H, Cuccaro, Michael L, Domenici, Enrico, Ferrero, Giovanni Battista, Gargus, J Jay, Herman, Gail E, Hertz-Picciotto, Irva, Maciel, Patricia, Manoach, Dara S, Passos-Bueno, Maria Rita, Persico, Antonio M, Renieri, Alessandra, Sutcliffe, James S, Tassone, Flora, Trabetti, Elisabetta, Campos, Gabriele, Cardaropoli, Simona, Carli, Diana, Chan, Marcus CY, Fallerini, Chiara, Giorgio, Elisa, Girardi, Ana Cristina, Hansen-Kiss, Emily, Lee, So Lun, Lintas, Carla, Ludena, Yunin, Nguyen, Rachel, Pavinato, Lisa, Pericak-Vance, Margaret, Pessah, Isaac N, Schmidt, Rebecca J, Smith, Moyra, Costa, Claudia IS, Trajkova, Slavica, Wang, Jaqueline YT, Yu, Mullin HC, Cutler, David J, De Rubeis, Silvia, Buxbaum, Joseph D, Daly, Mark J, Devlin, Bernie, Roeder, Kathryn, Sanders, Stephan J, and Talkowski, Michael E
Subjects: Biological Sciences, Bioinformatics and Computational Biology, Genetics, Autism, Brain Disorders, Pediatric, Biotechnology, Intellectual and Developmental Disabilities (IDD), Human Genome, Mental Health, Clinical Research, Aetiology, 2.1 Biological and endogenous factors, Mental health, Autism Spectrum Disorder, Autistic Disorder, DNA Copy Number Variations, Genetic Predisposition to Disease, Humans, Mutation, Autism Sequencing Consortium, Broad Institute Center for Common Disease Genomics, iPSYCH-BROAD Consortium, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract: Some individuals with autism spectrum disorder (ASD) carry functional mutations rarely observed in the general population. We explored the genes disrupted by these variants from joint analysis of protein-truncating variants (PTVs), missense variants and copy number variants (CNVs) in a cohort of 63,237 individuals. We discovered 72 genes associated with ASD at false discovery rate (FDR) ≤ 0.001 (185 at FDR ≤ 0.05). De novo PTVs, damaging missense variants and CNVs represented 57.5%, 21.1% and 8.44% of association evidence, while CNVs conferred greatest relative risk. Meta-analysis with cohorts ascertained for developmental delay (DD) (n = 91,605) yielded 373 genes associated with ASD/DD at FDR ≤ 0.001 (664 at FDR ≤ 0.05), some of which differed in relative frequency of mutation between ASD and DD cohorts. The DD-associated genes were enriched in transcriptomes of progenitor and immature neuronal cells, whereas genes showing stronger evidence in ASD were more enriched in maturing neurons and overlapped with schizophrenia-associated genes, emphasizing that these neuropsychiatric disorders may share common pathways to risk.
Published: 2022

4. GATK-gCNV enables the discovery of rare copy number variants from exome sequencing data

Author: Babadi, Mehrtash, Fu, Jack M., Lee, Samuel K., Smirnov, Andrey N., Gauthier, Laura D., Walker, Mark, Benjamin, David I., Zhao, Xuefang, Karczewski, Konrad J., Wong, Isaac, Collins, Ryan L., Sanchis-Juan, Alba, Brand, Harrison, Banks, Eric, and Talkowski, Michael E.
Published: 2023
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5. 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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6. 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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7. Narrowing the diagnostic gap: Genomes, episignatures, long-read sequencing, and health economic analyses in an exome-negative intellectual disability cohort

Author: Dias, Kerith-Rae, Shrestha, Rupendra, Schofield, Deborah, Evans, Carey-Anne, O’Heir, Emily, Zhu, Ying, Zhang, Futao, Standen, Krystle, Weisburd, Ben, Stenton, Sarah L., Sanchis-Juan, Alba, Brand, Harrison, Talkowski, Michael E., Ma, Alan, Ghedia, Sondy, Wilson, Meredith, Sandaradura, Sarah A., Smith, Janine, Kamien, Benjamin, Turner, Anne, Bakshi, Madhura, Adès, Lesley C., Mowat, David, Regan, Matthew, McGillivray, George, Savarirayan, Ravi, White, Susan M., Tan, Tiong Yang, Stark, Zornitza, Brown, Natasha J., Pérez-Jurado, Luis A., Krzesinski, Emma, Hunter, Matthew F., Akesson, Lauren, Fennell, Andrew Paul, Yeung, Alison, Boughtwood, Tiffany, Ewans, Lisa J., Kerkhof, Jennifer, Lucas, Christopher, Carey, Louise, French, Hugh, Rapadas, Melissa, Stevanovski, Igor, Deveson, Ira W., Cliffe, Corrina, Elakis, George, Kirk, Edwin P., Dudding-Byth, Tracy, Fletcher, Janice, Walsh, Rebecca, Corbett, Mark A., Kroes, Thessa, Gecz, Jozef, Meldrum, Cliff, Cliffe, Simon, Wall, Meg, Lunke, Sebastian, North, Kathryn, Amor, David J., Field, Michael, Sadikovic, Bekim, Buckley, Michael F., O’Donnell-Luria, Anne, and Roscioli, Tony
Published: 2024
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8. Expanding the genetics and phenotypes of ocular congenital cranial dysinnervation disorders

Author: Abarca-Barriga, Hugo, Al-Haddad, Christiane, Berman, Jeffrey L., Bothun, Erick D., Capasso, Jenina, Chacon-Camacho, Oscar Francisco, Chang, Lan, Christiansen, Stephen P., Ciccarelli, Maria Laura, Cordonnier, Monique, Cox, Gerald F., Curry, Cynthia J., Dagi, Linda R., Lee Dahm, Thomas, David, Karen L., Davitt, Bradley V., De Berardinis, Teresa, Demer, Joseph L., Désir, Julie, D’Esposito, Fabiana, Drack, Arlene V., Eggenberger, Eric, Elder, James E., Elliott, Alexandra T., Epley, K. David, Feldman, Hagit Baris, Ferreira, Carlos R., Flaherty, Maree P., Fulton, Anne B., Gerth-Kahlert, Christina, Gottlob, Irene, Grill, Stephen, Halliday, Dorothy J., Hanisch, Frank, Hay, Eleanor, Heidary, Gena, Holder, Christopher, Horton, Jonathan C., Iannaccone, Alessandro, Isenberg, Sherwin J., Johnston, Suzanne C., Kahana, Alon, Katowitz, James A., Kazlas, Melanie, Kerr, Natalie C., Kimonis, Virginia, Ko, Melissa W., Koc, Feray, Larsen, Dorte Ancher, Lay-Son, Guillermo, Ledoux, Danielle M., Levin, Alex V., Levy, Richard L., Lyons, Christopher J., Mackey, David A., Magli, Adriano, Mantagos, Iason S., Marti, Candice, Maystadt, Isabelle, McKenzie, Fiona, Menezes, Manoj P., Mikail, Claudia N., Miller, David T., Miller, Kathryn Bisceglia, Mills, Monte D., Miyana, Kaori, Moller, H.U., Mullineaux, Lisa, Nishimura, Julie K., Noble, A. Gwendolyn, Pandey, Pramod Kumar, Pavone, Piero, Penzien, Johann, Petersen, Robert, Phalen, James A., Poduri, Annapurna, Polo, Claudia R., Prasov, Lev, Ramos, Feliciano J., Ramos-Caceres, Maria, Robb, Richard M., Rossillion, Béatrice, Sahin, Mustafa, Singer, Harvey S., Smith, Lois E.H., Sorkin, Jeffrey A., Soul, Janet S., Staffieri, Sandra E., Stalker, Heather J., Stasheff, Steven F., Strassberg, Sonya, Strominger, Mitchell B., Taranath, Deepa Ajay, Thomas, Ioan Talfryn, Traboulsi, Elias I., Ugrin, Maria Cristina, VanderVeen, Deborah K., Vincent, Andrea L., Vogel G, Marlene C., Wabbels, Bettina, Wong, Agnes M.F., Woods, C. Geoffrey, Wu, Carolyn, Yang, Edward, Yeung, Alison, Young, Terri L., Zenteno, Juan C., Zubcov-Iwantscheff, Alexandra A., Zwaan, Johan, Jurgens, Julie A., Barry, Brenda J., Chan, Wai-Man, MacKinnon, Sarah, Whitman, Mary C., Matos Ruiz, Paola M., Pratt, Brandon M., England, Eleina M., Pais, Lynn, Lemire, Gabrielle, Groopman, Emily, Glaze, Carmen, Russell, Kathryn A., Singer-Berk, Moriel, Di Gioia, Silvio Alessandro, Lee, Arthur S., Andrews, Caroline, Shaaban, Sherin, Wirth, Megan M., Bekele, Sarah, Toffoloni, Melissa, Bradford, Victoria R., Foster, Emma E., Berube, Lindsay, Rivera-Quiles, Cristina, Mensching, Fiona M., Sanchis-Juan, Alba, Fu, Jack M., Wong, Isaac, Zhao, Xuefang, Wilson, Michael W., Weisburd, Ben, Lek, Monkol, Brand, Harrison, Talkowski, Michael E., MacArthur, Daniel G., O’Donnell-Luria, Anne, Robson, Caroline D., Hunter, David G., and Engle, Elizabeth C.
Published: 2024
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9. Author Correction: GATK-gCNV enables the discovery of rare copy number variants from exome sequencing data

