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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. 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

3. Biallelic and monoallelic variants in PLXNA1 are implicated in a novel neurodevelopmental disorder with variable cerebral and eye anomalies

Author

Dworschak, Gabriel C., Punetha, Jaya, Kalanithy, Jeshurun C., Mingardo, Enrico, Erdem, Haktan B., Akdemir, Zeynep C., Karaca, Ender, Mitani, Tadahiro, Marafi, Dana, Fatih, Jawid M., Jhangiani, Shalini N., Hunter, Jill V., Dakal, Tikam Chand, Dhabhai, Bhanupriya, Dabbagh, Omar, Alsaif, Hessa S., Alkuraya, Fowzan S., Maroofian, Reza, Houlden, Henry, Efthymiou, Stephanie, Dominik, Natalia, Salpietro, Vincenzo, Sultan, Tipu, Haider, Shahzad, Bibi, Farah, Thiele, Holger, Hoefele, Julia, Riedhammer, Korbinian M., Wagner, Matias, Guella, Ilaria, Demos, Michelle, Keren, Boris, Buratti, Julien, Charles, Perrine, Nava, Caroline, Héron, Delphine, Heide, Solveig, Valkanas, Elise, Waddell, Leigh B., Jones, Kristi J., Oates, Emily C., Cooper, Sandra T., MacArthur, Daniel, Syrbe, Steffen, Ziegler, Andreas, Platzer, Konrad, Okur, Volkan, Chung, Wendy K., O’Shea, Sarah A., Alcalay, Roy, Fahn, Stanley, Mark, Paul R., Guerrini, Renzo, Vetro, Annalisa, Hudson, Beth, Schnur, Rhonda E., Hoganson, George E., Burton, Jennifer E., McEntagart, Meriel, Lindenberg, Tobias, Yilmaz, Öznur, Odermatt, Benjamin, Pehlivan, Davut, Posey, Jennifer E., Lupski, James R., and Reutter, Heiko

Published
2021
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4. Genome and RNA sequencing boost neuromuscular diagnoses to 62% from 34% with exome sequencing alone

Author

Marchant, Rhett G., primary, Bryen, Samantha J., additional, Bahlo, Melanie, additional, Cairns, Anita, additional, Chao, Katherine R., additional, Corbett, Alastair, additional, Davis, Mark R., additional, Ganesh, Vijay S., additional, Ghaoui, Roula, additional, Jones, Kristi J., additional, Kornberg, Andrew J., additional, Lek, Monkol, additional, Liang, Christina, additional, MacArthur, Daniel G., additional, Oates, Emily C., additional, O'Donnell‐Luria, Anne, additional, O'Grady, Gina L., additional, Osei‐Owusu, Ikeoluwa A., additional, Rafehi, Haloom, additional, Reddel, Stephen W., additional, Roxburgh, Richard H., additional, Ryan, Monique M., additional, Sandaradura, Sarah A., additional, Scott, Liam W., additional, Valkanas, Elise, additional, Weisburd, Ben, additional, Young, Helen, additional, Evesson, Frances J., additional, Waddell, Leigh B., additional, and Cooper, Sandra T., additional

Published
2024
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5. 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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7. 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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9. Detection of variants in dystroglycanopathy-associated genes through the application of targeted whole-exome sequencing analysis to a large cohort of patients with unexplained limb-girdle muscle weakness

Author

Johnson, Katherine, Bertoli, Marta, Phillips, Lauren, Töpf, Ana, Van den Bergh, Peter, Vissing, John, Witting, Nanna, Nafissi, Shahriar, Jamal-Omidi, Shirin, Łusakowska, Anna, Kostera-Pruszczyk, Anna, Potulska-Chromik, Anna, Deconinck, Nicolas, Wallgren-Pettersson, Carina, Strang-Karlsson, Sonja, Colomer, Jaume, Claeys, Kristl G., De Ridder, Willem, Baets, Jonathan, von der Hagen, Maja, Fernández-Torrón, Roberto, Zulaica Ijurco, Miren, Espinal Valencia, Juan Bautista, Hahn, Andreas, Durmus, Hacer, Willis, Tracey, Xu, Liwen, Valkanas, Elise, Mullen, Thomas E., Lek, Monkol, MacArthur, Daniel G., and Straub, Volker

Published
2018
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10. 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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11. genetic diagnosis; limb-girdle weakness; neuromuscular disease; next-generation sequencing; targeted exome analysisweakness

Author

Töpf, Ana, Johnson, Katherine, Bates, Adam, Phillips, Lauren, Chao, Katherine R., England, Eleina M., Laricchia, Kristen M., Mullen, Thomas, Valkanas, Elise, Xu, Liwen, Bertoli, Marta, Blain, Alison, Casasús, Ana B., Duff, Jennifer, Mroczek, Magdalena, Specht, Sabine, Lek, Monkol, Ensini, Monica, MacArthur, Daniel G., Akay, Ela, Alonso-Pérez, Jorge, Baets, Jonathan, Barisic, Nina, Bastian, Alexandra, Borell, Sabine, Chamova, Teodora, Claeys, Kristl, Colomer, Jaume, Coppens, Sandra, Deconinck, Nicolas, de Ridder, Willem, Díaz-Manera, Jordi, Domínguez-González, Cristina, Duncan, Alexis, Durmus, Hacer, Fahmy, Nagia A., Farrugia, Maria Elena, Fernández-Torrón, Roberto, Gonzalez- Quereda, Lidia, Haberlova, Jana, von der Hagen, Maja, Hahn, Andreas, Jakovčević, Antonia, Jerico Pascual, Ivonne, Kapetanovic, Solange, Kenina, Viktorija, Kirschner, Janbernd, Klein, Andrea, Kölbel, Heike, Kostera-Pruszczyk, Anna, Kulshrestha, Richa, Lähdetie, Jaana, Layegh, Mahsa, Longman, Cheryl, López de Munain, Adolfo, Loscher, Wolfgang, Lusakowska, Anna, Maddison, Paul, Magot, Armelle, Majumdar, Anirban, Martí, Pilar, Martínez Arroyo, Amaia, Mazanec, Radim, Mercier, Sandra, Mongini, Tiziana, Muelas, Nuria, Nascimento, Andrés, Nafissi, Shahriar, Omidi, Shirin, Ortez, Carlos, Paquay, Stéphanie, Pereon, Yann, Perić, Stojan, Ponzalino, Valentina, Rakočević Stojanović, Vidosava, Remiche, Gauthier, Rodríguez Sainz, Aida, Rudnik, Sabine, Sanchez Albisua, Iciar, Santos, Manuela, Schara, Ulrike, Shatillo, Andriy, Sertić, Jadranka, Stephani, Ulrich, Strang- Karlsson, Sonja, Sznajer, Yves, Tanev, Ani, Tournev, Ivailo, Van den Bergh, Peter, Van Parijs, Vinciane, Vílchez, Juan, Vill, Katharina, Vissing, John, Wallgren-Pettersson, Carina, Wanschitz, Julia, Willis, Tracey, Witting, Nanna, Zulaica, Miren, and Straub, Volker

