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1. COL4A gene variants are common in children with hematuria and a family history of kidney disease

Author

Rheault, Michelle N., McLaughlin, Heather M., Mitchell, Asia, Blake, Lauren E., Devarajan, Prasad, Warady, Bradley A., and Gibson, Keisha L.

Subjects
Chronic kidney failure -- Risk factors -- Genetic aspects -- Demographic aspects, Genetic variation -- Analysis, Hematuria -- Risk factors -- Genetic aspects -- Demographic aspects, Health
Abstract

Background Inherited kidney diseases are a common cause of chronic kidney disease (CKD) in children. Identification of a monogenic cause of CKD is more common in children than in adults. This study evaluated the diagnostic yield and phenotypic spectrum of children who received genetic testing through the KIDNEYCODE sponsored genetic testing program. Methods Unrelated children < 18 years of age who received panel testing through the KIDNEYCODE sponsored genetic testing program from September 2019 through August 2021 were included (N = 832). Eligible children met at least one of the following clinician-reported criteria: estimated GFR [less than or equal to] 90 ml/min/1.73 m.sup.2, hematuria, a family history of kidney disease, or suspected or biopsy confirmed Alport syndrome or focal segmental glomerulosclerosis (FSGS) in the tested individual or family member. Results A positive genetic diagnosis was observed in 234 children (28.1%, 95% CI [25.2-31.4%]) in genes associated with Alport syndrome (N = 213), FSGS (N = 9), or other disorders (N = 12). Among children with a family history of kidney disease, 30.8% had a positive genetic diagnosis. Among those with hematuria and a family history of CKD, the genetic diagnostic rate increased to 40.4%. Conclusions Children with hematuria and a family history of CKD have a high likelihood of being diagnosed with a monogenic cause of kidney disease, identified through KIDNEYCODE panel testing, particularly COL4A variants. Early genetic diagnosis can be valuable in targeting appropriate therapy and identification of other at-risk family members. Graphical abstract A higher resolution version of the Graphical abstract is available as Supplementary information, Author(s): Michelle N. Rheault [sup.1] , Heather M. McLaughlin [sup.2] , Asia Mitchell [sup.2] , Lauren E. Blake [sup.2] , Prasad Devarajan [sup.3] , Bradley A. Warady [sup.4] , Keisha [...]

Published
2023
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2. Clinical utility of comprehensive gene panel testing for common and rare causes of skeletal dysplasia and other skeletal disorders: Results from the largest cohort to date.

Author

MacCarrick, Gretchen, Aradhya, Swaroop, Bailey, Mitch, Chu, Dorna, Hunt, Abigail, Izzo, Emanuela, Krakow, Deborah, Mackenzie, William, Poll, Sarah, Raggio, Cathleen, Shediac, Renée, White, Klane K., McLaughlin, Heather M., and Seratti, Guillermo

Abstract

Molecular genetics enables more precise diagnoses of skeletal dysplasia and other skeletal disorders (SDs). We investigated the clinical utility of multigene panel testing for 5011 unrelated individuals with SD in the United States (December 2019–April 2022). Median (range) age was 8 (0–90) years, 70.5% had short stature and/or disproportionate growth, 27.4% had a positive molecular diagnosis (MDx), and 30 individuals received two MDx. Genes most commonly contributing to MDx were FGFR3 (16.9%), ALPL (13.0%), and COL1A1 (10.3%). Most of the 112 genes associated with ≥1 MDx were primarily involved in signal transduction (n = 35), metabolism (n = 23), or extracellular matrix organization (n = 17). There were implications associated with specific care/treatment options for 84.4% (1158/1372) of MDx‐positive individuals; >50% were linked to conditions with targeted therapy approved or in clinical development, including osteogenesis imperfecta, achondroplasia, hypophosphatasia, and mucopolysaccharidosis. Forty individuals with initially inconclusive results became MDx‐positive following family testing. Follow‐up mucopolysaccharidosis enzyme activity testing was positive in 14 individuals (10 of these were not MDx‐positive). Our findings showed that inclusion of metabolic genes associated with SD increased the clinical utility of a gene panel and confirmed that integrated use of comprehensive gene panel testing with orthogonal testing reduced the burden of inconclusive results. [ABSTRACT FROM AUTHOR]

Published
2024
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3. PIGG variant pathogenicity assessment reveals characteristic features within 19 families

Author

Tremblay-Laganière, Camille, Maroofian, Reza, Nguyen, Thi Tuyet Mai, Karimiani, Ehsan Ghayoor, Kirmani, Salman, Akbar, Fizza, Ibrahim, Shahnaz, Afroze, Bushra, Doosti, Mohammad, Ashrafzadeh, Farah, Babaei, Meisam, Efthymiou, Stephanie, Christoforou, Marilena, Sultan, Tipu, Ladda, Roger L., McLaughlin, Heather M., Truty, Rebecca, Mahida, Sonal, Cohen, Julie S., Baranano, Kristin, Ismail, Fatima Y., Patel, Millan S., Lehman, Anna, Edmondson, Andrew C., Nagy, Amanda, Walker, Melissa A., Mercimek-Andrews, Saadet, Maki, Yuta, Sachdev, Rani, Macintosh, Rebecca, Palmer, Elizabeth E., Mancini, Grazia M.S., Barakat, Tahsin Stefan, Steinfeld, Robert, Rüsch, Christina T., Stettner, Georg M., Wagner, Matias, Wortmann, Saskia B., Kini, Usha, Brady, Angela F., Stals, Karen L., Ismayilova, Naila, Ellard, Sian, Bernardo, Danilo, Nugent, Kimberly, McLean, Scott D., Antonarakis, Stylianos E., Houlden, Henry, Kinoshita, Taroh, Campeau, Philippe M., and Murakami, Yoshiko

Published
2021
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4. A survey of current practices for genomic sequencing test interpretation and reporting processes in US laboratories.

Author

O'Daniel, Julianne M, McLaughlin, Heather M, Amendola, Laura M, Bale, Sherri J, Berg, Jonathan S, Bick, David, Bowling, Kevin M, Chao, Elizabeth C, Chung, Wendy K, Conlin, Laura K, Cooper, Gregory M, Das, Soma, Deignan, Joshua L, Dorschner, Michael O, Evans, James P, Ghazani, Arezou A, Goddard, Katrina A, Gornick, Michele, Farwell Hagman, Kelly D, Hambuch, Tina, Hegde, Madhuri, Hindorff, Lucia A, Holm, Ingrid A, Jarvik, Gail P, Knight Johnson, Amy, Mighion, Lindsey, Morra, Massimo, Plon, Sharon E, Punj, Sumit, Richards, C Sue, Santani, Avni, Shirts, Brian H, Spinner, Nancy B, Tang, Sha, Weck, Karen E, Wolf, Susan M, Yang, Yaping, and Rehm, Heidi L

Subjects
Disclosure, Genetic Testing: methods, standards, Humans, Incidental Findings, Information Dissemination, Laboratories: ethics, standards, Practice Guidelines as Topic, Research Report, Sample Size, Sequence Analysis, DNA: methods, standards, Surveys and Questionnaires
Abstract