Author: Babadi, Mehrtash, Fu, Jack M., Lee, Samuel K., Smirnov, Andrey N., Gauthier, Laura D., Walker, Mark, Benjamin, David I., Zhao, Xuefang, Karczewski, Konrad J., Wong, Isaac, Collins, Ryan L., Sanchis-Juan, Alba, Brand, Harrison, Banks, Eric, and Talkowski, Michael E.
Published: 2024
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10. De novo structural mutation rates and gamete-of-origin biases revealed through genome sequencing of 2,396 families

Author: Belyeu, Jonathan R, Brand, Harrison, Wang, Harold, Zhao, Xuefang, Pedersen, Brent S, Feusier, Julie, Gupta, Meenal, Nicholas, Thomas J, Brown, Joseph, Baird, Lisa, Devlin, Bernie, Sanders, Stephan J, Jorde, Lynn B, Talkowski, Michael E, and Quinlan, Aaron R
Subjects: Genetics, Biotechnology, Human Genome, Pediatric, Contraception/Reproduction, Brain Disorders, Intellectual and Developmental Disabilities (IDD), 2.1 Biological and endogenous factors, Aetiology, Aging, Autistic Disorder, Bias, DNA Copy Number Variations, DNA Mutational Analysis, Family, Female, Genome, Human, Germ Cells, Germ-Line Mutation, Humans, Male, Mutation Rate, Paternal Age, Point Mutation, autism, copy number variation, de novo mutation, genetic diversity, genomic structure, genomics, germline mutation, structural variation, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract: Each human genome includes de novo mutations that arose during gametogenesis. While these germline mutations represent a fundamental source of new genetic diversity, they can also create deleterious alleles that impact fitness. Whereas the rate and patterns of point mutations in the human germline are now well understood, far less is known about the frequency and features that impact de novo structural variants (dnSVs). We report a family-based study of germline mutations among 9,599 human genomes from 33 multigenerational CEPH-Utah families and 2,384 families from the Simons Foundation Autism Research Initiative. We find that de novo structural mutations detected by alignment-based, short-read WGS occur at an overall rate of at least 0.160 events per genome in unaffected individuals, and we observe a significantly higher rate (0.206 per genome) in ASD-affected individuals. In both probands and unaffected samples, nearly 73% of de novo structural mutations arose in paternal gametes, and we predict most de novo structural mutations to be caused by mutational mechanisms that do not require sequence homology. After multiple testing correction, we did not observe a statistically significant correlation between parental age and the rate of de novo structural variation in offspring. These results highlight that a spectrum of mutational mechanisms contribute to germline structural mutations and that these mechanisms most likely have markedly different rates and selective pressures than those leading to point mutations.
Published: 2021

11. Trio-based GWAS identifies novel associations and subtype-specific risk factors for cleft palate

Author: Robinson, Kelsey, Mosley, Trenell J., Rivera-González, Kenneth S., Jabbarpour, Christopher R., Curtis, Sarah W., Adeyemo, Wasiu Lanre, Beaty, Terri H., Butali, Azeez, Buxó, Carmen J., Cutler, David J., Epstein, Michael P., Gowans, Lord J.J., Hecht, Jacqueline T., Murray, Jeffrey C., Shaw, Gary M., Uribe, Lina Moreno, Weinberg, Seth M., Brand, Harrison, Marazita, Mary L., Lipinski, Robert J., and Leslie, Elizabeth J.
Published: 2023
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12. PLS3 missense variants affecting the actin-binding domains cause X-linked congenital diaphragmatic hernia and body-wall defects

Author: Petit, Florence, Longoni, Mauro, Wells, Julie, Maser, Richard S., Bogenschutz, Eric L., Dysart, Matthew J., Contreras, Hannah T.M., Frénois, Frederic, Pober, Barbara R., Clark, Robin D., Giampietro, Philip F., Ropers, Hilger H., Hu, Hao, Loscertales, Maria, Wagner, Richard, Ai, Xingbin, Brand, Harrison, Jourdain, Anne-Sophie, Delrue, Marie-Ange, Gilbert-Dussardier, Brigitte, Devisme, Louise, Keren, Boris, McCulley, David J., Qiao, Lu, Hernan, Rebecca, Wynn, Julia, Scott, Tiana M., Calame, Daniel G., Coban-Akdemir, Zeynep, Hernandez, Patricia, Hernandez-Garcia, Andres, Yonath, Hagith, Lupski, James R., Shen, Yufeng, Chung, Wendy K., Scott, Daryl A., Bult, Carol J., Donahoe, Patricia K., and High, Frances A.
Published: 2023
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13. 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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14. Genome-wide structural variant analysis identifies risk loci for non-Alzheimer’s dementias

Author: Soltis, Anthony R., Viollet, Coralie, Sukumar, Gauthaman, Alba, Camille, Lott, Nathaniel, McGrath Martinez, Elisa, Tuck, Meila, Singh, Jatinder, Bacikova, Dagmar, Zhang, Xijun, Hupalo, Daniel N., Adeleye, Adelani, Wilkerson, Matthew D., Pollard, Harvey B., Dalgard, Clifton L., Black, Sandra E., Gan-Or, Ziv, Keith, Julia, Masellis, Mario, Rogaeva, Ekaterina, Brice, Alexis, Lesage, Suzanne, Xiromerisiou, Georgia, Calvo, Andrea, Canosa, Antonio, Chio, Adriano, Logroscino, Giancarlo, Mora, Gabriele, Krüger, Reijko, May, Patrick, Alcolea, Daniel, Clarimon, Jordi, Fortea, Juan, Gonzalez-Aramburu, Isabel, Infante, Jon, Lage, Carmen, Lleó, Alberto, Pastor, Pau, Sanchez-Juan, Pascual, Brett, Francesca, Aarsland, Dag, Al-Sarraj, Safa, Attems, Johannes, Gentleman, Steve, Hardy, John A., Hodges, Angela K., Love, Seth, McKeith, Ian G., Morris, Christopher M., Morris, Huw R., Palmer, Laura, Pickering-Brown, Stuart, Ryten, Mina, Thomas, Alan J., Troakes, Claire, Albert, Marilyn S., Barrett, Matthew J., Beach, Thomas G., Bekris, Lynn M., Bennett, David A., Boeve, Bradley F., Dawson, Ted M., Dickson, Dennis W., Faber, Kelley, Ferman, Tanis, Ferrucci, Luigi, Flanagan, Margaret E., Foroud, Tatiana M., Ghetti, Bernardino, Gibbs, J. Raphael, Goate, Alison, Goldstein, David S., Graff-Radford, Neill R., Kaufmann, Horacio, Kukull, Walter A., Leverenz, James B., Lopez, Grisel, Mao, Qinwen, Masliah, Eliezer, Monuki, Edwin, Newell, Kathy L., Palma, Jose-Alberto, Perkins, Matthew, Pletnikova, Olga, Renton, Alan E., Resnick, Susan M., Rosenthal, Liana S., Ross, Owen A., Scherzer, Clemens R., Serrano, Geidy E., Shakkottai, Vikram G., Sidransky, Ellen, Tanaka, Toshiko, Tayebi, Nahid, Topol, Eric, Torkamani, Ali, Troncoso, Juan C., Woltjer, Randy, Wszolek, Zbigniew K., Scholz, Sonja W., Baloh, Robert H., Bowser, Robert, Broach, James, Camu, William, Chiò, Adriano, Cooper-Knock, John, Drepper, Carsten, Drory, Vivian E., Dunckley, Travis L., Feldman, Eva, Fratta, Pietro, Gerhard, Glenn, Gibson, Summer B., Glass, Jonathan D., Harms, Matthew B., Heiman-Patterson, Terry D., Jansson, Lilja, Kirby, Janine, Kwan, Justin, Laaksovirta, Hannu, Landers, John E., Landi, Francesco, Le Ber, Isabelle, Lumbroso, Serge, MacGowan, Daniel J.L., Maragakis, Nicholas J., Mouzat, Kevin, Myllykangas, Liisa, Orrell, Richard W., Ostrow, Lyle W., Pamphlett, Roger, Pioro, Erik, Pulst, Stefan M., Ravits, John M., Robberecht, Wim, Rothstein, Jeffrey D., Sendtner, Michael, Shaw, Pamela J., Sidle, Katie C., Simmons, Zachary, Stein, Thor, Stone, David J., Tienari, Pentti J., Traynor, Bryan J., Valori, Miko, Van Damme, Philip, Van Deerlin, Vivianna M., Van Den Bosch, Ludo, Zinman, Lorne, Kaivola, Karri, Chia, Ruth, Ding, Jinhui, Rasheed, Memoona, Fujita, Masashi, Menon, Vilas, Walton, Ronald L., Collins, Ryan L., Billingsley, Kimberley, Brand, Harrison, Talkowski, Michael, Zhao, Xuefang, Dewan, Ramita, Stark, Ali, Ray, Anindita, Solaiman, Sultana, Alvarez Jerez, Pilar, Malik, Laksh, Tienari, Pentti, Mazzini, Letizia, D'Alfonso, Sandra, Moglia, Cristina, and De Jager, Philip L.
Published: 2023
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15. A structural variation reference for medical and population genetics