Subjects
genetic diagnosis, limb-girdle weakness, neuromuscular disease, next-generation sequencing, targeted exome analysis
Abstract

Purpose: Several hundred genetic muscle diseases have been described, all of which are rare. Their clinical and genetic heterogeneity means that a genetic diagnosis is challenging. We established an international consortium, MYO-SEQ, to aid the work-ups of muscle disease patients and to better understand disease etiology. Methods: Exome sequencing was applied to 1001 undiagnosed patients recruited from more than 40 neuromuscular disease referral centers ; standardized phenotypic information was collected for each patient. Exomes were examined for variants in 429 genes associated with muscle conditions. Results: We identified suspected pathogenic variants in 52% of patients across 87 genes. We detected 401 novel variants, 116 of which were recurrent. Variants in CAPN3, DYSF, ANO5, DMD, RYR1, TTN, COL6A2, and SGCA collectively accounted for over half of the solved cases ; while variants in newer disease genes, such as BVES and POGLUT1, were also found. The remaining well-characterized unsolved patients (48%) need further investigation. Conclusion: Using our unique infrastructure, we developed a pathway to expedite muscle disease diagnoses. Our data suggest that exome sequencing should be used for pathogenic variant detection in patients with suspected genetic muscle diseases, focusing first on the most common disease genes described here, and subsequently in rarer and newly characterized disease genes. .

Published
2020

12. Sequential targeted exome sequencing of 1001 patients affected by unexplained limb-girdle weakness.

Author

UCL - SSS/DDUV - Institut de Duve, UCL - SSS/DDUV/BCHM - Biochimie-Recherche métabolique, UCL - SSS/IONS - Institute of NeuroScience, UCL - SSS/IONS/NEUR - Clinical Neuroscience, UCL - (SLuc) Service de neurologie, UCL - (SLuc) Service de neurologie pédiatrique, Töpf, Ana, Johnson, Katherine, Bates, Adam, Phillips, Lauren, Chao, Katherine R, England, Eleina M, Laricchia, Kristen M, Mullen, Thomas, Valkanas, Elise, Xu, Liwen, Bertoli, Marta, Blain, Alison, Casasús, Ana B, Duff, Jennifer, Mroczek, Magdalena, Specht, Sabine, Lek, Monkol, Ensini, Monica, MacArthur, Daniel G, MYO-SEQ consortium, Straub, Volker, Paquay, Stéphanie, Van den Bergh, Peter, Van Parys, Vinciane, UCL - SSS/DDUV - Institut de Duve, UCL - SSS/DDUV/BCHM - Biochimie-Recherche métabolique, UCL - SSS/IONS - Institute of NeuroScience, UCL - SSS/IONS/NEUR - Clinical Neuroscience, UCL - (SLuc) Service de neurologie, UCL - (SLuc) Service de neurologie pédiatrique, Töpf, Ana, Johnson, Katherine, Bates, Adam, Phillips, Lauren, Chao, Katherine R, England, Eleina M, Laricchia, Kristen M, Mullen, Thomas, Valkanas, Elise, Xu, Liwen, Bertoli, Marta, Blain, Alison, Casasús, Ana B, Duff, Jennifer, Mroczek, Magdalena, Specht, Sabine, Lek, Monkol, Ensini, Monica, MacArthur, Daniel G, MYO-SEQ consortium, Straub, Volker, Paquay, Stéphanie, Van den Bergh, Peter, and Van Parys, Vinciane

Abstract

PURPOSE: Several hundred genetic muscle diseases have been described, all of which are rare. Their clinical and genetic heterogeneity means that a genetic diagnosis is challenging. We established an international consortium, MYO-SEQ, to aid the work-ups of muscle disease patients and to better understand disease etiology. METHODS: Exome sequencing was applied to 1001 undiagnosed patients recruited from more than 40 neuromuscular disease referral centers; standardized phenotypic information was collected for each patient. Exomes were examined for variants in 429 genes associated with muscle conditions. RESULTS: We identified suspected pathogenic variants in 52% of patients across 87 genes. We detected 401 novel variants, 116 of which were recurrent. Variants in CAPN3, DYSF, ANO5, DMD, RYR1, TTN, COL6A2, and SGCA collectively accounted for over half of the solved cases; while variants in newer disease genes, such as BVES and POGLUT1, were also found. The remaining well-characterized unsolved patients (48%) need further investigation. CONCLUSION: Using our unique infrastructure, we developed a pathway to expedite muscle disease diagnoses. Our data suggest that exome sequencing should be used for pathogenic variant detection in patients with suspected genetic muscle diseases, focusing first on the most common disease genes described here, and subsequently in rarer and newly characterized disease genes.