While the diagnostic success of genomic sequencing expands, the complexity of this testing should not be overlooked. Numerous laboratory processes are required to support the identification, interpretation, and reporting of clinically significant variants. This study aimed to examine the workflow and reporting procedures among US laboratories to highlight shared practices and identify areas in need of standardization.Surveys and follow-up interviews were conducted with laboratories offering exome and/or genome sequencing to support a research program or for routine clinical services. The 73-item survey elicited multiple choice and free-text responses that were later clarified with phone interviews.Twenty-one laboratories participated. Practices highly concordant across all groups included consent documentation, multiperson case review, and enabling patient opt-out of incidental or secondary findings analysis. Noted divergence included use of phenotypic data to inform case analysis and interpretation and reporting of case-specific quality metrics and methods. Few laboratory policies detailed procedures for data reanalysis, data sharing, or patient access to data.This study provides an overview of practices and policies of experienced exome and genome sequencing laboratories. The results enable broader consideration of which practices are becoming standard approaches, where divergence remains, and areas of development in best practice guidelines that may be helpful.Genet Med advance online publication 03 Novemeber 2016.

Published
2017

5. Automated typing of red blood cell and platelet antigens: a whole-genome sequencing study

Author

Bates, David W., Blout, Carrie, Christensen, Kurt D., Cirino, Allison L., Ho, Carolyn Y., Krier, Joel B., Lehmann, Lisa S., MacRae, Calum A., Morton, Cynthia C., Perry, Denise L., Seidman, Christine E., Sunyaev, Shamil R., Vassy, Jason L., Schonman, Erica, Nguyen, Tiffany, Steffens, Eleanor, Betting, Wendi Nicole, Aronson, Samuel J., Ceyhan-Birsoy, Ozge, Machini, Kalotina, McLaughlin, Heather M., Azzariti, Danielle R., Tsai, Ellen A., Blumenthal-Barby, Jennifer, Feuerman, Lindsay Z., McGuire, Amy L., Lee, Kaitlyn, Robinson, Jill O., Slashinski, Melody J., Diamond, Pamela M., Davis, Kelly, Ubel, Peter A., Kraft, Peter, Roberts, J. Scott, Garber, Judy E., Hambuch, Tina, Murray, Michael F., Kohane, Isaac, Kong, Sek Won, Lane, William J, Westhoff, Connie M, Gleadall, Nicholas S, Aguad, Maria, Smeland-Wagman, Robin, Vege, Sunitha, Simmons, Daimon P, Mah, Helen H, Lebo, Matthew S, Walter, Klaudia, Soranzo, Nicole, Di Angelantonio, Emanuele, Danesh, John, Roberts, David J, Watkins, Nick A, Ouwehand, Willem H, Butterworth, Adam S, Kaufman, Richard M, Rehm, Heidi L, Silberstein, Leslie E, and Green, Robert C

Published
2018
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9. De novo missense variants in PPP1CB are associated with intellectual disability and congenital heart disease

Author

Ma, Lijiang, Bayram, Yavuz, McLaughlin, Heather M., Cho, Megan T., Krokosky, Alyson, Turner, Clesson E., Lindstrom, Kristin, Bupp, Caleb P., Mayberry, Katey, Mu, Weiyi, Bodurtha, Joann, Weinstein, Veronique, Zadeh, Neda, Alcaraz, Wendy, Powis, Zöe, Shao, Yunru, Scott, Daryl A., Lewis, Andrea M., White, Janson J., Jhangiani, Shalani N., Gulec, Elif Yilmaz, Lalani, Seema R., Lupski, James R., Retterer, Kyle, Schnur, Rhonda E., Wentzensen, Ingrid M., Bale, Sherri, and Chung, Wendy K.

Published
2016
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10. List of Contributors

Author

Allison, Kimberly H., primary, Allyse, Megan A., additional, Arcenas, Rodney C., additional, Bartel, Michael J., additional, Behdad, Amir, additional, Bennett, Katie M., additional, Berg, Jonathan S., additional, Best, D. Hunter, additional, Betz, Bryan L., additional, Booker, Jessica K., additional, Borowski, Kristi S., additional, Bourlet, Thomas, additional, Brissot, Pierre, additional, Brown, Noah A., additional, Bula, Marcin, additional, Caprioli, Richard M., additional, Chakraborty, Subhankar, additional, Coleman, William B., additional, Crooks, Kristy R., additional, Dong, Jianli, additional, Drabkin, Harry A., additional, Duncan, Daniel L., additional, Fareed, Jawed, additional, Ferreira-Gonzalez, Andrea, additional, Funke, Birgit H., additional, Furtado, Larissa V., additional, Gallinella, Giorgio, additional, Gonzalo, Sonzalo, additional, Grattard, Florence, additional, Gutierrez, Danielle B., additional, Haskell, Gloria T., additional, Hedayat, Amin A., additional, Highsmith, W. Edward, additional, Hsiao, Susan J., additional, Iqbal, Omer, additional, Ismail, Nahed, additional, Jouanolle, Anne-Marie, additional, Kerr, Sarah E., additional, Loréal, Olivier, additional, McLaughlin, Heather M., additional, Memmi, Meriam, additional, Michalak, Tomasz I., additional, Miller, Melissa B., additional, Mulrooney-Cousins, Patricia M., additional, Nikiforov, Yuri E., additional, Norris, Jeremy L., additional, Patel, Nirali M., additional, Perrotta, Peter L., additional, Pinsky, Benjamin A., additional, Pirmohamed, Munir, additional, Plongla, Rongpong, additional, Pozzetto, Bruno, additional, Pratt, Victoria M., additional, Procop, Gary W., additional, Raimondo, Massimo, additional, Rao, ✠Kathleen W., additional, Scott, Stuart A., additional, Shi, Chanjuan, additional, Shiau, Carolyn J., additional, Si, Yue, additional, Smith, Steven C., additional, Smolkin, Matthew B., additional, Stellrecht, Kathleen A., additional, Tan, Susanna K., additional, Thomas, Jessica S., additional, Tomlins, Scott A., additional, Trembath, Dimitri G., additional, Tsao, Ming-Sound, additional, Tsongalis, Gregory J., additional, Turner, Richard M., additional, Turner, Scott A., additional, Udager, Aaron M., additional, Verhoeven, Paul, additional, Walker, David H., additional, Wick, Myra J., additional, Willoughby, Kathryn, additional, Yan, Shaofeng, additional, and Yen-Lieberman, Belinda, additional

Published
2017
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11. Detect Lysosomal Storage Diseases: A no-charge, sponsored, testing program that enables access to genetic testing, treatment, and clinical trials for individuals with suspected lysosomal disorders

Author

McLaughlin, Heather M., primary, Clarke, Michele, additional, Crosby, Kathleen, additional, Furgerson, Matthew, additional, Leal-Pardinas, Fernanda, additional, Mitchell, Asia, additional, Pappadakis, Jennifer A., additional, Solyom, Alexander, additional, Tress, Jenna, additional, and Johnson, Britt A., additional