Author: Collins, Ryan L, Brand, Harrison, Karczewski, Konrad J, Zhao, Xuefang, Alföldi, Jessica, Francioli, Laurent C, Khera, Amit V, Lowther, Chelsea, Gauthier, Laura D, Wang, Harold, Watts, Nicholas A, Solomonson, Matthew, O’Donnell-Luria, Anne, Baumann, Alexander, Munshi, Ruchi, Walker, Mark, Whelan, Christopher W, Huang, Yongqing, Brookings, Ted, Sharpe, Ted, Stone, Matthew R, Valkanas, Elise, Fu, Jack, Tiao, Grace, Laricchia, Kristen M, Ruano-Rubio, Valentin, Stevens, Christine, Gupta, Namrata, Cusick, Caroline, Margolin, Lauren, Taylor, Kent D, Lin, Henry J, Rich, Stephen S, Post, Wendy S, Chen, Yii-Der Ida, Rotter, Jerome I, Nusbaum, Chad, Philippakis, Anthony, Lander, Eric, Gabriel, Stacey, Neale, Benjamin M, Kathiresan, Sekar, Daly, Mark J, Banks, Eric, MacArthur, Daniel G, and Talkowski, Michael E
Subjects: Biological Sciences, Bioinformatics and Computational Biology, Genetics, Biotechnology, Human Genome, Generic health relevance, Disease, Female, Genetic Testing, Genetic Variation, Genetics, Medical, Genetics, Population, Genome, Human, Genotyping Techniques, Humans, Male, Middle Aged, Mutation, Polymorphism, Single Nucleotide, Racial Groups, Reference Standards, Selection, Genetic, Whole Genome Sequencing, Genome Aggregation Database Production Team, Genome Aggregation Database Consortium, General Science & Technology
Abstract: Structural variants (SVs) rearrange large segments of DNA1 and can have profound consequences in evolution and human disease2,3. As national biobanks, disease-association studies, and clinical genetic testing have grown increasingly reliant on genome sequencing, population references such as the Genome Aggregation Database (gnomAD)4 have become integral in the interpretation of single-nucleotide variants (SNVs)5. However, there are no reference maps of SVs from high-coverage genome sequencing comparable to those for SNVs. Here we present a reference of sequence-resolved SVs constructed from 14,891 genomes across diverse global populations (54% non-European) in gnomAD. We discovered a rich and complex landscape of 433,371 SVs, from which we estimate that SVs are responsible for 25-29% of all rare protein-truncating events per genome. We found strong correlations between natural selection against damaging SNVs and rare SVs that disrupt or duplicate protein-coding sequence, which suggests that genes that are highly intolerant to loss-of-function are also sensitive to increased dosage6. We also uncovered modest selection against noncoding SVs in cis-regulatory elements, although selection against protein-truncating SVs was stronger than all noncoding effects. Finally, we identified very large (over one megabase), rare SVs in 3.9% of samples, and estimate that 0.13% of individuals may carry an SV that meets the existing criteria for clinically important incidental findings7. This SV resource is freely distributed via the gnomAD browser8 and will have broad utility in population genetics, disease-association studies, and diagnostic screening.
Published: 2020

16. Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism

Author: Satterstrom, F Kyle, Kosmicki, Jack A, Wang, Jiebiao, Breen, Michael S, De Rubeis, Silvia, An, Joon-Yong, Peng, Minshi, Collins, Ryan, Grove, Jakob, Klei, Lambertus, Stevens, Christine, Reichert, Jennifer, Mulhern, Maureen S, Artomov, Mykyta, Gerges, Sherif, Sheppard, Brooke, Xu, Xinyi, Bhaduri, Aparna, Norman, Utku, Brand, Harrison, Schwartz, Grace, Nguyen, Rachel, Guerrero, Elizabeth E, Dias, Caroline, Consortium, Autism Sequencing, Aleksic, Branko, Anney, Richard, Barbosa, Mafalda, Bishop, Somer, Brusco, Alfredo, Bybjerg-Grauholm, Jonas, Carracedo, Angel, Chan, Marcus CY, Chiocchetti, Andreas G, Chung, Brian HY, Coon, Hilary, Cuccaro, Michael L, Curró, Aurora, Bernardina, Bernardo Dalla, Doan, Ryan, Domenici, Enrico, Dong, Shan, Fallerini, Chiara, Fernández-Prieto, Montserrat, Ferrero, Giovanni Battista, Freitag, Christine M, Fromer, Menachem, Gargus, J Jay, Geschwind, Daniel, Giorgio, Elisa, González-Peñas, Javier, Guter, Stephen, Halpern, Danielle, Hansen-Kiss, Emily, He, Xin, Herman, Gail E, Hertz-Picciotto, Irva, Hougaard, David M, Hultman, Christina M, Ionita-Laza, Iuliana, Jacob, Suma, Jamison, Jesslyn, Jugessur, Astanand, Kaartinen, Miia, Knudsen, Gun Peggy, Kolevzon, Alexander, Kushima, Itaru, Lee, So Lun, Lehtimäki, Terho, Lim, Elaine T, Lintas, Carla, Lipkin, W Ian, Lopergolo, Diego, Lopes, Fátima, Ludena, Yunin, Maciel, Patricia, Magnus, Per, Mahjani, Behrang, Maltman, Nell, Manoach, Dara S, Meiri, Gal, Menashe, Idan, Miller, Judith, Minshew, Nancy, Montenegro, Eduarda MS, Moreira, Danielle, Morrow, Eric M, Mors, Ole, Mortensen, Preben Bo, Mosconi, Matthew, Muglia, Pierandrea, Neale, Benjamin M, Nordentoft, Merete, Ozaki, Norio, Palotie, Aarno, Parellada, Mara, Passos-Bueno, Maria Rita, Pericak-Vance, Margaret, Persico, Antonio M, and Pessah, Isaac
Subjects: Biological Sciences, Bioinformatics and Computational Biology, Biomedical and Clinical Sciences, Genetics, Brain Disorders, Mental Health, Pediatric, Human Genome, Clinical Research, Autism, Intellectual and Developmental Disabilities (IDD), Neurosciences, Aetiology, 2.1 Biological and endogenous factors, Mental health, Neurological, Autistic Disorder, Case-Control Studies, Cell Lineage, Cerebral Cortex, Cohort Studies, Exome, Female, Gene Expression Regulation, Developmental, Gene Frequency, Genetic Predisposition to Disease, Humans, Male, Mutation, Missense, Neurobiology, Neurons, Phenotype, Sex Factors, Single-Cell Analysis, Exome Sequencing, Autism Sequencing Consortium, iPSYCH-Broad Consortium, autism spectrum disorder, cell type, cytoskeleton, excitatory neurons, excitatory-inhibitory balance, exome sequencing, genetics, inhibitory neurons, liability, neurodevelopment, Medical and Health Sciences, Developmental Biology, Biological sciences, Biomedical and clinical sciences
Abstract: We present the largest exome sequencing study of autism spectrum disorder (ASD) to date (n = 35,584 total samples, 11,986 with ASD). Using an enhanced analytical framework to integrate de novo and case-control rare variation, we identify 102 risk genes at a false discovery rate of 0.1 or less. Of these genes, 49 show higher frequencies of disruptive de novo variants in individuals ascertained to have severe neurodevelopmental delay, whereas 53 show higher frequencies in individuals ascertained to have ASD; comparing ASD cases with mutations in these groups reveals phenotypic differences. Expressed early in brain development, most risk genes have roles in regulation of gene expression or neuronal communication (i.e., mutations effect neurodevelopmental and neurophysiological changes), and 13 fall within loci recurrently hit by copy number variants. In cells from the human cortex, expression of risk genes is enriched in excitatory and inhibitory neuronal lineages, consistent with multiple paths to an excitatory-inhibitory imbalance underlying ASD.
Published: 2020

17. Rare variants found in clinical gene panels illuminate the genetic and allelic architecture of orofacial clefting

Author: Diaz Perez, Kimberly K., Curtis, Sarah W., Sanchis-Juan, Alba, Zhao, Xuefang, Head, Taylor, Ho, Samantha, Carter, Bridget, McHenry, Toby, Bishop, Madison R., Valencia-Ramirez, Luz Consuelo, Restrepo, Claudia, Hecht, Jacqueline T., Uribe, Lina Moreno, Wehby, George, Weinberg, Seth M., Beaty, Terri H., Murray, Jeffrey C., Feingold, Eleanor, Marazita, Mary L., Cutler, David J., Epstein, Michael P., Brand, Harrison, and Leslie, Elizabeth J.
Published: 2023
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18. A neurodevelopmental disorder caused by a novel de novo SVA insertion in exon 13 of the SRCAP gene

Author: Zhao, Boxun, Madden, Jill A., Lin, Jasmine, Berry, Gerard T., Wojcik, Monica H., Zhao, Xuefang, Brand, Harrison, Talkowski, Michael, Lee, Eunjung Alice, and Agrawal, Pankaj B.
Published: 2022
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19. 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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20. Rare germline structural variants increase risk for pediatric solid tumors

Author: Gillani, Riaz, primary, Collins, Ryan L, additional, Crowdis, Jett, additional, Garza, Amanda, additional, Jones, Jill K, additional, Walker, Mark, additional, Sanchis-Juan, Alba, additional, Whelan, Christopher W., additional, Pierce-Hoffman, Emma, additional, Talkowski, Michael E, additional, Brand, Harrison, additional, Haigis, Kevin M, additional, LoPiccolo, Jaclyn, additional, AlDubayan, Saud H., additional, Gusev, Alexander H., additional, Crompton, Brian D, additional, Janeway, Katherine, additional, and Van Allen, Eliezer, additional
Published: 2024
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21. Multi-platform discovery of haplotype-resolved structural variation in human genomes.