Published
2020

13. Contribution of non-coding mutations to RPGRIP1-mediated inherited retinal degeneration

Author

Jamshidi, Farzad, Place, Emily M., Mehrotra, Sudeep, Navarro-Gomez, Daniel, Maher, Mathew, Branham, Kari E., Valkanas, Elise, Cherry, Timothy J., Lek, Monkol, MacArthur, Daniel, Pierce, Eric A., and Bujakowska, Kinga M.

Subjects
Adult, Male, non-coding mutations, Whole Genome Sequencing, inherited retinal degeneration, DNA Mutational Analysis, Retinal Degeneration, intronic mutations, Chromosome Mapping, Proteins, Article, Pedigree, Cytoskeletal Proteins, HEK293 Cells, whole-genome sequencing, Mutation, Exome Sequencing, Humans, DNA, Intergenic, Female, RPGRIP1
Abstract

With the advent of gene therapies for inherited retinal degenerations (IRDs), genetic diagnostics will have an increasing role in clinical decision-making. Yet the genetic cause of disease cannot be identified using exon-based sequencing for a significant portion of patients. We hypothesized that noncoding pathogenic variants contribute significantly to the genetic causality of IRDs and evaluated patients with single coding pathogenic variants in RPGRIP1 to test this hypothesis.IRD families underwent targeted panel sequencing. Unsolved cases were explored by exome and genome sequencing looking for additional pathogenic variants. Candidate pathogenic variants were then validated by Sanger sequencing, quantitative polymerase chain reaction, and in vitro splicing assays in two cell lines analyzed through amplicon sequencing.Among 1722 families, 3 had biallelic loss-of-function pathogenic variants in RPGRIP1 while 7 had a single disruptive coding pathogenic variants. Exome and genome sequencing revealed potential noncoding pathogenic variants in these 7 families. In 6, the noncoding pathogenic variants were shown to lead to loss of function in vitro.Noncoding pathogenic variants were identified in 6 of 7 families with single coding pathogenic variants in RPGRIP1. The results suggest that noncoding pathogenic variants contribute significantly to the genetic causality of IRDs and RPGRIP1-mediated IRDs are more common than previously thought.

Published
2018

14. WGS and RNA Studies Diagnose Noncoding DMD Variants in Males With High Creatine Kinase

Author

Waddell, Leigh B., primary, Bryen, Samantha J., additional, Cummings, Beryl B., additional, Bournazos, Adam, additional, Evesson, Frances J., additional, Joshi, Himanshu, additional, Marshall, Jamie L., additional, Tukiainen, Taru, additional, Valkanas, Elise, additional, Weisburd, Ben, additional, Sadedin, Simon, additional, Davis, Mark R., additional, Faiz, Fathimath, additional, Gooding, Rebecca, additional, Sandaradura, Sarah A., additional, O'Grady, Gina L., additional, Tchan, Michel C., additional, Mowat, David R., additional, Oates, Emily C., additional, Farrar, Michelle A., additional, Sampaio, Hugo, additional, Ma, Alan, additional, Neas, Katherine, additional, Wang, Min-Xia, additional, Charlton, Amanda, additional, Chan, Charles, additional, Kenwright, Diane N., additional, Graf, Nicole, additional, Arbuckle, Susan, additional, Clarke, Nigel F., additional, MacArthur, Daniel G., additional, Jones, Kristi J., additional, Lek, Monkol, additional, and Cooper, Sandra T., additional

Published
2021
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15. Sequential targeted exome sequencing of 1001 patients affected by unexplained limb-girdle weakness

Author

Töpf, Ana, primary, Johnson, Katherine, additional, Bates, Adam, additional, Phillips, Lauren, additional, Chao, Katherine R., additional, England, Eleina M., additional, Laricchia, Kristen M., additional, Mullen, Thomas, additional, Valkanas, Elise, additional, Xu, Liwen, additional, Bertoli, Marta, additional, Blain, Alison, additional, Casasús, Ana B., additional, Duff, Jennifer, additional, Mroczek, Magdalena, additional, Specht, Sabine, additional, Lek, Monkol, additional, Ensini, Monica, additional, MacArthur, Daniel G., additional, Akay, Ela, additional, Alonso-Pérez, Jorge, additional, Baets, Jonathan, additional, Barisic, Nina, additional, Bastian, Alexandra, additional, Borell, Sabine, additional, Chamova, Teodora, additional, Claeys, Kristl, additional, Colomer, Jaume, additional, Coppens, Sandra, additional, Deconinck, Nicolas, additional, de Ridder, Willem, additional, Díaz-Manera, Jordi, additional, Domínguez-González, Cristina, additional, Duncan, Alexis, additional, Durmus, Hacer, additional, Fahmy, Nagia A., additional, Farrugia, Maria Elena, additional, Fernández-Torrón, Roberto, additional, Gonzalez-Quereda, Lidia, additional, Haberlova, Jana, additional, von der Hagen, Maja, additional, Hahn, Andreas, additional, Jakovčević, Antonia, additional, Jerico Pascual, Ivonne, additional, Kapetanovic, Solange, additional, Kenina, Viktorija, additional, Kirschner, Janbernd, additional, Klein, Andrea, additional, Kölbel, Heike, additional, Kostera-Pruszczyk, Anna, additional, Kulshrestha, Richa, additional, Lähdetie, Jaana, additional, Layegh, Mahsa, additional, Longman, Cheryl, additional, López de Munain, Adolfo, additional, Loscher, Wolfgang, additional, Lusakowska, Anna, additional, Maddison, Paul, additional, Magot, Armelle, additional, Majumdar, Anirban, additional, Martí, Pilar, additional, Martínez Arroyo, Amaia, additional, Mazanec, Radim, additional, Mercier, Sandra, additional, Mongini, Tiziana, additional, Muelas, Nuria, additional, Nascimento, Andrés, additional, Nafissi, Shahriar, additional, Omidi, Shirin, additional, Ortez, Carlos, additional, Paquay, Stéphanie, additional, Pereon, Yann, additional, Perić, Stojan, additional, Ponzalino, Valentina, additional, Rakočević Stojanović, Vidosava, additional, Remiche, Gauthier, additional, Rodríguez Sainz, Aida, additional, Rudnik, Sabine, additional, Sanchez Albisua, Iciar, additional, Santos, Manuela, additional, Schara, Ulrike, additional, Shatillo, Andriy, additional, Sertić, Jadranka, additional, Stephani, Ulrich, additional, Strang-Karlsson, Sonja, additional, Sznajer, Yves, additional, Tanev, Ani, additional, Tournev, Ivailo, additional, Van den Bergh, Peter, additional, Van Parijs, Vinciane, additional, Vílchez, Juan, additional, Vill, Katharina, additional, Vissing, John, additional, Wallgren-Pettersson, Carina, additional, Wanschitz, Julia, additional, Willis, Tracey, additional, Witting, Nanna, additional, Zulaica, Miren, additional, and Straub, Volker, additional