Published
2022
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12. Correction to:De novo variants in SNAP25 cause an early-onset developmental and epileptic encephalopathy (Genetics in Medicine, (2021), 23, 4, (653-660), 10.1038/s41436-020-01020-w)

Author

Klöckner, Chiara, Sticht, Heinrich, Zacher, Pia, Popp, Bernt, Babcock, Holly E., Bakker, Dewi P., Barwick, Katy, Bonfert, Michaela V., Bönnemann, Carsten G., Brilstra, Eva H., Chung, Wendy K., Clarke, Angus J., Devine, Patrick, Donkervoort, Sandra, Fraser, Jamie L., Friedman, Jennifer, Gates, Alyssa, Ghoumid, Jamal, Hobson, Emma, Horvath, Gabriella, Keller-Ramey, Jennifer, Keren, Boris, Kurian, Manju A., Lee, Virgina, Leppig, Kathleen A., Lundgren, Johan, McDonald, Marie T., McLaughlin, Heather M., McTague, Amy, Mefford, Heather C., Mignot, Cyril, Mikati, Mohamad A., Nava, Caroline, Raymond, F. Lucy, Sampson, Julian R., Sanchis-Juan, Alba, Shashi, Vandana, Shieh, Joseph T.C., Shinawi, Marwan, Slavotinek, Anne, Stödberg, Tommy, Stong, Nicholas, Sullivan, Jennifer A., Taylor, Ashley C., Toler, Tomi L., van den Boogaard, Marie José, van der Crabben, Saskia N., van Gassen, Koen L.I., van Jaarsveld, Richard H., Møller, Rikke S., Lemke, Johannes W, and Platzer, Konrad

Abstract

Unfortunately, in the first sentence in the abstract, a spelling mistake was introduced during the production process after our proofreading. The wording was changed from “aims” to “aimsed.” Heather M. McLaughlin was not listed among the authors. The original article has been corrected.

Published
2021
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13. COQ6 mutations in human patients produce nephrotic syndrome with sensorineural deafness

Author

Heeringa, Saskia F., Chernin, Gil, Chaki, Moumita, Zhou, Weibin, Sloan, Alexis J., Ji, Ziming, Xie, Letian X., Salviati, Leonardo, Hurd, Toby W., Vega-Warner, Virginia, Killen, Paul D., Raphael, Yehoash, Ashraf, hazia, Ovunc, Bugsu, Schoeb, Dominik S., McLaughlin, Heather M., Airik, Rannar, Vlangos, Christopher N., Gbadegesin, Rasheed, Hinkes, Bernward, Saisawat, Pawaree, Trevisson, Eva, Doimo, Mara, Casarin, Alberto, Pertegato, Vanessa, Giorgi, Gianpietro, Prokisch, Holger, Rotig, Agnes, Nurnberg, Gudrun, Becker, Christian, Wang, Su, Ozaltin, Fatih, Topaloglu, Rezan, Bakkaloglu, Aysin, Bakkaloglu, Sevcan A., Muller, Dominik, Beissert, Antje, Mir, Sevgi, Berdeli, Afig, Ozen, Seza, Zenker, Martin, Matejas, Verena, Santos-Ocana, Carlos, Navas, Placido, Kusakabe, Takehiro, Kispert, Andreas, Akman, Sema, Soliman, Neveen A., Krick, Stefanie, Mundel, Peter, Reiser, Jochen, Nurnberg, Peter, Clarke, Catherine F., Wiggins, Roger C., Faul, Christian, and Hildebrandt, Friedhelm

Subjects
Gene mutations -- Health aspects -- Research, Nephrotic syndrome -- Genetic aspects -- Risk factors -- Research, Deafness -- Genetic aspects -- Risk factors -- Research, Health care industry
Abstract

Steroid-resistant nephrotic syndrome (SRNS) is a frequent cause of end-stage renal failure. Identification of single-gene causes of SRNS has generated some insights into its pathogenesis; however, additional genes and disease [...]

Published
2011
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14. Compound heterozygosity for loss-of-function lysyl-tRNA synthetase mutations in a patient with peripheral neuropathy

Author

McLaughlin, Heather M., Sakaguchi, Reiko, Cuiping Liu, Igarashi, Takao, Pehlivan, Davut, Chu, Kristine, Iyer, Ram, Cruz, Pedro, Cherukuri, Praveen F., Hansen, Nancy F., Mullikin, James C., Biesecker, Leslie G., Wilson, Thomas E., Ionasescu, Victor, Nicholson, Garth, Searby, Charles, Talbot, Kevin, Vance, Jeffrey M., Zuchner, Stephan, Szigeti, Kinga, Lupski, James R., Ya-Ming Hou, Green, Eric D., and Antonellis, Anthony

Subjects
Charcot-Marie-Tooth disease -- Genetic aspects, Gene mutations -- Analysis, Lysine -- Research, Peripheral nerve diseases -- Research, Transfer RNA -- Research, Biological sciences
Abstract

A large-scale mutation screen of some genes encoding aminoacyl-tRNA synthetases (ARSs) in patients with Charcot-Marie-Tooth (CMT) disease characterized by peripheral neuropathy is undertaken to explore the role of ARSs in CMT disease. Results reveal that multiple mutations of the lysyl-tRNA synthetase (KARS) gene belonging to the ARS gene family, which severely affect related enzyme activity, are found in a single patient with CMT.

Published
2010

15. Syndromic neurodevelopmental disorder associated with de novo variants inDDX23

Author

Burns, William, primary, Bird, Lynne M., additional, Heron, Delphine, additional, Keren, Boris, additional, Ramachandra, Divya, additional, Thiffault, Isabelle, additional, Del Viso, Florencia, additional, Amudhavalli, Shivarajan, additional, Engleman, Kendra, additional, Parenti, Ilaria, additional, Kaiser, Frank J., additional, Wierzba, Jolanta, additional, Riedhammer, Korbinian M., additional, Liptay, Susanne, additional, Zadeh, Neda, additional, Porrmann, Joseph, additional, Fischer, Andrea, additional, Gößwein, Sophie, additional, McLaughlin, Heather M., additional, Telegrafi, Aida, additional, Langley, Katherine G., additional, Steet, Richard, additional, Louie, Raymond J., additional, and Lyons, Michael J., additional

Published
2021
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16. Correction to: De novo variants in SNAP25 cause an early-onset developmental and epileptic encephalopathy