Author: Chaisson, Mark JP, Sanders, Ashley D, Zhao, Xuefang, Malhotra, Ankit, Porubsky, David, Rausch, Tobias, Gardner, Eugene J, Rodriguez, Oscar L, Guo, Li, Collins, Ryan L, Fan, Xian, Wen, Jia, Handsaker, Robert E, Fairley, Susan, Kronenberg, Zev N, Kong, Xiangmeng, Hormozdiari, Fereydoun, Lee, Dillon, Wenger, Aaron M, Hastie, Alex R, Antaki, Danny, Anantharaman, Thomas, Audano, Peter A, Brand, Harrison, Cantsilieris, Stuart, Cao, Han, Cerveira, Eliza, Chen, Chong, Chen, Xintong, Chin, Chen-Shan, Chong, Zechen, Chuang, Nelson T, Lambert, Christine C, Church, Deanna M, Clarke, Laura, Farrell, Andrew, Flores, Joey, Galeev, Timur, Gorkin, David U, Gujral, Madhusudan, Guryev, Victor, Heaton, William Haynes, Korlach, Jonas, Kumar, Sushant, Kwon, Jee Young, Lam, Ernest T, Lee, Jong Eun, Lee, Joyce, Lee, Wan-Ping, Lee, Sau Peng, Li, Shantao, Marks, Patrick, Viaud-Martinez, Karine, Meiers, Sascha, Munson, Katherine M, Navarro, Fabio CP, Nelson, Bradley J, Nodzak, Conor, Noor, Amina, Kyriazopoulou-Panagiotopoulou, Sofia, Pang, Andy WC, Qiu, Yunjiang, Rosanio, Gabriel, Ryan, Mallory, Stütz, Adrian, Spierings, Diana CJ, Ward, Alistair, Welch, AnneMarie E, Xiao, Ming, Xu, Wei, Zhang, Chengsheng, Zhu, Qihui, Zheng-Bradley, Xiangqun, Lowy, Ernesto, Yakneen, Sergei, McCarroll, Steven, Jun, Goo, Ding, Li, Koh, Chong Lek, Ren, Bing, Flicek, Paul, Chen, Ken, Gerstein, Mark B, Kwok, Pui-Yan, Lansdorp, Peter M, Marth, Gabor T, Sebat, Jonathan, Shi, Xinghua, Bashir, Ali, Ye, Kai, Devine, Scott E, Talkowski, Michael E, Mills, Ryan E, Marschall, Tobias, Korbel, Jan O, Eichler, Evan E, and Lee, Charles
Subjects: Humans, Chromosome Mapping, Genomics, Haplotypes, Genome, Human, Algorithms, Databases, Genetic, INDEL Mutation, Genomic Structural Variation, High-Throughput Nucleotide Sequencing, Whole Genome Sequencing, Genome, Human, Databases, Genetic
Abstract: The incomplete identification of structural variants (SVs) from whole-genome sequencing data limits studies of human genetic diversity and disease association. Here, we apply a suite of long-read, short-read, strand-specific sequencing technologies, optical mapping, and variant discovery algorithms to comprehensively analyze three trios to define the full spectrum of human genetic variation in a haplotype-resolved manner. We identify 818,054 indel variants (
Published: 2019

22. Genome-wide de novo risk score implicates promoter variation in autism spectrum disorder

Author: An, Joon-Yong, Lin, Kevin, Zhu, Lingxue, Werling, Donna M, Dong, Shan, Brand, Harrison, Wang, Harold Z, Zhao, Xuefang, Schwartz, Grace B, Collins, Ryan L, Currall, Benjamin B, Dastmalchi, Claudia, Dea, Jeanselle, Duhn, Clif, Gilson, Michael C, Klei, Lambertus, Liang, Lindsay, Markenscoff-Papadimitriou, Eirene, Pochareddy, Sirisha, Ahituv, Nadav, Buxbaum, Joseph D, Coon, Hilary, Daly, Mark J, Kim, Young Shin, Marth, Gabor T, Neale, Benjamin M, Quinlan, Aaron R, Rubenstein, John L, Sestan, Nenad, State, Matthew W, Willsey, A Jeremy, Talkowski, Michael E, Devlin, Bernie, Roeder, Kathryn, and Sanders, Stephan J
Subjects: Human Genome, Genetics, Biotechnology, Intellectual and Developmental Disabilities (IDD), Mental Health, Brain Disorders, Autism, Pediatric, 2.1 Biological and endogenous factors, Aetiology, Mental health, Autism Spectrum Disorder, Binding Sites, Conserved Sequence, DNA Mutational Analysis, Genetic Loci, Genetic Variation, Humans, Mutation, Pedigree, Promoter Regions, Genetic, Risk, Transcription Factors, General Science & Technology
Abstract: Whole-genome sequencing (WGS) has facilitated the first genome-wide evaluations of the contribution of de novo noncoding mutations to complex disorders. Using WGS, we identified 255,106 de novo mutations among sample genomes from members of 1902 quartet families in which one child, but not a sibling or their parents, was affected by autism spectrum disorder (ASD). In contrast to coding mutations, no noncoding functional annotation category, analyzed in isolation, was significantly associated with ASD. Casting noncoding variation in the context of a de novo risk score across multiple annotation categories, however, did demonstrate association with mutations localized to promoter regions. We found that the strongest driver of this promoter signal emanates from evolutionarily conserved transcription factor binding sites distal to the transcription start site. These data suggest that de novo mutations in promoter regions, characterized by evolutionary and functional signatures, contribute to ASD.
Published: 2018

23. An analytical framework for whole-genome sequence association studies and its implications for autism spectrum disorder

Author: Werling, Donna M, Brand, Harrison, An, Joon-Yong, Stone, Matthew R, Zhu, Lingxue, Glessner, Joseph T, Collins, Ryan L, Dong, Shan, Layer, Ryan M, Markenscoff-Papadimitriou, Eirene, Farrell, Andrew, Schwartz, Grace B, Wang, Harold Z, Currall, Benjamin B, Zhao, Xuefang, Dea, Jeanselle, Duhn, Clif, Erdman, Carolyn A, Gilson, Michael C, Yadav, Rachita, Handsaker, Robert E, Kashin, Seva, Klei, Lambertus, Mandell, Jeffrey D, Nowakowski, Tomasz J, Liu, Yuwen, Pochareddy, Sirisha, Smith, Louw, Walker, Michael F, Waterman, Matthew J, He, Xin, Kriegstein, Arnold R, Rubenstein, John L, Sestan, Nenad, McCarroll, Steven A, Neale, Benjamin M, Coon, Hilary, Willsey, A Jeremy, Buxbaum, Joseph D, Daly, Mark J, State, Matthew W, Quinlan, Aaron R, Marth, Gabor T, Roeder, Kathryn, Devlin, Bernie, Talkowski, Michael E, and Sanders, Stephan J
Subjects: Biological Sciences, Genetics, Intellectual and Developmental Disabilities (IDD), Brain Disorders, Pediatric, Autism, Biotechnology, Mental Health, Human Genome, 2.1 Biological and endogenous factors, Aetiology, Autism Spectrum Disorder, Female, Genetic Predisposition to Disease, Genome, Genome-Wide Association Study, Humans, INDEL Mutation, Male, Polymorphism, Single Nucleotide, Protein Isoforms, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract: Genomic association studies of common or rare protein-coding variation have established robust statistical approaches to account for multiple testing. Here we present a comparable framework to evaluate rare and de novo noncoding single-nucleotide variants, insertion/deletions, and all classes of structural variation from whole-genome sequencing (WGS). Integrating genomic annotations at the level of nucleotides, genes, and regulatory regions, we define 51,801 annotation categories. Analyses of 519 autism spectrum disorder families did not identify association with any categories after correction for 4,123 effective tests. Without appropriate correction, biologically plausible associations are observed in both cases and controls. Despite excluding previously identified gene-disrupting mutations, coding regions still exhibited the strongest associations. Thus, in autism, the contribution of de novo noncoding variation is probably modest in comparison to that of de novo coding variants. Robust results from future WGS studies will require large cohorts and comprehensive analytical strategies that consider the substantial multiple-testing burden.
Published: 2018