Published
2020
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16. Systematic evaluation of genome sequencing for the assessment of fetal structural anomalies

Author

Lowther, Chelsea, primary, Valkanas, Elise, additional, Giordano, Jessica L., additional, Wang, Harold Z., additional, Currall, Benjamin B., additional, O’Keefe, Kathryn, additional, Pierce-Hoffman, Emma, additional, Kurtas, Nehir E., additional, Whelan, Christopher W., additional, Hao, Stephanie P., additional, Weisburd, Ben, additional, Jalili, Vahid, additional, Fu, Jack, additional, Wong, Isaac, additional, Collins, Ryan L., additional, Zhao, Xuefang, additional, Austin-Tse, Christina A., additional, Evangelista, Emily, additional, Lemire, Gabrielle, additional, Aggarwal, Vimla S., additional, Lucente, Diane, additional, Gauthier, Laura D., additional, Tolonen, Charlotte, additional, Sahakian, Nareh, additional, Stevens, Christine, additional, An, Joon-Yong, additional, Dong, Shan, additional, Norton, Mary E., additional, MacKenzie, Tippi, additional, Devlin, Bernie, additional, Gilmore, Kelly, additional, Powell, Bradford C., additional, Brandt, Alicia, additional, Vetrini, Francesco, additional, DiVito, Michelle, additional, Sanders, Stephan J., additional, MacArthur, Daniel G., additional, Hodge, Jennelle C., additional, O’Donnell-Luria, Anne, additional, Rehm, Heidi L., additional, Vora, Neeta L., additional, Levy, Brynn, additional, Brand, Harrison, additional, Wapner, Ronald J., additional, and Talkowski, Michael E., additional

Published
2020
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17. An open resource of structural variation 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, 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, Margolin, Lauren, Taylor, Kent D., Lin, Henry J., Rich, Stephen S., Post, Wendy, 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
Structural variation, 0303 health sciences, 03 medical and health sciences, 0302 clinical medicine, Resource (biology), business.industry, Environmental resource management, Population genetics, Biology, business, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract

SUMMARYStructural variants (SVs) rearrange large segments of the genome and can have profound consequences for evolution and human diseases. As national biobanks, disease association studies, and clinical genetic testing grow increasingly reliant on genome sequencing, population references such as the Genome Aggregation Database (gnomAD) have become integral for interpreting genetic variation. To date, no large-scale reference maps of SVs exist from high-coverage sequencing comparable to those available for point mutations in protein-coding genes. Here, we constructed a reference atlas of SVs across 14,891 genomes from diverse global populations (54% non-European) as a component of gnomAD. We discovered a rich landscape of 433,371 distinct SVs, including 5,295 multi-breakpoint complex SVs across 11 mutational subclasses, and examples of localized chromosome shattering, as in chromothripsis. The average individual harbored 7,439 SVs, which accounted for 25-29% of all rare protein-truncating events per genome. We found strong correlations between constraint against damaging point mutations and rare SVs that both disrupt and duplicate protein-coding sequence, suggesting intolerance to reciprocal dosage alterations for a subset of tightly regulated genes. We also uncovered modest selection against noncoding SVs in cis-regulatory elements, although selection against protein-truncating SVs was stronger than any effect on noncoding SVs. Finally, we benchmarked carrier rates for medically relevant SVs, finding very large (≥1Mb) rare SVs in 3.8% of genomes (~1:26 individuals) and clinically reportable incidental SVs in 0.18% of genomes (~1:556 individuals). These data have been integrated directly into the gnomAD browser (https://gnomad.broadinstitute.org) and will have broad utility for population genetics, disease association, and diagnostic screening.

Published
2019
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18. Impact of PYROXD1 deficiency on cellular respiration and correlations with genetic analyses of limb-girdle muscular dystrophy in Saudi Arabia and Sudan

Author

Saha, Madhurima, primary, Reddy, Hemakumar M., additional, Salih, Mustafa A., additional, Estrella, Elicia, additional, Jones, Michael D., additional, Mitsuhashi, Satomi, additional, Cho, Kyung-Ah, additional, Suzuki-Hatano, Silveli, additional, Rizzo, Skylar A., additional, Hamad, Muddathir H., additional, Mukhtar, Maowia M., additional, Hamed, Ahlam A., additional, Elseed, Maha A., additional, Lek, Monkol, additional, Valkanas, Elise, additional, MacArthur, Daniel G., additional, Kunkel, Louis M., additional, Pacak, Christina A., additional, Draper, Isabelle, additional, and Kang, Peter B., additional

Published
2018
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19. matchbox: An open-source tool for patient matching via the Matchmaker Exchange

Author

Arachchi, Harindra, primary, Wojcik, Monica H, additional, Weisburd, Benjamin, additional, Jacobsen, Julius O. B., additional, Valkanas, Elise, additional, Baxter, Samantha, additional, Byrne, Alicia B., additional, O'Donnell-Luria, Anne H., additional, Haendel, Melissa, additional, Smedley, Damian, additional, MacArthur, Daniel G., additional, Philippakis, Anthony A., additional, and Rehm, Heidi L., additional

Published
2018
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21. Defining Disease, Diagnosis, and Translational Medicine within a Homeostatic Perturbation Paradigm: The National Institutes of Health Undiagnosed Diseases Program Experience