Author

Klöckner, Chiara, primary, Sticht, Heinrich, additional, Zacher, Pia, additional, Popp, Bernt, additional, Babcock, Holly E., additional, Bakker, Dewi P., additional, Barwick, Katy, additional, Bonfert, Michaela V., additional, Bönnemann, Carsten G., additional, Brilstra, Eva H., additional, Chung, Wendy K., additional, Clarke, Angus J., additional, Devine, Patrick, additional, Donkervoort, Sandra, additional, Fraser, Jamie L., additional, Friedman, Jennifer, additional, Gates, Alyssa, additional, Ghoumid, Jamal, additional, Hobson, Emma, additional, Horvath, Gabriella, additional, Keller-Ramey, Jennifer, additional, Keren, Boris, additional, Kurian, Manju A., additional, Lee, Virgina, additional, Leppig, Kathleen A., additional, Lundgren, Johan, additional, McDonald, Marie T., additional, McLaughlin, Heather M., additional, McTague, Amy, additional, Mefford, Heather C., additional, Mignot, Cyril, additional, Mikati, Mohamad A., additional, Nava, Caroline, additional, Raymond, F. Lucy, additional, Sampson, Julian R., additional, Sanchis-Juan, Alba, additional, Shashi, Vandana, additional, Shieh, Joseph T.C., additional, Shinawi, Marwan, additional, Slavotinek, Anne, additional, Stödberg, Tommy, additional, Stong, Nicholas, additional, Sullivan, Jennifer A., additional, Taylor, Ashley C., additional, Toler, Tomi L., additional, van den Boogaard, Marie-José, additional, van der Crabben, Saskia N., additional, van Gassen, Koen L.I., additional, van Jaarsveld, Richard H., additional, Van Ziffle, Jessica, additional, Wadley, Alexandrea F., additional, Wagner, Matias, additional, Wigby, Kristen, additional, Wortmann, Saskia B., additional, Zarate, Yuri A., additional, Møller, Rikke S., additional, Lemke, Johannes R., additional, and Platzer, Konrad, additional

Published
2021
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17. De novo variants in SNAP25 cause an early-onset developmental and epileptic encephalopathy

Author

Klöckner, Chiara, primary, Sticht, Heinrich, additional, Zacher, Pia, additional, Popp, Bernt, additional, Babcock, Holly E., additional, Bakker, Dewi P., additional, Barwick, Katy, additional, Bonfert, Michaela V., additional, Bönnemann, Carsten G., additional, Brilstra, Eva H., additional, Chung, Wendy K., additional, Clarke, Angus J., additional, Devine, Patrick, additional, Donkervoort, Sandra, additional, Fraser, Jamie L., additional, Friedman, Jennifer, additional, Gates, Alyssa, additional, Ghoumid, Jamal, additional, Hobson, Emma, additional, Horvath, Gabriella, additional, Keller-Ramey, Jennifer, additional, Keren, Boris, additional, Kurian, Manju A., additional, Lee, Virgina, additional, Leppig, Kathleen A., additional, Lundgren, Johan, additional, McDonald, Marie T., additional, McLaughlin, Heather M., additional, McTague, Amy, additional, Mefford, Heather C., additional, Mignot, Cyril, additional, Mikati, Mohamad A., additional, Nava, Caroline, additional, Raymond, F. Lucy, additional, Sampson, Julian R., additional, Sanchis-Juan, Alba, additional, Shashi, Vandana, additional, Shieh, Joseph T.C., additional, Shinawi, Marwan, additional, Slavotinek, Anne, additional, Stödberg, Tommy, additional, Stong, Nicholas, additional, Sullivan, Jennifer A., additional, Taylor, Ashley C., additional, Toler, Tomi L., additional, van den Boogaard, Marie-José, additional, van der Crabben, Saskia N., additional, van Gassen, Koen L.I., additional, van Jaarsveld, Richard H., additional, Van Ziffle, Jessica, additional, Wadley, Alexandrea F., additional, Wagner, Matias, additional, Wigby, Kristen, additional, Wortmann, Saskia B., additional, Zarate, Yuri A., additional, Møller, Rikke S., additional, Lemke, Johannes R., additional, and Platzer, Konrad, additional

Published
2021
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24. Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy

Author

O'Donnell-Luria, Anne H, Pais, Lynn S, Faundes, Víctor, Wood, Jordan C, Sveden, Abigail, Luria, Victor, Abou Jamra, Rami, Accogli, Andrea, Amburgey, Kimberly, Anderlid, Britt Marie, Azzarello-Burri, Silvia, Basinger, Alice A, Bianchini, Claudia, Bird, Lynne M, Buchert, Rebecca, Carre, Wilfrid, Ceulemans, Sophia, Charles, Perrine, Cox, Helen, Culliton, Lisa, Currò, Aurora, Deciphering Developmental Disorders (DDD) Study, Demurger, Florence, Dowling, James J, Duban-Bedu, Benedicte, Dubourg, Christèle, Eiset, Saga Elise, Escobar, Luis F, Ferrarini, Alessandra, Haack, Tobias B, Hashim, Mona, Heide, Solveig, Helbig, Katherine L, Helbig, Ingo, Heredia, Raul, Héron, Delphine, Isidor, Bertrand, Jonasson, Amy R, Joset, Pascal, Keren, Boris, Kok, Fernando, Kroes, Hester Y, Lavillaureix, Alinoë, Lu, Xin, Maas, Saskia M, Maegawa, Gustavo HB, Marcelis, Carlo LM, Mark, Paul R, Masruha, Marcelo R, McLaughlin, Heather M, McWalter, Kirsty, Melchinger, Esther U, Mercimek-Andrews, Saadet, Nava, Caroline, Pendziwiat, Manuela, Person, Richard, Ramelli, Gian Paolo, Ramos, Luiza LP, Rauch, Anita, Reavey, Caitlin, Renieri, Alessandra, Rieß, Angelika, Sanchez-Valle, Amarilis, Sattar, Shifteh, Saunders, Carol, Schwarz, Niklas, Smol, Thomas, Srour, Myriam, Steindl, Katharina, Syrbe, Steffen, Taylor, Jenny C, Telegrafi, Aida, Thiffault, Isabelle, Trauner, Doris A, van der Linden, Helio, van Koningsbruggen, Silvana, Villard, Laurent, Vogel, Ida, Vogt, Julie, Weber, Yvonne G, Wentzensen, Ingrid M, Widjaja, Elysa, Zak, Jaroslav, Baxter, Samantha, Banka, Siddharth, and Rodan, Lance H

Subjects
Adult, Male, Heterozygote, Adolescent, Intellectual and Developmental Disabilities (IDD), Autism, global developmental delay, Haploinsufficiency, Neurodegenerative, H3K4 methylation, Medical and Health Sciences, Young Adult, Clinical Research, Deciphering Developmental Disorders (DDD) Study, Humans, 2.1 Biological and endogenous factors, Aetiology, Child, Preschool, Pediatric, Genetics & Heredity, Epilepsy, Neurosciences, Infant, Genetic Variation, Biological Sciences, neurodevelopmental disorder, Pedigree, KMT2E, Brain Disorders, DNA-Binding Proteins, Phenotype, epileptic encephalopathy, Mental Health, Neurodevelopmental Disorders, intellectual disability, Neurological, Female
Abstract

We delineate a KMT2E-related neurodevelopmental disorder on the basis of 38 individuals in 36 families. This study includes 31 distinct heterozygous variants in KMT2E (28 ascertained from Matchmaker Exchange and three previously reported), and four individuals with chromosome 7q22.2-22.23 microdeletions encompassing KMT2E (one previously reported). Almost all variants occurred de novo, and most were truncating. Most affected individuals with protein-truncating variants presented with mild intellectual disability. One-quarter of individuals met criteria for autism. Additional common features include macrocephaly, hypotonia, functional gastrointestinal abnormalities, and a subtle facial gestalt. Epilepsy was present in about one-fifth of individuals with truncating variants and was responsive to treatment with anti-epileptic medications in almost all. More than 70% of the individuals were male, and expressivity was variable by sex; epilepsy was more common in females and autism more common in males. The four individuals with microdeletions encompassing KMT2E generally presented similarly to those with truncating variants, but the degree of developmental delay was greater. The group of four individuals with missense variants in KMT2E presented with the most severe developmental delays. Epilepsy was present in all individuals with missense variants, often manifesting as treatment-resistant infantile epileptic encephalopathy. Microcephaly was also common in this group. Haploinsufficiency versus gain-of-function or dominant-negative effects specific to these missense variants in KMT2E might explain this divergence in phenotype, but requires independent validation. Disruptive variants in KMT2E are an under-recognized cause of neurodevelopmental abnormalities.