24. Improving prenatal diagnosis through standards and aggregation

Author: Duyzend, Michael H., primary, Cacheiro, Pilar, additional, Jacobsen, Julius O. B., additional, Giordano, Jessica, additional, Brand, Harrison, additional, Wapner, Ronald J., additional, Talkowski, Michael E., additional, Robinson, Peter N., additional, and Smedley, Damian, additional
Published: 2024
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25. Neptune: an environment for the delivery of genomic medicine

Author: Eric, Venner, Yi, Victoria, Murdock, David, Kalla, Sara E., Wu, Tsung-Jung, Sabo, Aniko, Li, Shoudong, Meng, Qingchang, Tian, Xia, Murugan, Mullai, Cohen, Michelle, Kovar, Christie, Wei, Wei-Qi, Chung, Wendy K., Weng, Chunhua, Wiesner, Georgia L., Jarvik, Gail P., Muzny, Donna, Gibbs, Richard A., Abrams, Debra, Adunyah, Samuel E., Albertson-Junkans, Ladia, Almoguera, Berta, Ames, Darren C., Appelbaum, Paul, Aronson, Samuel, Aufox, Sharon, Babb, Lawrence J., Balasubramanian, Adithya, Bangash, Hana, Basford, Melissa, Bastarache, Lisa, Baxter, Samantha, Behr, Meckenzie, Benoit, Barbara, Bhoj, Elizabeth, Bielinski, Suzette J., Bland, Harris T., Blout, Carrie, Borthwick, Kenneth, Bottinger, Erwin P., Bowser, Mark, Brand, Harrison, Brilliant, Murray, Brodeur, Wendy, Caraballo, Pedro, Carrell, David, Carroll, Andrew, Castillo, Lisa, Castro, Victor, Chandanavelli, Gauthami, Chiang, Theodore, Chisholm, Rex L., Christensen, Kurt D., Chung, Wendy, Chute, Christopher G., City, Brittany, Cobb, Beth L., Connolly, John J., Crane, Paul, Crew, Katherine, Crosslin, David R., Dayal, Jyoti, De Andrade, Mariza, De la Cruz, Jessica, Denny, Josh C., Denson, Shawn, DeSmet, Tim, Dikilitas, Ozan, Dinsmore, Michael J., Dodge, Sheila, Dunlea, Phil, Edwards, Todd L., Eng, Christine M., Fasel, David, Fedotov, Alex, Feng, Qiping, Fleharty, Mark, Foster, Andrea, Freimuth, Robert, Friedrich, Christopher, Fullerton, Stephanie M., Funke, Birgit, Gabriel, Stacey, Gainer, Vivian, Gharavi, Ali, Glazer, Andrew M., Glessner, Joseph T., Goehringer, Jessica, Gordon, Adam S., Graham, Chet, Green, Robert C., Gundelach, Justin H., Hain, Heather S., Hakonarson, Hakon, Harden, Maegan V., Harley, John, Harr, Margaret, Hartzler, Andrea, Hayes, M. Geoffrey, Hebbring, Scott, Henrikson, Nora, Hershey, Andrew, Hoell, Christin, Holm, Ingrid, Howell, Kayla M., Hripcsak, George, Hu, Jianhong, Hynes, Elizabeth Duffy, Jayaseelan, Joy C., Jiang, Yunyun, Joo, Yoonjung Yoonie, Jose, Sheethal, Josyula, Navya Shilpa, Justice, Anne E., Kalra, Divya, Karlson, Elizabeth W., Keating, Brendan J., Kelly, Melissa A., Kenny, Eimear E., Key, Dustin, Kiryluk, Krzysztof, Kitchner, Terrie, Klanderman, Barbara, Klee, Eric, Kochan, David C., Korchina, Viktoriya, Kottyan, Leah, Kudalkar, Emily, Rahm, Alanna Kulchak, Kullo, Iftikhar J., Lammers, Philip, Larson, Eric B., Lebo, Matthew S., Leduc, Magalie, Lee, Ming Ta (Michael), Lennon, Niall J., Leppig, Kathleen A., Leslie, Nancy D., Li, Rongling, Liang, Wayne H., Lin, Chiao-Feng, Linder, Jodell E., Lindor, Noralane M., Lingren, Todd, Linneman, James G., Liu, Cong, Liu, Wen, Liu, Xiuping, Lynch, John, Lyon, Hayley, Macbeth, Alyssa, Mahadeshwar, Harshad, Mahanta, Lisa, Malin, Bradley, Manolio, Teri, Marasa, Maddalena, Marsolo, Keith, McGowan, Michelle L., McNally, Elizabeth, Meldrim, Jim, Mentch, Frank, Rasouly, Hila Milo, Mosley, Jonathan, Mukherjee, Shubhabrata, Mullen, Thomas E., Muniz, Jesse, Murdock, David R., Murphy, Shawn, Myers, Melanie F., Namjou, Bahram, Ni, Yizhao, Onofrio, Robert C., Obeng, Aniwaa Owusu, Person, Thomas N., Peterson, Josh F., Petukhova, Lynn, Pisieczko, Cassandra J., Pratap, Siddharth, Prows, Cynthia A., Puckelwartz, Megan J., Raj, Ritika, Ralston, James D., Ramaprasan, Arvind, Ramirez, Andrea, Rasmussen, Luke, Rasmussen-Torvik, Laura, Raychaudhuri, Soumya, Rehm, Heidi L., Ritchie, Marylyn D., Rives, Catherine, Riza, Beenish, Roden, Dan M., Rosenthal, Elisabeth A., Santani, Avni, Dan, Schaid, Scherer, Steven, Scott, Stuart, Scrol, Aaron, Sengupta, Soumitra, Shang, Ning, Sharma, Himanshu, Sharp, Richard R., Singh, Rajbir, Sleiman, Patrick M.A., Slowik, Kara, Smith, Joshua C., Smith, Maureen E., Smoot, Duane T., Smoller, Jordan W., Sohn, Sunghwan, Stanaway, Ian B., Starren, Justin, Stroud, Mary, Su, Jessica, Taylor, Casey Overby, Tolwinski, Kasia, Van Driest, Sara L., Vargas, Sean M., Varugheese, Matthew, Veenstra, David, Venner, Eric, Verbitsky, Miguel, Vicente, Gina, Wagner, Michael, Walker, Kimberly, Walunas, Theresa, Wang, Liwen, Wang, Qiaoyan, Weiss, Scott T., Wells, Quinn S., White, Peter S., Wiley, Ken L., Jr, Williams, Janet L., Williams, Marc S., Wilson, Michael W., Witkowski, Leora, Woods, Laura Allison, Woolf, Betty, Wynn, Julia, Yang, Yaping, Zhang, Ge, Zhang, Lan, and Zouk, Hana
Published: 2021
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26. Structural Chromosomal Rearrangements Require Nucleotide-Level Resolution: Lessons from Next-Generation Sequencing in Prenatal Diagnosis

Author: Ordulu, Zehra, Kammin, Tammy, Brand, Harrison, Pillalamarri, Vamsee, Redin, Claire E, Collins, Ryan L, Blumenthal, Ian, Hanscom, Carrie, Pereira, Shahrin, Bradley, India, Crandall, Barbara F, Gerrol, Pamela, Hayden, Mark A, Hussain, Naveed, Kanengisser-Pines, Bibi, Kantarci, Sibel, Levy, Brynn, Macera, Michael J, Quintero-Rivera, Fabiola, Spiegel, Erica, Stevens, Blair, Ulm, Janet E, Warburton, Dorothy, Wilkins-Haug, Louise E, Yachelevich, Naomi, Gusella, James F, Talkowski, Michael E, and Morton, Cynthia C
Subjects: Biological Sciences, Biomedical and Clinical Sciences, Genetics, Genetic Testing, Pediatric, Human Genome, Clinical Research, Prevention, Biotechnology, Alleles, Chromosome Aberrations, Chromosome Mapping, Congenital Abnormalities, Female, Gene Expression Regulation, Gene Rearrangement, Genome, Human, Genomics, High-Throughput Nucleotide Sequencing, Humans, Karyotyping, Male, Nucleotides, Pregnancy, Prenatal Diagnosis, SOX9 Transcription Factor, Sequence Analysis, DNA, Translocation, Genetic, Medical and Health Sciences, Genetics & Heredity, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract: In this exciting era of "next-gen cytogenetics," integrating genomic sequencing into the prenatal diagnostic setting is possible within an actionable time frame and can provide precise delineation of balanced chromosomal rearrangements at the nucleotide level. Given the increased risk of congenital abnormalities in newborns with de novo balanced chromosomal rearrangements, comprehensive interpretation of breakpoints could substantially improve prediction of phenotypic outcomes and support perinatal medical care. Herein, we present and evaluate sequencing results of balanced chromosomal rearrangements in ten prenatal subjects with respect to the location of regulatory chromatin domains (topologically associated domains [TADs]). The genomic material from all subjects was interpreted to be "normal" by microarray analyses, and their rearrangements would not have been detected by cell-free DNA (cfDNA) screening. The findings of our systematic approach correlate with phenotypes of both pregnancies with untoward outcomes (5/10) and with healthy newborns (3/10). Two pregnancies, one with a chromosomal aberration predicted to be of unknown clinical significance and another one predicted to be likely benign, were terminated prior to phenotype-genotype correlation (2/10). We demonstrate that the clinical interpretation of structural rearrangements should not be limited to interruption, deletion, or duplication of specific genes and should also incorporate regulatory domains of the human genome with critical ramifications for the control of gene expression. As detailed in this study, our molecular approach to both detecting and interpreting the breakpoints of structural rearrangements yields unparalleled information in comparison to other commonly used first-tier diagnostic methods, such as non-invasive cfDNA screening and microarray analysis, to provide improved genetic counseling for phenotypic outcome in the prenatal setting.
Published: 2016