Author

Gall, Timothy, primary, Valkanas, Elise, additional, Bello, Christofer, additional, Markello, Thomas, additional, Adams, Christopher, additional, Bone, William P., additional, Brandt, Alexander J., additional, Brazill, Jennifer M., additional, Carmichael, Lynn, additional, Davids, Mariska, additional, Davis, Joie, additional, Diaz-Perez, Zoraida, additional, Draper, David, additional, Elson, Jeremy, additional, Flynn, Elise D., additional, Godfrey, Rena, additional, Groden, Catherine, additional, Hsieh, Cheng-Kang, additional, Fischer, Roxanne, additional, Golas, Gretchen A., additional, Guzman, Jessica, additional, Huang, Yan, additional, Kane, Megan S., additional, Lee, Elizabeth, additional, Li, Chong, additional, Links, Amanda E., additional, Maduro, Valerie, additional, Malicdan, May Christine V., additional, Malik, Fayeza S., additional, Nehrebecky, Michele, additional, Park, Joun, additional, Pemberton, Paul, additional, Schaffer, Katherine, additional, Simeonov, Dimitre, additional, Sincan, Murat, additional, Smedley, Damian, additional, Valivullah, Zaheer, additional, Wahl, Colleen, additional, Washington, Nicole, additional, Wolfe, Lynne A., additional, Xu, Karen, additional, Zhu, Yi, additional, Gahl, William A., additional, Tifft, Cynthia J., additional, Toro, Camillo, additional, Adams, David R., additional, He, Miao, additional, Robinson, Peter N., additional, Haendel, Melissa A., additional, Zhai, R. Grace, additional, and Boerkoel, Cornelius F., additional

Published
2017
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22. Pharmacogenomic incidental findings in 308 families: The NIH Undiagnosed Diseases Program experience

Author

Lee, Elizabeth M.J., primary, Xu, Karen, additional, Mosbrook, Emma, additional, Links, Amanda, additional, Guzman, Jessica, additional, Adams, David R., additional, Flynn, Elise, additional, Valkanas, Elise, additional, Toro, Camillo, additional, Tifft, Cynthia J., additional, Boerkoel, Cornelius F., additional, Gahl, William A., additional, and Sincan, Murat, additional

Published
2016
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23. The sensitivity of exome sequencing in identifying pathogenic mutations for LGMD in the United States

Author

Reddy, Hemakumar M, primary, Cho, Kyung-Ah, additional, Lek, Monkol, additional, Estrella, Elicia, additional, Valkanas, Elise, additional, Jones, Michael D, additional, Mitsuhashi, Satomi, additional, Darras, Basil T, additional, Amato, Anthony A, additional, Lidov, Hart GW, additional, Brownstein, Catherine A, additional, Margulies, David M, additional, Yu, Timothy W, additional, Salih, Mustafa A, additional, Kunkel, Louis M, additional, MacArthur, Daniel G, additional, and Kang, Peter B, additional

Published
2016
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24. Phenotypic evolution of UNC80 loss of function

Author

Valkanas, Elise, primary, Schaffer, Katherine, additional, Dunham, Christopher, additional, Maduro, Valerie, additional, du Souich, Christèle, additional, Rupps, Rosemarie, additional, Adams, David R., additional, Baradaran-Heravi, Alireza, additional, Flynn, Elise, additional, Malicdan, May C., additional, Gahl, William A., additional, Toro, Camilo, additional, and Boerkoel, Cornelius F., additional

Published
2016
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25. Computational evaluation of exome sequence data using human and model organism phenotypes improves diagnostic efficiency

Author

Bone, William P., primary, Washington, Nicole L., additional, Buske, Orion J., additional, Adams, David R., additional, Davis, Joie, additional, Draper, David, additional, Flynn, Elise D., additional, Girdea, Marta, additional, Godfrey, Rena, additional, Golas, Gretchen, additional, Groden, Catherine, additional, Jacobsen, Julius, additional, Köhler, Sebastian, additional, Lee, Elizabeth M.J., additional, Links, Amanda E., additional, Markello, Thomas C., additional, Mungall, Christopher J., additional, Nehrebecky, Michele, additional, Robinson, Peter N., additional, Sincan, Murat, additional, Soldatos, Ariane G., additional, Tifft, Cynthia J., additional, Toro, Camilo, additional, Trang, Heather, additional, Valkanas, Elise, additional, Vasilevsky, Nicole, additional, Wahl, Colleen, additional, Wolfe, Lynne A., additional, Boerkoel, Cornelius F., additional, Brudno, Michael, additional, Haendel, Melissa A., additional, Gahl, William A., additional, and Smedley, Damian, additional

Published
2016
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26. Recurrent Mutations in the Basic Domain of TWIST2 Cause Ablepharon Macrostomia and Barber-Say Syndromes