Published
2019

25. Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy

Author

O’Donnell-Luria, Anne H., primary, Pais, Lynn S., additional, Faundes, Víctor, additional, Wood, Jordan C., additional, Sveden, Abigail, additional, Luria, Victor, additional, Abou Jamra, Rami, additional, Accogli, Andrea, additional, Amburgey, Kimberly, additional, Anderlid, Britt Marie, additional, Azzarello-Burri, Silvia, additional, Basinger, Alice A., additional, Bianchini, Claudia, additional, Bird, Lynne M., additional, Buchert, Rebecca, additional, Carre, Wilfrid, additional, Ceulemans, Sophia, additional, Charles, Perrine, additional, Cox, Helen, additional, Culliton, Lisa, additional, Currò, Aurora, additional, Demurger, Florence, additional, Dowling, James J., additional, Duban-Bedu, Benedicte, additional, Dubourg, Christèle, additional, Eiset, Saga Elise, additional, Escobar, Luis F., additional, Ferrarini, Alessandra, additional, Haack, Tobias B., additional, Hashim, Mona, additional, Heide, Solveig, additional, Helbig, Katherine L., additional, Helbig, Ingo, additional, Heredia, Raul, additional, Héron, Delphine, additional, Isidor, Bertrand, additional, Jonasson, Amy R., additional, Joset, Pascal, additional, Keren, Boris, additional, Kok, Fernando, additional, Kroes, Hester Y., additional, Lavillaureix, Alinoë, additional, Lu, Xin, additional, Maas, Saskia M., additional, Maegawa, Gustavo H.B., additional, Marcelis, Carlo L.M., additional, Mark, Paul R., additional, Masruha, Marcelo R., additional, McLaughlin, Heather M., additional, McWalter, Kirsty, additional, Melchinger, Esther U., additional, Mercimek-Andrews, Saadet, additional, Nava, Caroline, additional, Pendziwiat, Manuela, additional, Person, Richard, additional, Ramelli, Gian Paolo, additional, Ramos, Luiza L.P., additional, Rauch, Anita, additional, Reavey, Caitlin, additional, Renieri, Alessandra, additional, Rieß, Angelika, additional, Sanchez-Valle, Amarilis, additional, Sattar, Shifteh, additional, Saunders, Carol, additional, Schwarz, Niklas, additional, Smol, Thomas, additional, Srour, Myriam, additional, Steindl, Katharina, additional, Syrbe, Steffen, additional, Taylor, Jenny C., additional, Telegrafi, Aida, additional, Thiffault, Isabelle, additional, Trauner, Doris A., additional, van der Linden, Helio, additional, van Koningsbruggen, Silvana, additional, Villard, Laurent, additional, Vogel, Ida, additional, Vogt, Julie, additional, Weber, Yvonne G., additional, Wentzensen, Ingrid M., additional, Widjaja, Elysa, additional, Zak, Jaroslav, additional, Baxter, Samantha, additional, Banka, Siddharth, additional, Rodan, Lance H., additional, McRae, Jeremy F., additional, Clayton, Stephen, additional, Fitzgerald, Tomas W., additional, Kaplanis, Joanna, additional, Prigmore, Elena, additional, Rajan, Diana, additional, Sifrim, Alejandro, additional, Aitken, Stuart, additional, Akawi, Nadia, additional, Alvi, Mohsan, additional, Ambridge, Kirsty, additional, Barrett, Daniel M., additional, Bayzetinova, Tanya, additional, Jones, Philip, additional, Jones, Wendy D., additional, King, Daniel, additional, Krishnappa, Netravathi, additional, Mason, Laura E., additional, Singh, Tarjinder, additional, Tivey, Adrian R., additional, Ahmed, Munaza, additional, Anjum, Uruj, additional, Archer, Hayley, additional, Armstrong, Ruth, additional, Awada, Jana, additional, Balasubramanian, Meena, additional, Baralle, Diana, additional, Barnicoat, Angela, additional, Batstone, Paul, additional, Baty, David, additional, Bennett, Chris, additional, Berg, Jonathan, additional, Bernhard, Birgitta, additional, Bevan, A. Paul, additional, Bitner-Glindzicz, Maria, additional, Blair, Edward, additional, Blyth, Moira, additional, Bohanna, David, additional, Bourdon, Louise, additional, Bourn, David, additional, Bradley, Lisa, additional, Brady, Angela, additional, Brent, Simon, additional, Brewer, Carole, additional, Brunstrom, Kate, additional, Bunyan, David J., additional, Burn, John, additional, Canham, Natalie, additional, Castle, Bruce, additional, Chandler, Kate, additional, Chatzimichali, Elena, additional, Cilliers, Deirdre, additional, Clarke, Angus, additional, Clasper, Susan, additional, Clayton-Smith, Jill, additional, Clowes, Virginia, additional, Coates, Andrea, additional, Cole, Trevor, additional, Colgiu, Irina, additional, Collins, Amanda, additional, Collinson, Morag N., additional, Connell, Fiona, additional, Cooper, Nicola, additional, Cresswell, Lara, additional, Cross, Gareth, additional, Crow, Yanick, additional, D’Alessandro, Mariella, additional, Dabir, Tabib, additional, Davidson, Rosemarie, additional, Davies, Sally, additional, de Vries, Dylan, additional, Dean, John, additional, Deshpande, Charu, additional, Devlin, Gemma, additional, Dixit, Abhijit, additional, Dobbie, Angus, additional, Donaldson, Alan, additional, Donnai, Dian, additional, Donnelly, Deirdre, additional, Donnelly, Carina, additional, Douglas, Angela, additional, Douzgou, Sofia, additional, Duncan, Alexis, additional, Eason, Jacqueline, additional, Ellard, Sian, additional, Ellis, Ian, additional, Elmslie, Frances, additional, Evans, Karenza, additional, Everest, Sarah, additional, Fendick, Tina, additional, Fisher, Richard, additional, Flinter, Frances, additional, Foulds, Nicola, additional, Fry, Andrew, additional, Fryer, Alan, additional, Gardiner, Carol, additional, Gaunt, Lorraine, additional, Ghali, Neeti, additional, Gibbons, Richard, additional, Gill, Harinder, additional, Goodship, Judith, additional, Goudie, David, additional, Gray, Emma, additional, Green, Andrew, additional, Greene, Philip, additional, Greenhalgh, Lynn, additional