27. A cell type-aware framework for nominating non-coding variants in Mendelian regulatory disorders

Author: Lee, Arthur S, primary, Ayers, Lauren J, additional, Kosicki, Michael, additional, Chan, Wai-Man, additional, Fozo, Lydia N, additional, Pratt, Brandon M, additional, Collins, Thomas E, additional, Zhao, Boxun, additional, Rose, Matthew F, additional, Sanchis-Juan, Alba, additional, Fu, Jack M, additional, Wong, Isaac, additional, Zhao, Xuefang, additional, Tenney, Alan P, additional, Lee, Cassia, additional, Laricchia, Kristen M, additional, Barry, Brenda J, additional, Bradford, Victoria R, additional, Lek, Monkol, additional, MacArthur, Daniel G, additional, Lee, Eunjung Alice, additional, Talkowski, Michael E, additional, Brand, Harrison, additional, Pennacchio, Len A, additional, and Engle, Elizabeth C, additional
Published: 2023
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28. High-Resolution and Noninvasive Fetal Exome Screening

Author: Brand, Harrison, primary, Whelan, Christopher W., additional, Duyzend, Michael, additional, Lemanski, John, additional, Salani, Monica, additional, Hao, Stephanie P., additional, Wong, Isaac, additional, Valkanas, Elise, additional, Cusick, Caroline, additional, Genetti, Casie, additional, Dobson, Lori, additional, Studwell, Courtney, additional, Gianforcaro, Kathleen, additional, Wilkins-Haug, Louise, additional, Guseh, Stephanie, additional, Currall, Benjamin, additional, Gray, Kathryn, additional, and Talkowski, Michael E., additional
Published: 2023
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29. 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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30. Evidence for secondary-variant genetic burden and non-random distribution across biological modules in a recessive ciliopathy

Author: Kousi, Maria, Söylemez, Onuralp, Ozanturk, Aysegül, Mourtzi, Niki, Akle, Sebastian, Jungreis, Irwin, Muller, Jean, Cassa, Christopher A., Brand, Harrison, Mokry, Jill Anne, Wolf, Maxim Y., Sadeghpour, Azita, McFadden, Kelsey, Lewis, Richard A., Talkowski, Michael E., Dollfus, Hélène, Kellis, Manolis, Davis, Erica E., Sunyaev, Shamil R., and Katsanis, Nicholas
Published: 2020
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31. Genome-wide association studies in dogs and humans identify ADAMTS20 as a risk variant for cleft lip and palate.

Author: Wolf, Zena T, Brand, Harrison A, Shaffer, John R, Leslie, Elizabeth J, Arzi, Boaz, Willet, Cali E, Cox, Timothy C, McHenry, Toby, Narayan, Nicole, Feingold, Eleanor, Wang, Xioajing, Sliskovic, Saundra, Karmi, Nili, Safra, Noa, Sanchez, Carla, Deleyiannis, Frederic WB, Murray, Jeffrey C, Wade, Claire M, Marazita, Mary L, and Bannasch, Danika L
Subjects: Brain, Animals, Dogs, Humans, Cleft Palate, Cleft Lip, Haplotypes, Frameshift Mutation, Polymorphism, Single Nucleotide, ADAM Proteins, Genome-Wide Association Study, ADAMTS Proteins, Polymorphism, Single Nucleotide, Genetics, Developmental Biology
Abstract: Cleft lip with or without cleft palate (CL/P) is the most commonly occurring craniofacial birth defect. We provide insight into the genetic etiology of this birth defect by performing genome-wide association studies in two species: dogs and humans. In the dog, a genome-wide association study of 7 CL/P cases and 112 controls from the Nova Scotia Duck Tolling Retriever (NSDTR) breed identified a significantly associated region on canine chromosome 27 (unadjusted p=1.1 x 10(-13); adjusted p= 2.2 x 10(-3)). Further analysis in NSDTR families and additional full sibling cases identified a 1.44 Mb homozygous haplotype (chromosome 27: 9.29 - 10.73 Mb) segregating with a more complex phenotype of cleft lip, cleft palate, and syndactyly (CLPS) in 13 cases. Whole-genome sequencing of 3 CLPS cases and 4 controls at 15X coverage led to the discovery of a frameshift mutation within ADAMTS20 (c.1360_1361delAA (p.Lys453Ilefs*3)), which segregated concordant with the phenotype. In a parallel study in humans, a family-based association analysis (DFAM) of 125 CL/P cases, 420 unaffected relatives, and 392 controls from a Guatemalan cohort, identified a suggestive association (rs10785430; p =2.67 x 10-6) with the same gene, ADAMTS20. Sequencing of cases from the Guatemalan cohort was unable to identify a causative mutation within the coding region of ADAMTS20, but four coding variants were found in additional cases of CL/P. In summary, this study provides genetic evidence for a role of ADAMTS20 in CL/P development in dogs and as a candidate gene for CL/P development in humans.
Published: 2015

32. Harmonizing Clinical Sequencing and Interpretation for the eMERGE III Network

Author: Zouk, Hana, Venner, Eric, Lennon, Niall J., Muzny, Donna M., Abrams, Debra, Adunyah, Samuel, Albertson-Junkans, Ladia, Ames, Darren C., Appelbaum, Paul, Aronson, Samuel, Aufox, Sharon, Babb, Lawrence J., Balasubramanian, Adithya, Bangash, Hana, Basford, Melissa, Bastarache, Lisa, Baxter, Samantha, Behr, Meckenzie, Benoit, Barbara, Bhoj, Elizabeth, Bielinski, Suzette J., Bland, Sarah T., Blout, Carrie, Borthwick, Kenneth, Bottinger, Erwin P., Bowser, Mark, Brand, Harrison, Brilliant, Murray, Brodeur, Wendy, Caraballo, Pedro, Carrell, David, Carroll, Andrew, Almoguera, Berta, Castillo, Lisa, Castro, Victor, Chandanavelli, Gauthami, Chiang, Theodore, Chisholm, Rex L., Christensen, Kurt D., Chung, Wendy, Chute, Christopher G., City, Brittany, Cobb, Beth L., Connolly, John J., Crane, Paul, Crew, Katherine, Crosslin, David, De Andrade, Mariza, De la Cruz, Jessica, Denson, Shawn, Denny, Josh, DeSmet, Tim, Dikilitas, Ozan, Friedrich, Christopher, Fullerton, Stephanie M., Funke, Birgit, Gabriel, Stacey, Gainer, Vivian, Gharavi, Ali, Glazer, Andrew M., Glessner, Joseph T., Goehringer, Jessica, Gordon, Adam S., Graham, Chet, Green, Robert C., Gundelach, Justin H., Dayal, Jyoti, Hain, Heather S., Hakonarson, Hakon, Harden, Maegan V., Harley, John, Harr, Margaret, Hartzler, Andrea, Hayes, M. Geoffrey, Hebbring, Scott, Henrikson, Nora, Hershey, Andrew, Hoell, Christin, Holm, Ingrid, Howell, Kayla M., Hripcsak, George, Hu, Jianhong, Jarvik, Gail P., Jayaseelan, Joy C., Jiang, Yunyun, Joo, Yoonjung Yoonie, Jose, Sheethal, Josyula, Navya Shilpa, Justice, Anne E., Kalla, Sara E., Kalra, Divya, Karlson, Elizabeth, Kelly, Melissa A., Keating, Brendan J., Kenny, Eimear E., Key, Dustin, Kiryluk, Krzysztof, Kitchner, Terrie, Klanderman, Barbara, Klee, Eric, Kochan, David C., Korchina, Viktoriya, Kottyan, Leah, Kovar, Christie, Kudalkar, Emily, Kullo, Iftikhar J., Lammers, Philip, Larson, Eric B., Lebo, Matthew S., Leduc, Magalie, Lee, Ming Ta (Michael), Leppig, Kathleen A., Leslie, Nancy D., Li, Rongling, Liang, Wayne H., Lin, Chiao-Feng, Linder, Jodell, Lindor, Noralane M., Lingren, Todd, Linneman, James G., Liu, Cong, Liu, Wen, Liu, Xiuping, Lynch, John, Lyon, Hayley, Macbeth, Alyssa, Mahadeshwar, Harshad, Mahanta, Lisa, Malin, Brad, Manolio, Teri, Marasa, Maddalena, Marsolo, Keith, Dinsmore, Michael J., Dodge, Sheila, Hynes, Elizabeth Duffy, Dunlea, Phil, Edwards, Todd L., Eng, Christine M., Fasel, David, Fedotov, Alex, Feng, Qiping, Fleharty, Mark, Foster, Andrea, Freimuth, Robert, McGowan, Michelle L., McNally, Elizabeth, Meldrim, Jim, Mentch, Frank, Mosley, Jonathan, Mukherjee, Shubhabrata, Mullen, Thomas E., Muniz, Jesse, Murdock, David R., Murphy, Shawn, Murugan, Mullai, Myers, Melanie F., Namjou, Bahram, Ni, Yizhao, Obeng, Aniwaa Owusu, Onofrio, Robert C., Taylor, Casey Overby, Person, Thomas N., Peterson, Josh F., Petukhova, Lynn, Pisieczko, Cassandra J., Pratap, Siddharth, Prows, Cynthia A., Puckelwartz, Megan J., Rahm, Alanna Kulchak, Raj, Ritika, Ralston, James D., Ramaprasan, Arvind, Ramirez, Andrea, Rasmussen, Luke, Rasmussen-Torvik, Laura, Rasouly, Hila Milo, Raychaudhuri, Soumya, Ritchie, Marylyn D., Rives, Catherine, Riza, Beenish, Roden, Dan, Rosenthal, Elisabeth A., Santani, Avni, Schaid, Dan, Scherer, Steven, Scott, Stuart, Scrol, Aaron, Sengupta, Soumitra, Shang, Ning, Sharma, Himanshu, Sharp, Richard R., Singh, Rajbir, Sleiman, Patrick M.A., Slowik, Kara, Smith, Joshua C., Smith, Maureen E., Smoller, Jordan W., Sohn, Sunghwan, Stanaway, Ian B., Starren, Justin, Stroud, Mary, Su, Jessica, Tolwinski, Kasia, Van Driest, Sara L., Vargas, Sean M., Varugheese, Matthew, Veenstra, David, Verbitsky, Miguel, Vicente, Gina, Wagner, Michael, Walker, Kimberly, Walunas, Theresa, Wang, Liwen, Wang, Qiaoyan, Wei, Wei-Qi, Weiss, Scott T., Wiesner, Georgia L., Wells, Quinn, Weng, Chunhua, White, Peter S., Wiley, Ken L., Jr., Williams, Janet L., Williams, Marc S., Wilson, Michael W., Witkowski, Leora, Woods, Laura Allison, Woolf, Betty, Wu, Tsung-Jung, Wynn, Julia, Yang, Yaping, Yi, Victoria, Zhang, Ge, Zhang, Lan, Rehm, Heidi L., and Gibbs, Richard A.
Published: 2019
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33. 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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34. 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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35. O11: An atlas of 1.2M structural variants across global populations in the Genome Aggregation Database (gnomAD)