Author

Marchegiani, Shannon, Davis, Taylor, Tessadori, Federico, van Haaften, Gijs, Brancati, Francesco, Hoischen, Alexander, Huang, Haigen, Valkanas, Elise, Pusey, Barbara, Schanze, Denny, Venselaar, Hanka, Vulto-van Silfhout, Anneke T, Wolfe, Lynne A, Tifft, Cynthia J, Zerfas, Patricia M, Zambruno, Giovanna, Kariminejad, Ariana, Sabbagh-Kermani, Farahnaz, Lee, Janice, Tsokos, Maria G, Lee, Chyi-Chia R, Ferraz, Victor, da Silva, Eduarda Morgana, Stevens, Cathy A, Roche, Nathalie, Bartsch, Oliver, Farndon, Peter, Bermejo-Sanchez, Eva, Brooks, Brian P, Maduro, Valerie, Dallapiccola, Bruno, Ramos, Feliciano J, Chung, Hon-Yin Brian, Le Caignec, Cédric, Martins, Fabiana, Jacyk, Witold K, Mazzanti, Laura, Brunner, Han G, Bakkers, Jeroen, Lin, Shuo, Malicdan, May Christine V, Boerkoel, Cornelius F, Gahl, William A, de Vries, Bert B A, van Haelst, Mieke M, Zenker, Martin, Markello, Thomas C, Marchegiani, Shannon, Davis, Taylor, Tessadori, Federico, van Haaften, Gijs, Brancati, Francesco, Hoischen, Alexander, Huang, Haigen, Valkanas, Elise, Pusey, Barbara, Schanze, Denny, Venselaar, Hanka, Vulto-van Silfhout, Anneke T, Wolfe, Lynne A, Tifft, Cynthia J, Zerfas, Patricia M, Zambruno, Giovanna, Kariminejad, Ariana, Sabbagh-Kermani, Farahnaz, Lee, Janice, Tsokos, Maria G, Lee, Chyi-Chia R, Ferraz, Victor, da Silva, Eduarda Morgana, Stevens, Cathy A, Roche, Nathalie, Bartsch, Oliver, Farndon, Peter, Bermejo-Sanchez, Eva, Brooks, Brian P, Maduro, Valerie, Dallapiccola, Bruno, Ramos, Feliciano J, Chung, Hon-Yin Brian, Le Caignec, Cédric, Martins, Fabiana, Jacyk, Witold K, Mazzanti, Laura, Brunner, Han G, Bakkers, Jeroen, Lin, Shuo, Malicdan, May Christine V, Boerkoel, Cornelius F, Gahl, William A, de Vries, Bert B A, van Haelst, Mieke M, Zenker, Martin, and Markello, Thomas C

Published
2015

27. Recurrent Mutations in the Basic Domain of TWIST2 Cause Ablepharon Macrostomia and Barber-Say Syndromes

Author

Genetica Groep Van Haaften, Child Health, Medische Fysiologie, Circulatory Health, Hubrecht Institute with UMC, Genetica Klinische Genetica, Marchegiani, Shannon, Davis, Taylor, Tessadori, Federico, van Haaften, Gijs, Brancati, Francesco, Hoischen, Alexander, Huang, Haigen, Valkanas, Elise, Pusey, Barbara, Schanze, Denny, Venselaar, Hanka, Vulto-van Silfhout, Anneke T, Wolfe, Lynne A, Tifft, Cynthia J, Zerfas, Patricia M, Zambruno, Giovanna, Kariminejad, Ariana, Sabbagh-Kermani, Farahnaz, Lee, Janice, Tsokos, Maria G, Lee, Chyi-Chia R, Ferraz, Victor, da Silva, Eduarda Morgana, Stevens, Cathy A, Roche, Nathalie, Bartsch, Oliver, Farndon, Peter, Bermejo-Sanchez, Eva, Brooks, Brian P, Maduro, Valerie, Dallapiccola, Bruno, Ramos, Feliciano J, Chung, Hon-Yin Brian, Le Caignec, Cédric, Martins, Fabiana, Jacyk, Witold K, Mazzanti, Laura, Brunner, Han G, Bakkers, Jeroen, Lin, Shuo, Malicdan, May Christine V, Boerkoel, Cornelius F, Gahl, William A, de Vries, Bert B A, van Haelst, Mieke M, Zenker, Martin, Markello, Thomas C, Genetica Groep Van Haaften, Child Health, Medische Fysiologie, Circulatory Health, Hubrecht Institute with UMC, Genetica Klinische Genetica, Marchegiani, Shannon, Davis, Taylor, Tessadori, Federico, van Haaften, Gijs, Brancati, Francesco, Hoischen, Alexander, Huang, Haigen, Valkanas, Elise, Pusey, Barbara, Schanze, Denny, Venselaar, Hanka, Vulto-van Silfhout, Anneke T, Wolfe, Lynne A, Tifft, Cynthia J, Zerfas, Patricia M, Zambruno, Giovanna, Kariminejad, Ariana, Sabbagh-Kermani, Farahnaz, Lee, Janice, Tsokos, Maria G, Lee, Chyi-Chia R, Ferraz, Victor, da Silva, Eduarda Morgana, Stevens, Cathy A, Roche, Nathalie, Bartsch, Oliver, Farndon, Peter, Bermejo-Sanchez, Eva, Brooks, Brian P, Maduro, Valerie, Dallapiccola, Bruno, Ramos, Feliciano J, Chung, Hon-Yin Brian, Le Caignec, Cédric, Martins, Fabiana, Jacyk, Witold K, Mazzanti, Laura, Brunner, Han G, Bakkers, Jeroen, Lin, Shuo, Malicdan, May Christine V, Boerkoel, Cornelius F, Gahl, William A, de Vries, Bert B A, van Haelst, Mieke M, Zenker, Martin, and Markello, Thomas C

Published
2015

28. Recurrent Mutations in the Basic Domain of TWIST2 Cause Ablepharon Macrostomia and Barber-Say Syndromes

Author

Marchegiani, Shannon, primary, Davis, Taylor, additional, Tessadori, Federico, additional, van Haaften, Gijs, additional, Brancati, Francesco, additional, Hoischen, Alexander, additional, Huang, Haigen, additional, Valkanas, Elise, additional, Pusey, Barbara, additional, Schanze, Denny, additional, Venselaar, Hanka, additional, Vulto-van Silfhout, Anneke T., additional, Wolfe, Lynne A., additional, Tifft, Cynthia J., additional, Zerfas, Patricia M., additional, Zambruno, Giovanna, additional, Kariminejad, Ariana, additional, Sabbagh-Kermani, Farahnaz, additional, Lee, Janice, additional, Tsokos, Maria G., additional, Lee, Chyi-Chia R., additional, Ferraz, Victor, additional, da Silva, Eduarda Morgana, additional, Stevens, Cathy A., additional, Roche, Nathalie, additional, Bartsch, Oliver, additional, Farndon, Peter, additional, Bermejo-Sanchez, Eva, additional, Brooks, Brian P., additional, Maduro, Valerie, additional, Dallapiccola, Bruno, additional, Ramos, Feliciano J., additional, Chung, Hon-Yin Brian, additional, Le Caignec, Cédric, additional, Martins, Fabiana, additional, Jacyk, Witold K., additional, Mazzanti, Laura, additional, Brunner, Han G., additional, Bakkers, Jeroen, additional, Lin, Shuo, additional, Malicdan, May Christine V., additional, Boerkoel, Cornelius F., additional, Gahl, William A., additional, de Vries, Bert B.A., additional, van Haelst, Mieke M., additional, Zenker, Martin, additional, and Markello, Thomas C., additional