, Gribble, Susan, additional, Harrison, Rachel, additional, Harrison, Lucy, additional, Harrison, Victoria, additional, Hawkins, Rose, additional, He, Liu, additional, Hellens, Stephen, additional, Henderson, Alex, additional, Hewitt, Sarah, additional, Hildyard, Lucy, additional, Hobson, Emma, additional, Holden, Simon, additional, Holder, Muriel, additional, Holder, Susan, additional, Hollingsworth, Georgina, additional, Homfray, Tessa, additional, Humphreys, Mervyn, additional, Hurst, Jane, additional, Hutton, Ben, additional, Ingram, Stuart, additional, Irving, Melita, additional, Islam, Lily, additional, Jackson, Andrew, additional, Jarvis, Joanna, additional, Jenkins, Lucy, additional, Johnson, Diana, additional, Jones, Elizabeth, additional, Josifova, Dragana, additional, Joss, Shelagh, additional, Kaemba, Beckie, additional, Kazembe, Sandra, additional, Kelsell, Rosemary, additional, Kerr, Bronwyn, additional, Kingston, Helen, additional, Kini, Usha, additional, Kinning, Esther, additional, Kirby, Gail, additional, Kirk, Claire, additional, Kivuva, Emma, additional, Kraus, Alison, additional, Kumar, Dhavendra, additional, Kumar, V. K. Ajith, additional, Lachlan, Katherine, additional, Lam, Wayne, additional, Lampe, Anne, additional, Langman, Caroline, additional, Lees, Melissa, additional, Lim, Derek, additional, Longman, Cheryl, additional, Lowther, Gordon, additional, Lynch, Sally A., additional, Magee, Alex, additional, Maher, Eddy, additional, Male, Alison, additional, Mansour, Sahar, additional, Marks, Karen, additional, Martin, Katherine, additional, Maye, Una, additional, McCann, Emma, additional, McConnell, Vivienne, additional, McEntagart, Meriel, additional, McGowan, Ruth, additional, McKay, Kirsten, additional, McKee, Shane, additional, McMullan, Dominic J., additional, McNerlan, Susan, additional, McWilliam, Catherine, additional, Mehta, Sarju, additional, Metcalfe, Kay, additional, Middleton, Anna, additional, Miedzybrodzka, Zosia, additional, Miles, Emma, additional, Mohammed, Shehla, additional, Montgomery, Tara, additional, Moore, David, additional, Morgan, Sian, additional, Morton, Jenny, additional, Mugalaasi, Hood, additional, Murday, Victoria, additional, Murphy, Helen, additional, Naik, Swati, additional, Nemeth, Andrea, additional, Nevitt, Louise, additional, Newbury-Ecob, Ruth, additional, Norman, Andrew, additional, O’Shea, Rosie, additional, Ogilvie, Caroline, additional, Ong, Kai-Ren, additional, Park, Soo-Mi, additional, Parker, Michael J., additional, Patel, Chirag, additional, Paterson, Joan, additional, Payne, Stewart, additional, Perrett, Daniel, additional, Phipps, Julie, additional, Pilz, Daniela T., additional, Pollard, Martin, additional, Pottinger, Caroline, additional, Poulton, Joanna, additional, Pratt, Norman, additional, Prescott, Katrina, additional, Price, Sue, additional, Pridham, Abigail, additional, Procter, Annie, additional, Purnell, Hellen, additional, Quarrell, Oliver, additional, Ragge, Nicola, additional, Rahbari, Raheleh, additional, Randall, Josh, additional, Rankin, Julia, additional, Raymond, Lucy, additional, Rice, Debbie, additional, Robert, Leema, additional, Roberts, Eileen, additional, Roberts, Jonathan, additional, Roberts, Paul, additional, Roberts, Gillian, additional, Ross, Alison, additional, Rosser, Elisabeth, additional, Saggar, Anand, additional, Samant, Shalaka, additional, Sampson, Julian, additional, Sandford, Richard, additional, Sarkar, Ajoy, additional, Schweiger, Susann, additional, Scott, Richard, additional, Scurr, Ingrid, additional, Selby, Ann, additional, Seller, Anneke, additional, Sequeira, Cheryl, additional, Shannon, Nora, additional, Sharif, Saba, additional, Shaw-Smith, Charles, additional, Shearing, Emma, additional, Shears, Debbie, additional, Sheridan, Eamonn, additional, Simonic, Ingrid, additional, Singzon, Roldan, additional, Skitt, Zara, additional, Smith, Audrey, additional, Smith, Kath, additional, Smithson, Sarah, additional, Sneddon, Linda, additional, Splitt, Miranda, additional, Squires, Miranda, additional, Stewart, Fiona, additional, Stewart, Helen, additional, Straub, Volker, additional, Suri, Mohnish, additional, Sutton, Vivienne, additional, Swaminathan, Ganesh Jawahar, additional, Sweeney, Elizabeth, additional, Tatton-Brown, Kate, additional, Taylor, Cat, additional, Taylor, Rohan, additional, Tein, Mark, additional, Temple, I. Karen, additional, Thomson, Jenny, additional, Tischkowitz, Marc, additional, Tomkins, Susan, additional, Torokwa, Audrey, additional, Treacy, Becky, additional, Turner, Claire, additional, Turnpenny, Peter, additional, Tysoe, Carolyn, additional, Vandersteen, Anthony, additional, Varghese, Vinod, additional, Vasudevan, Pradeep, additional, Vijayarangakannan, Parthiban, additional, Wakeling, Emma, additional, Wallwark, Sarah, additional, Waters, Jonathon, additional, Weber, Astrid, additional, Wellesley, Diana, additional, Whiteford, Margo, additional, Widaa, Sara, additional, Wilcox, Sarah, additional, Wilkinson, Emily, additional, Williams, Denise, additional, Williams, Nicola, additional, Wilson, Louise, additional, Woods, Geoff, additional, Wragg, Christopher, additional, Wright, Michael, additional, Yates, Laura, additional, Yau, Michael, additional, Nellåker, Chris, additional, Parker, Michael, additional, Firth, Helen V., additional, Wright, Caroline F., additional, FitzPatrick, David R., additional, Barrett, Jeffrey C., additional, and Hurles, Matthew E., additional

Published
2019
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26. PIGGvariant pathogenicity assessment reveals characteristic features within 19 families