Author: Brand, Harrison, Zhao, Xuefang, Fu, Jack, Collins, Ryan, Wong, Isaac, Liao, Cal, Wang, Lily, Baxter, Samantha, Solomonson, Matthew, Darnowsky, Philip, Chapman, Sinéad, Stevens, Christine, Cusick, Caroline, Sanchis-Juan, Alba, Walker, Mark, Kurtas, Nehir, Chao, Katherine, Gabriel, Stacey, Banks, Eric, O’Donnell-Luria, Anne, MacArthur, Daniel, Rehm, Heidi, Neale, Benjamin, Daly, Mark, Samocha, Kaitlin, Karczewski, Konrad, and Talkowski, Michael
Published: 2024
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36. A harmonized public resource of deeply sequenced diverse human genomes

Author: Koenig, Zan, Yohannes, Mary T., Nkambule, Lethukuthula L., Zhao, Xuefang, Goodrich, Julia K., Kim, Heesu Ally, Wilson, Michael W., Tiao, Grace, Hao, Stephanie P., Sahakian, Nareh, Chao, Katherine R., Walker, Mark A., Lyu, Yunfei, Rehm, Heidi L., Neale, Benjamin M., Talkowski, Michael E., Daly, Mark J., Brand, Harrison, Karczewski, Konrad J., Atkinson, Elizabeth G., and Martin, Alicia R.
Abstract: Underrepresented populations are often excluded from genomic studies owing in part to a lack of resources supporting their analyses. The 1000 Genomes Project (1kGP) and Human Genome Diversity Project (HGDP), which have recently been sequenced to high coverage, are valuable genomic resources because of the global diversity they capture and their open data sharing policies. Here, we harmonized a high-quality set of 4094 whole genomes from 80 populations in the HGDP and 1kGP with data from the Genome Aggregation Database (gnomAD) and identified over 153 million high-quality SNVs, indels, and SVs. We performed a detailed ancestry analysis of this cohort, characterizing population structure and patterns of admixture across populations, analyzing site frequency spectra, and measuring variant counts at global and subcontinental levels. We also show substantial added value from this data set compared with the prior versions of the component resources, typically combined via liftOver and variant intersection; for example, we catalog millions of new genetic variants, mostly rare, compared with previous releases. In addition to unrestricted individual-level public release, we provide detailed tutorials for conducting many of the most common quality-control steps and analyses with these data in a scalable cloud-computing environment and publicly release this new phased joint callset for use as a haplotype resource in phasing and imputation pipelines. This jointly called reference panel will serve as a key resource to support research of diverse ancestry populations.
Published: 2024
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37. Trio-based GWAS identifies novel associations and subtype-specific risk factors for cleft palate

Author: Robinson, Kelsey, primary, Mosley, Trenell, additional, Curtis, Sarah, additional, Beaty, Terri H., additional, Butali, Azeez, additional, Cutler, David J., additional, Epstein, Michael P., additional, Buxó-Martinez, Carmen J., additional, Shaw, Gary M., additional, Hecht, Jacqueline T., additional, Uribe, Lina Moreno, additional, Murray, Jeffrey C., additional, Brand, Harrison, additional, Weinberg, Seth M., additional, Marazita, Mary L., additional, and Leslie, Elizabeth J., additional
Published: 2023
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38. O34: Application of long-read sequencing and telomere-to-telomere genome assembly unveils complex rearrangements and cryptic breakpoints of Robertsonian translocation and ring chromosomes*

Author: Quintero-Rivera, Fabiola, primary, Mostovoy, Yulia, additional, Boone, Philip, additional, Huang, Steve, additional, Garimella, Kiran, additional, Martinez-Agosto, Julian, additional, Russell, Bianca, additional, Bowers, Tera, additional, De Smet, Tim, additional, Gabriel, Stacey, additional, Gusella, James, additional, Brand, Harrison, additional, and Talkowski, Michael, additional
Published: 2023
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39. O39: Comprehensive, high-resolution, and non-invasive prenatal screening of coding variation*

Author: Duyzend, Michael, primary, Brand, Harrison, additional, Whelan, Christopher, additional, Lemanski, John, additional, Salani, Monica, additional, Hao, Stephanie, additional, Wong, Isaac, additional, Valkanas, Elise, additional, Cusick, Caroline, additional, Dobson, Lori, additional, Studwell, Courtney, additional, Gianforcaro, Kathleen, additional, Guseh, Stephanie, additional, Currall, Benjamin, additional, Gray, Kathryn, additional, and Talkowski, Michael, additional
Published: 2023
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40. A harmonized public resource of deeply sequenced diverse human genomes

Author: Koenig, Zan, Yohannes, Mary T., Nkambule, Lethukuthula L., Goodrich, Julia K., Kim, Heesu Ally, Zhao, Xuefang, Wilson, Michael W., Tiao, Grace, Hao, Stephanie P., Sahakian, Nareh, Chao, Katherine R., Talkowski, Michael E., Daly, Mark J., Brand, Harrison, Karczewski, Konrad J., Atkinson, Elizabeth G., and Martin, Alicia R.
Subjects: Article
Abstract: Underrepresented populations are often excluded from genomic studies due in part to a lack of resources supporting their analysis. The 1000 Genomes Project (1kGP) and Human Genome Diversity Project (HGDP), which have recently been sequenced to high coverage, are valuable genomic resources because of the global diversity they capture and their open data sharing policies. Here, we harmonized a high quality set of 4,096 whole genomes from HGDP and 1kGP with data from gnomAD and identified over 155 million high-quality SNVs, indels, and SVs. We performed a detailed ancestry analysis of this cohort, characterizing population structure and patterns of admixture across populations, analyzing site frequency spectra, and measuring variant counts at global and subcontinental levels. We also demonstrate substantial added value from this dataset compared to the prior versions of the component resources, typically combined via liftover and variant intersection; for example, we catalog millions of new genetic variants, mostly rare, compared to previous releases. In addition to unrestricted individual-level public release, we provide detailed tutorials for conducting many of the most common quality control steps and analyses with these data in a scalable cloud-computing environment and publicly release this new phased joint callset for use as a haplotype resource in phasing and imputation pipelines. This jointly called reference panel will serve as a key resource to support research of diverse ancestry populations.
Published: 2023