Published
2015
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29. The sensitivity of exome sequencing in identifying pathogenic mutations for LGMD in the United States

Author

Reddy, Hemakumar M., Cho, Kyung-Ah, Lek, Monkol, Estrella, Elicia, Valkanas, Elise, Jones, Michael D., Mitsuhashi, Satomi, Darras, Basil T., Amato, Anthony A., Lidov, Hart G.W., Brownstein, Catherine A., Margulies, David M., Yu, Timothy W., Salih, Mustafa A., Kunkel, Louis M., MacArthur, Daniel G., and Kang, Peter B.

Abstract

The current study characterizes a cohort of limb-girdle muscular dystrophy (LGMD) in the United States using whole exome sequencing. Fifty-five families affected by LGMD were recruited using an institutionally-approved protocol. Exome sequencing was performed on probands and selected parental samples. Pathogenic mutations and co-segregation patterns were confirmed by Sanger sequencing. Twenty-two families (40%) had novel and previously reported pathogenic mutations, primarily in LGMD genes, but also in genes for Duchenne muscular dystrophy, facioscapulohumeral muscular dystrophy, congenital myopathy, myofibrillar myopathy, inclusion body myopathy, and Pompe disease. One family was diagnosed via clinical testing. Dominant mutations were identified in COL6A1, COL6A3, FLNC, LMNA, RYR1, SMCHD1, and VCP, recessive mutations in ANO5, CAPN3, GAA, LAMA2, SGCA, and SGCG, and X-linked mutations in DMD. A previously reported variant in DMD was confirmed to be benign. Exome sequencing is a powerful diagnostic tool for LGMD. Despite careful phenotypic screening, pathogenic mutations were found in other muscle disease genes, largely accounting for the increased sensitivity of exome sequencing. Our experience suggests that broad sequencing panels are useful for these analyses due to the phenotypic overlap of many neuromuscular conditions. The confirmation of a benign DMD variant illustrates the potential of exome sequencing to help determine pathogenicity.

Published
2016
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30. Author Correction: 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.

Abstract

A Correction to this paper has been published: https://doi.org/10.1038/s41586-020-03176-6.

Published
2021
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31. Detection of variants in dystroglycanopathy-associated genes through the application of targeted whole-exome sequencing analysis to a large cohort of patients with unexplained limb-girdle muscle weakness

Author

Johnson, Katherine, Bertoli, Marta, Phillips, Lauren, Töpf, Ana, Van Den Bergh, Peter, Vissing, John, Witting, Nanna, Nafissi, Shahriar, Jamal-Omidi, Shirin, Usakowska, Anna, Kostera-Pruszczyk, Anna, Potulska-Chromik, Anna, Deconinck, Nicolas, Wallgren-Pettersson, Carina, Strang-Karlsson, Sonja, Colomer, Jaume, Claeys, Kristl G., De Ridder, Willem, Baets, Jonathan, Von Der Hagen, Maja, Fernández-Torrón, Roberto, Zulaica Ijurco, Miren, Espinal Valencia, Juan Bautista, Hahn, Andreas, Durmus, Hacer, Willis, Tracey, Xu, Liwen, Valkanas, Elise, Mullen, Thomas E., Lek, Monkol, MacArthur, Daniel G., and Straub, Volker

Subjects
3. Good health
Abstract

Skeletal muscle 8(1), 23 (2018). doi:10.1186/s13395-018-0170-1

32. matchbox: An open-source tool for patient matching via the Matchmaker Exchange

Author

Harindra Arachchi, Anne H. O’Donnell-Luria, Monica H. Wojcik, Alicia B. Byrne, Samantha Baxter, Daniel G. MacArthur, Anthony A. Philippakis, Melissa A. Haendel, Elise Valkanas, Heidi L. Rehm, Benjamin Weisburd, Julius O.B. Jacobsen, Damian Smedley, Arachchi, Harindra, Wojcik, Monica H, Weisburd, Benjamin, Jacobsen, Julius OB, Valkanas, Elise, Baxter, Samantha, Byrne, Alicia B, O'Donnell-Luria, Anne H, Haendel, Melilssa, Smedley, Damian, MacArthur, Daniel G, Philippakis, Anthony A, and Rehm, Heidi L

Subjects
0301 basic medicine, Matching (statistics), Process (engineering), rare diseas, Information Storage and Retrieval, Web Browser, Biology, matchbox, Article, Bridge (nautical), Access to Information, World Wide Web, Novel gene, 03 medical and health sciences, Rare Diseases, novel gene, Genetics, Humans, Genetic Predisposition to Disease, open-source, Genetic Association Studies, Genetics (clinical), Information Dissemination, Patient Selection, Scale (chemistry), Phenotype, 030104 developmental biology, Open source, Matchmaker Exchange, Software
Abstract

Rare disease investigators constantly face challenges in identifying additional cases to build evidence for gene‐disease causality. The Matchmaker Exchange (MME) addresses this limitation by providing a mechanism for matching patients across genomic centers via a federated network. The MME has revolutionized searching for additional cases by making it possible to query across institutional boundaries, so that what was once a laborious and manual process of contacting researchers is now automated and computable. However, while the MME network is beginning to scale, the growth of additional nodes is limited by the lack of easy‐to‐use solutions that can be implemented by any rare disease database owner, even one without significant software engineering resources. Here we describe matchbox, which is an open‐source, platform‐independent, portable bridge between any given rare disease genomic center and the MME network, which has already led to novel gene discoveries. We also describe how matchbox greatly reduces the barrier to participation by overcoming challenges for new databases to join the MME. Refereed/Peer-reviewed