Author

Tremblay-Laganière, Camille, Maroofian, Reza, Nguyen, Thi Tuyet Mai, Karimiani, Ehsan Ghayoor, Kirmani, Salman, Akbar, Fizza, Ibrahim, Shahnaz, Afroze, Bushra, Doosti, Mohammad, Ashrafzadeh, Farah, Babaei, Meisam, Efthymiou, Stephanie, Christoforou, Marilena, Sultan, Tipu, Ladda, Roger L., McLaughlin, Heather M., Truty, Rebecca, Mahida, Sonal, Cohen, Julie S., Baranano, Kristin, Ismail, Fatima Y., Patel, Millan S., Lehman, Anna, Edmondson, Andrew C., Nagy, Amanda, Walker, Melissa A., Mercimek-Andrews, Saadet, Maki, Yuta, Sachdev, Rani, Macintosh, Rebecca, Palmer, Elizabeth E., Mancini, Grazia M.S., Barakat, Tahsin Stefan, Steinfeld, Robert, Rüsch, Christina T., Stettner, Georg M., Wagner, Matias, Wortmann, Saskia B., Kini, Usha, Brady, Angela F., Stals, Karen L., Ismayilova, Naila, Ellard, Sian, Bernardo, Danilo, Nugent, Kimberly, McLean, Scott D., Antonarakis, Stylianos E., Houlden, Henry, Kinoshita, Taroh, Campeau, Philippe M., and Murakami, Yoshiko

Abstract

Phosphatidylinositol Glycan Anchor Biosynthesis, class G (PIGG) is an ethanolamine phosphate transferase catalyzing the modification of glycosylphosphatidylinositol (GPI). GPI serves as an anchor on the cell membrane for surface proteins called GPI-anchored proteins (GPI-APs). Pathogenic variants in genes involved in the biosynthesis of GPI cause inherited GPI deficiency (IGD), which still needs to be further characterized.

Published
2021
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27. Automated typing of red blood cell and platelet antigens: a whole-genome sequencing study

Author

Lane, William J, primary, Westhoff, Connie M, additional, Gleadall, Nicholas S, additional, Aguad, Maria, additional, Smeland-Wagman, Robin, additional, Vege, Sunitha, additional, Simmons, Daimon P, additional, Mah, Helen H, additional, Lebo, Matthew S, additional, Walter, Klaudia, additional, Soranzo, Nicole, additional, Di Angelantonio, Emanuele, additional, Danesh, John, additional, Roberts, David J, additional, Watkins, Nick A, additional, Ouwehand, Willem H, additional, Butterworth, Adam S, additional, Kaufman, Richard M, additional, Rehm, Heidi L, additional, Silberstein, Leslie E, additional, Green, Robert C, additional, Bates, David W., additional, Blout, Carrie, additional, Christensen, Kurt D., additional, Cirino, Allison L., additional, Ho, Carolyn Y., additional, Krier, Joel B., additional, Lehmann, Lisa S., additional, MacRae, Calum A., additional, Morton, Cynthia C., additional, Perry, Denise L., additional, Seidman, Christine E., additional, Sunyaev, Shamil R., additional, Vassy, Jason L., additional, Schonman, Erica, additional, Nguyen, Tiffany, additional, Steffens, Eleanor, additional, Betting, Wendi Nicole, additional, Aronson, Samuel J., additional, Ceyhan-Birsoy, Ozge, additional, Machini, Kalotina, additional, McLaughlin, Heather M., additional, Azzariti, Danielle R., additional, Tsai, Ellen A., additional, Blumenthal-Barby, Jennifer, additional, Feuerman, Lindsay Z., additional, McGuire, Amy L., additional, Lee, Kaitlyn, additional, Robinson, Jill O., additional, Slashinski, Melody J., additional, Diamond, Pamela M., additional, Davis, Kelly, additional, Ubel, Peter A., additional, Kraft, Peter, additional, Roberts, J. Scott, additional, Garber, Judy E., additional, Hambuch, Tina, additional, Murray, Michael F., additional, Kohane, Isaac, additional, and Kong, Sek Won, additional

Published
2018
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28. TRPV6 Variants Interfere with Maternal-Fetal Calcium Transport through the Placenta and Cause Transient Neonatal Hyperparathyroidism

Author

Suzuki, Yoshiro, primary, Chitayat, David, additional, Sawada, Hirotake, additional, Deardorff, Matthew A., additional, McLaughlin, Heather M., additional, Begtrup, Amber, additional, Millar, Kathryn, additional, Harrington, Jennifer, additional, Chong, Karen, additional, Roifman, Maian, additional, Grand, Katheryn, additional, Tominaga, Makoto, additional, Takada, Fumio, additional, Shuster, Shirley, additional, Obara, Megumi, additional, Mutoh, Hiroshi, additional, Kushima, Reiko, additional, and Nishimura, Gen, additional

Published
2018
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29. De novo variants in SNAP25cause an early-onset developmental and epileptic encephalopathy

Author

Klöckner, Chiara, Sticht, Heinrich, Zacher, Pia, Popp, Bernt, Babcock, Holly E., Bakker, Dewi P., Barwick, Katy, Bonfert, Michaela V., Bönnemann, Carsten G., Brilstra, Eva H., Chung, Wendy K., Clarke, Angus J., Devine, Patrick, Donkervoort, Sandra, Fraser, Jamie L., Friedman, Jennifer, Gates, Alyssa, Ghoumid, Jamal, Hobson, Emma, Horvath, Gabriella, Keller-Ramey, Jennifer, Keren, Boris, Kurian, Manju A., Lee, Virgina, Leppig, Kathleen A., Lundgren, Johan, McDonald, Marie T., McLaughlin, Heather M., McTague, Amy, Mefford, Heather C., Mignot, Cyril, Mikati, Mohamad A., Nava, Caroline, Raymond, F. Lucy, Sampson, Julian R., Sanchis-Juan, Alba, Shashi, Vandana, Shieh, Joseph T.C., Shinawi, Marwan, Slavotinek, Anne, Stödberg, Tommy, Stong, Nicholas, Sullivan, Jennifer A., Taylor, Ashley C., Toler, Tomi L., van den Boogaard, Marie-José, van der Crabben, Saskia N., van Gassen, Koen L.I., van Jaarsveld, Richard H., Van Ziffle, Jessica, Wadley, Alexandrea F., Wagner, Matias, Wigby, Kristen, Wortmann, Saskia B., Zarate, Yuri A., Møller, Rikke S., Lemke, Johannes R., and Platzer, Konrad

Abstract

This study aims to provide a comprehensive description of the phenotypic and genotypic spectrum of SNAP25developmental and epileptic encephalopathy (SNAP25-DEE) by reviewing newly identified and previously reported individuals.