41. Genome-Wide Analysis of Structural Variants in Parkinson Disease

Author: Billingsley, Kimberley J, Ding, Jinhui, Hernandez, Dena, Torkamani, Ali, Ryten, Mina, Hardy, John, Consortium, UK Brain Expression, Chia, Ruth, Scholz, Sonja W, Traynor, Bryan J, Dalgard, Clifton L, Ehrlich, Debra J, Jerez, Pilar Alvarez, Tanaka, Toshiko, Ferrucci, Luigi, Beach, Thomas G, Serrano, Geidy E, Quinn, John P, Bubb, Vivien J, Collins, Ryan L, Zhao, Xuefang, Walker, Mark, Pierce-Hoffman, Emma, Illarionova, Anastasia, Brand, Harrison, Talkowski, Michael E, Casey, Bradford, Cookson, Mark R, Markham, Androo, Nalls, Mike A, Mahmoud, Medhat, Sedlazeck, Fritz J, Blauwendraat, Cornelis, Gibbs, J Raphael, Levine, Kristin, Singleton, Andrew B, Grenn, Francis P, Makarious, Mary B, Moore, Anni, Vitale, Daniel, and Reed, Xylena
Subjects: Neurology, Neurology (clinical), ddc:610
Abstract: Identification of genetic risk factors for Parkinson disease (PD) has to date been primarily limited to the study of single nucleotide variants, which only represent a small fraction of the genetic variation in the human genome. Consequently, causal variants for most PD risk are not known. Here we focused on structural variants (SVs), which represent a major source of genetic variation in the human genome. We aimed to discover SVs associated with PD risk by performing the first large-scale characterization of SVs in PD.We leveraged a recently developed computational pipeline to detect and genotype SVs from 7,772 Illumina short-read whole genome sequencing samples. Using this set of SV variants, we performed a genome-wide association study using 2,585 cases and 2,779 controls and identified SVs associated with PD risk. Furthermore, to validate the presence of these variants, we generated a subset of matched whole-genome long-read sequencing data.We genotyped and tested 3,154 common SVs, representing over 412 million nucleotides of previously uncatalogued genetic variation. Using long-read sequencing data, we validated the presence of three novel deletion SVs that are associated with risk of PD from our initial association analysis, including a 2 kb intronic deletion within the gene LRRN4.We identified three SVs associated with genetic risk of PD. This study represents the most comprehensive assessment of the contribution of SVs to the genetic risk of PD to date. ANN NEUROL 2023.
Published: 2023

42. Phenotype and genetic analysis of data collected within the first year of NeuroDev

Author: Kipkemoi, Patricia, Kim, Heesu Ally, Christ, Bjorn, O’Heir, Emily, Allen, Jake, Austin-Tse, Christina, Baxter, Samantha, Brand, Harrison, Bryant, Sam, Buser, Nick, de Menil, Victoria, Eastman, Emma, Murugasen, Serini, Galvin, Alice, Kombe, Martha, Ngombo, Alfred, Mkubwa, Beatrice, Mwangi, Paul, Kipkoech, Collins, Lovgren, Alysia, MacArthur, Daniel G., Melly, Brigitte, Mwangasha, Katini, Martin, Alicia, Nkambule, Lethukuthula L., Sanchis-Juan, Alba, Singer-Berk, Moriel, Talkowski, Michael E., VanNoy, Grace, van der Merwe, Celia, Newton, Charles, O’Donnell-Luria, Anne, Abubakar, Amina, Donald, Kirsten A., and Robinson, Elise B.
Published: 2023
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43. CHD8 regulates neurodevelopmental pathways associated with autism spectrum disorder in neural progenitors

Author: Sugathan, Aarathi, Biagioli, Marta, Golzio, Christelle, Erdin, Serkan, Blumenthal, Ian, Manavalan, Poornima, Ragavendran, Ashok, Brand, Harrison, Lucente, Diane, Miles, Judith, Sheridan, Steven D., Stortchevoi, Alexei, Kellis, Manolis, Haggarty, Stephen J., Katsanis, Nicholas, Gusella, James F., and Talkowski, Michael E.
Published: 2014
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44. GATK-gCNV: A Rare Copy Number Variant Discovery Algorithm and Its Application to Exome Sequencing in the UK Biobank

Author: Babadi, Mehrtash, primary, Fu, Jack M., additional, Lee, Samuel K., additional, Smirnov, Andrey N., additional, Gauthier, Laura D., additional, Walker, Mark, additional, Benjamin, David I., additional, Karczewski, Konrad J., additional, Wong, Isaac, additional, Collins, Ryan L., additional, Sanchis-Juan, Alba, additional, Brand, Harrison, additional, Banks, Eric, additional, and Talkowski, Michael E., additional
Published: 2022
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45. Rare variants found in clinical gene panels illuminate the genetic and allelic architecture of orofacial clefting

Author: Diaz Perez, Kimberly K., primary, Curtis, Sarah W., additional, Sanchis-Juan, Alba, additional, Zhao, Xuefang, additional, Head, S. Taylor, additional, Ho, Samantha, additional, Carter, Bridget, additional, McHenry, Toby, additional, Bishop, Madison R., additional, Valencia-Ramirez, Luz Consuelo, additional, Restrepo, Claudia, additional, Hecht, Jacqueline T., additional, Uribe, Lina Moreno, additional, Wehby, George, additional, Weinberg, Seth M., additional, Beaty, Terri H., additional, Murray, Jeffrey C., additional, Feingold, Eleanor, additional, Marazita, Mary L., additional, Cutler, David J., additional, Epstein, Michael P., additional, Brand, Harrison, additional, and Leslie, Elizabeth J., additional
Published: 2022
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46. A cross-disorder dosage sensitivity map of the human genome

Author: Collins, Ryan L., primary, Glessner, Joseph T., additional, Porcu, Eleonora, additional, Lepamets, Maarja, additional, Brandon, Rhonda, additional, Lauricella, Christopher, additional, Han, Lide, additional, Morley, Theodore, additional, Niestroj, Lisa-Marie, additional, Ulirsch, Jacob, additional, Everett, Selin, additional, Howrigan, Daniel P., additional, Boone, Philip M., additional, Fu, Jack, additional, Karczewski, Konrad J., additional, Kellaris, Georgios, additional, Lowther, Chelsea, additional, Lucente, Diane, additional, Mohajeri, Kiana, additional, Nõukas, Margit, additional, Nuttle, Xander, additional, Samocha, Kaitlin E., additional, Trinh, Mi, additional, Ullah, Farid, additional, Võsa, Urmo, additional, Hurles, Matthew E., additional, Aradhya, Swaroop, additional, Davis, Erica E., additional, Finucane, Hilary, additional, Gusella, James F., additional, Janze, Aura, additional, Katsanis, Nicholas, additional, Matyakhina, Ludmila, additional, Neale, Benjamin M., additional, Sanders, David, additional, Warren, Stephanie, additional, Hodge, Jennelle C., additional, Lal, Dennis, additional, Ruderfer, Douglas M., additional, Meck, Jeanne, additional, Mägi, Reedik, additional, Esko, Tõnu, additional, Reymond, Alexandre, additional, Kutalik, Zoltán, additional, Hakonarson, Hakon, additional, Sunyaev, Shamil, additional, Brand, Harrison, additional, Talkowski, Michael E., additional, Metspalu, Andres, additional, Nelis, Mari, additional, and Milani, Lili, additional
Published: 2022
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47. FSHD type 2 and Bosma arhinia microphthalmia syndrome: Two faces of the same mutation

Author: Mul, Karlien, Lemmers, Richard J.L.F., Kriek, Marjolein, van der Vliet, Patrick J., van den Boogaard, Marlinde L., Badrising, Umesh A., Graham, John M., Jr, Lin, Angela E., Brand, Harrison, Moore, Steven A., Johnson, Katherine, Evangelista, Teresinha, Töpf, Ana, Straub, Volker, Kapetanovic García, Solange, Sacconi, Sabrina, Tawil, Rabi, Tapscott, Stephen J., Voermans, Nicol C., van Engelen, Baziel G.M., Horlings, Corinne G.C., Shaw, Natalie D., and van der Maarel, Silvère M.
Published: 2018
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48. 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., Klemp, Kara C., Braddock, Stephen R., Brand, Harrison, Wong, Isaac, Talkowski, Michael E., O’Donnell-Luria, Anne, Lai, Abbe, Hill, Robert Sean, Mochida, Ganeshwaran H., Doan, Ryan N., Barkovich, A. James, Yang, Edward, Amrom, Dina, Andermann, Eva, Poduri, Annapurna, and Walsh, Christopher 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 provided satisfactory molecular explanations. Known genes most frequently implicated by polymicrogyria-associated variants in this cohort were PIK3R2, TUBB2B, COL4A1, and SCN3A. Six candidate novel polymicrogyria genes were identified or confirmed: de novo missense variants in PANX1, QRICH1, and SCN2A and compound heterozygous variants in TMEM161B, KIF26A, and MAN2C1, each with consistent genotype-phenotype relationships in multiple families. CONCLUSIONS AND RELEVANCE: This study’s findings reveal a higher than previously recognized rate of identifiable genetic causes, specifically of channelopathies, in individuals with polymicrogyria and support the utility of exome sequencing for families affected with polymicrogyria.
Published: 2023
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49. Prevalence and Phenotypic Effects of Copy Number Variants in Isolated Hypogonadotropic Hypogonadism

Author: Stamou, Maria I, primary, Brand, Harrison, additional, Wang, Mei, additional, Wong, Isaac, additional, Lippincott, Margaret F, additional, Plummer, Lacey, additional, Crowley, William F, additional, Talkowski, Michael, additional, Seminara, Stephanie, additional, and Balasubramanian, Ravikumar, additional
Published: 2022
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50. 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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