Published
2018
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33. Recurrent Mutations in the Basic Domain of TWIST2 Cause Ablepharon Macrostomia and Barber-Say Syndromes

Author

Elise Valkanas, Hon-Yin Brian Chung, Peter Farndon, Patricia M. Zerfas, Oliver Bartsch, Martin Zenker, Jeroen Bakkers, Alexander Hoischen, Feliciano J. Ramos, Eva Bermejo-Sánchez, Haigen Huang, Gijs van Haaften, Lynne A. Wolfe, Taylor Davis, Eduarda Morgana da Silva, Han G. Brunner, W. K. Jacyk, Bruno Dallapiccola, Laura Mazzanti, Cathy A. Stevens, Mieke M. van Haelst, Hanka Venselaar, Cornelius F. Boerkoel, Francesco Brancati, Cynthia J. Tifft, May Christine V. Malicdan, Nathalie Roche, Bert B.A. de Vries, Victor Evangelista de Faria Ferraz, Chyi-Chia Richard Lee, Brian P. Brooks, Farahnaz Sabbagh-Kermani, Federico Tessadori, Denny Schanze, Barbara N. Pusey, Ariana Kariminejad, Valerie Maduro, Janice Lee, Giovanna Zambruno, Shuo Lin, Cédric Le Caignec, Thomas C. Markello, Maria Tsokos, Shannon Marchegiani, Fabiana Martins, William A. Gahl, Anneke T. Vulto-van Silfhout, Other departments, Human genetics, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Reproduction & Development (AR&D), MUMC+: DA Klinische Genetica (5), RS: GROW - Developmental Biology, RS: GROW - R4 - Reproductive and Perinatal Medicine, Marchegiani, Shannon, Davis, Taylor, Tessadori, Federico, Van Haaften, Gij, Brancati, Francesco, Hoischen, Alexander, Huang, Haigen, Valkanas, Elise, Pusey, Barbara, Schanze, Denny, Venselaar, Hanka, Vulto-Van Silfhout, Anneke T., Wolfe, Lynne A., Tifft, Cynthia J., Zerfas, Patricia M., Zambruno, Giovanna, Kariminejad, Ariana, Sabbagh-Kermani, Farahnaz, Lee, Janice, Tsokos, Maria G., Lee, Chyi-Chia R., Ferraz, Victor, Da Silva, Eduarda Morgana, Stevens, Cathy A., Roche, Nathalie, Bartsch, Oliver, Farndon, Peter, Bermejo-Sanchez, Eva, Brooks, Brian P., Maduro, Valerie, Dallapiccola, Bruno, Ramos, Feliciano J., Chung, Hon-Yin Brian, Le Caignec, Cédric, Martins, Fabiana, Jacyk, Witold K., Mazzanti, Laura, Brunner, Han G., Bakkers, Jeroen, Lin, Shuo, Malicdan, May Christine V., Boerkoel, Cornelius F., Gahl, William A., De Vries, Bert B.A., Van Haelst, Mieke M., Zenker, Martin, Markello, Thomas C., and Hubrecht Institute for Developmental Biology and Stem Cell Research

Subjects
Models, Molecular, Candidate gene, Hirsutism, Protein Conformation, HeLa Cell, medicine.disease_cause, Transcriptome, Twist transcription factor, Models, Genetics(clinical), Exome, Eye Abnormalities, Non-U.S. Gov't, Genetics (clinical), Zebrafish, Genetics, Mutation, Microscopy, Macrostomia, Setleis syndrome, Hypertelorism, Research Support, Non-U.S. Gov't, Hypertrichosi, Eyelid Disease, GENÉTICA, Phenotype, Eyelid Diseases, Abnormalities, Multiple, Sequence Analysis, Human, Chromatin Immunoprecipitation, Molecular Sequence Data, Mutation, Missense, Hypertrichosis, Amino Acid Sequence, Animals, Base Sequence, HeLa Cells, Humans, Electron, Missense, Repressor Proteins, DNA, Skin Abnormalities, Twist Transcription Factor, Molecular, Other Research Radboud Institute for Molecular Life Sciences [Radboudumc 0], Biology, Research Support, Article, Frameshift mutation, Genetic, Ablepharon macrostomia syndrome, Skin Abnormalitie, medicine, Journal Article, Abnormalities, Multiple, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Animal, Twist-Related Protein 1, Sequence Analysis, DNA, Repressor Protein, medicine.disease, Eye Abnormalitie, Microscopy, Electron, sense organs, Nanomedicine Radboud Institute for Molecular Life Sciences [Radboudumc 19]
Abstract

Contains fulltext : 153827.pdf (Publisher’s version ) (Open Access) Ablepharon macrostomia syndrome (AMS) and Barber-Say syndrome (BSS) are rare congenital ectodermal dysplasias characterized by similar clinical features. To establish the genetic basis of AMS and BSS, we performed extensive clinical phenotyping, whole exome and candidate gene sequencing, and functional validations. We identified a recurrent de novo mutation in TWIST2 in seven independent AMS-affected families, as well as another recurrent de novo mutation affecting the same amino acid in ten independent BSS-affected families. Moreover, a genotype-phenotype correlation was observed, because the two syndromes differed based solely upon the nature of the substituting amino acid: a lysine at TWIST2 residue 75 resulted in AMS, whereas a glutamine or alanine yielded BSS. TWIST2 encodes a basic helix-loop-helix transcription factor that regulates the development of mesenchymal tissues. All identified mutations fell in the basic domain of TWIST2 and altered the DNA-binding pattern of Flag-TWIST2 in HeLa cells. Comparison of wild-type and mutant TWIST2 expressed in zebrafish identified abnormal developmental phenotypes and widespread transcriptome changes. Our results suggest that autosomal-dominant TWIST2 mutations cause AMS or BSS by inducing protean effects on the transcription factor's DNA binding.

Published
2015
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