Published
2021
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30. A survey of current practices for genomic sequencing test interpretation and reporting processes in US laboratories

Author

O’Daniel, Julianne M., primary, McLaughlin, Heather M., additional, Amendola, Laura M., additional, Bale, Sherri J., additional, Berg, Jonathan S., additional, Bick, David, additional, Bowling, Kevin M., additional, Chao, Elizabeth C., additional, Chung, Wendy K., additional, Conlin, Laura K., additional, Cooper, Gregory M., additional, Das, Soma, additional, Deignan, Joshua L., additional, Dorschner, Michael O., additional, Evans, James P., additional, Ghazani, Arezou A., additional, Goddard, Katrina A., additional, Gornick, Michele, additional, Farwell Hagman, Kelly D., additional, Hambuch, Tina, additional, Hegde, Madhuri, additional, Hindorff, Lucia A., additional, Holm, Ingrid A., additional, Jarvik, Gail P., additional, Knight Johnson, Amy, additional, Mighion, Lindsey, additional, Morra, Massimo, additional, Plon, Sharon E., additional, Punj, Sumit, additional, Richards, C. Sue, additional, Santani, Avni, additional, Shirts, Brian H., additional, Spinner, Nancy B., additional, Tang, Sha, additional, Weck, Karen E., additional, Wolf, Susan M., additional, Yang, Yaping, additional, and Rehm, Heidi L., additional

Published
2017
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31. De Novo Truncating Variants in ASXL2 Are Associated with a Unique and Recognizable Clinical Phenotype

Author

Shashi, Vandana, primary, Pena, Loren D.M., additional, Kim, Katherine, additional, Burton, Barbara, additional, Hempel, Maja, additional, Schoch, Kelly, additional, Walkiewicz, Magdalena, additional, McLaughlin, Heather M., additional, Cho, Megan, additional, Stong, Nicholas, additional, Hickey, Scott E., additional, Shuss, Christine M., additional, Freemark, Michael S., additional, Bellet, Jane S., additional, Keels, Martha Ann, additional, Bonner, Melanie J., additional, El-Dairi, Maysantoine, additional, Butler, Megan, additional, Kranz, Peter G., additional, Stumpel, Constance T.R.M., additional, Klinkenberg, Sylvia, additional, Oberndorff, Karin, additional, Alawi, Malik, additional, Santer, Rene, additional, Petrovski, Slavé, additional, Kuismin, Outi, additional, Korpi-Heikkilä, Satu, additional, Pietilainen, Olli, additional, Aarno, Palotie, additional, Kurki, Mitja I., additional, Hoischen, Alexander, additional, Need, Anna C., additional, Goldstein, David B., additional, and Kortüm, Fanny, additional

Published
2017
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32. Recurrent De Novo and Biallelic Variation of ATAD3A , Encoding a Mitochondrial Membrane Protein, Results in Distinct Neurological Syndromes

Author

Harel, Tamar, primary, Yoon, Wan Hee, additional, Garone, Caterina, additional, Gu, Shen, additional, Coban-Akdemir, Zeynep, additional, Eldomery, Mohammad K., additional, Posey, Jennifer E., additional, Jhangiani, Shalini N., additional, Rosenfeld, Jill A., additional, Cho, Megan T., additional, Fox, Stephanie, additional, Withers, Marjorie, additional, Brooks, Stephanie M., additional, Chiang, Theodore, additional, Duraine, Lita, additional, Erdin, Serkan, additional, Yuan, Bo, additional, Shao, Yunru, additional, Moussallem, Elie, additional, Lamperti, Costanza, additional, Donati, Maria A., additional, Smith, Joshua D., additional, McLaughlin, Heather M., additional, Eng, Christine M., additional, Walkiewicz, Magdalena, additional, Xia, Fan, additional, Pippucci, Tommaso, additional, Magini, Pamela, additional, Seri, Marco, additional, Zeviani, Massimo, additional, Hirano, Michio, additional, Hunter, Jill V., additional, Srour, Myriam, additional, Zanigni, Stefano, additional, Lewis, Richard Alan, additional, Muzny, Donna M., additional, Lotze, Timothy E., additional, Boerwinkle, Eric, additional, Gibbs, Richard A., additional, Hickey, Scott E., additional, Graham, Brett H., additional, Yang, Yaping, additional, Buhas, Daniela, additional, Martin, Donna M., additional, Potocki, Lorraine, additional, Graziano, Claudio, additional, Bellen, Hugo J., additional, and Lupski, James R., additional

Published
2016
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33. De Novo Truncating Variants in ASXL2 Are Associated with a Unique and Recognizable Clinical Phenotype

Author

Shashi, Vandana, primary, Pena, Loren D.M., additional, Kim, Katherine, additional, Burton, Barbara, additional, Hempel, Maja, additional, Schoch, Kelly, additional, Walkiewicz, Magdalena, additional, McLaughlin, Heather M., additional, Cho, Megan, additional, Stong, Nicholas, additional, Hickey, Scott E., additional, Shuss, Christine M., additional, Freemark, Michael S., additional, Bellet, Jane S., additional, Keels, Martha Ann, additional, Bonner, Melanie J., additional, El-Dairi, Maysantoine, additional, Butler, Megan, additional, Kranz, Peter G., additional, Stumpel, Constance T.R.M., additional, Klinkenberg, Sylvia, additional, Oberndorff, Karin, additional, Alawi, Malik, additional, Santer, Rene, additional, Petrovski, Slavé, additional, Kuismin, Outi, additional, Korpi-Heikkilä, Satu, additional, Pietilainen, Olli, additional, Aarno, Palotie, additional, Kurki, Mitja I., additional, Hoischen, Alexander, additional, Need, Anna C., additional, Goldstein, David B., additional, Kortüm, Fanny, additional, Bacino, A., additional, Lee, Brendan H., additional, Balasubramanyam, Ashok, additional, Burrage, Lindsay C., additional, Clark, Gary D., additional, Craigen, William J., additional, Dhar, Shweta U., additional, Emrick, Lisa T., additional, Graham, Brett H., additional, Jain, Mahim, additional, Lalani, Seema R., additional, Lewis, Richard A., additional, Moretti, Paolo M., additional, Nicholas, Sarah K., additional, Orange, Jordan S., additional, Posey, Jennifer E., additional, Potocki, Lorraine, additional, Rosenfeld, Jill A., additional, Scott, Daryl A., additional, Hanchard, Neil A., additional, Alyssa, Tran A., additional, Mercedes, Alejandro E., additional, Mashid, Azamian S., additional, Bellen, Hugo J., additional, Yamamoto, Shinya, additional, Wangler, Michael F., additional, Westerfield, Monte, additional, Postlethwait, John H., additional, Eng, Christine M., additional, Yang, Yaping, additional, Muzny, Donna M., additional, Ward, Patricia A., additional, Ramoni, Rachel B., additional, McCray, Alexa T., additional, Kohane, Issac S., additional, Holm, Ingrid A., additional, Might, Matthew, additional, Mazur, Paul, additional, Splinter, Kimberly, additional, Esteves, Cecilia, additional, Shashi, Vandana, additional, Jiang, Yong-hui, additional, McConkie-Rosell, Allyn, additional, Spillmann, Rebecca C., additional, Sullivan, Jennifer A., additional, Walley, Nicole M., additional, Beggs, Alan H., additional, Loscalzo, Joseph, additional, MacRae, Calum A., additional, Silverman, Edwin K., additional, Stoler, Joan M., additional, Sweetser, David A., additional, Maas, Richard L., additional, Krier, Joel B., additional, Rodan, Lance H., additional, Walsh, Chris A., additional, Cooper, Cynthia M., additional, Pallais, Juan C., additional, Donnell-Fink, Laurel A., additional, Krieg, Elizabeth L., additional, Lincoln, Sharyn A., additional, Briere, Lauren C., additional, Jacob, Howard J., additional, Worthey, Elizabeth A., additional, Lazar, Joe, additional, Strong, Kim A., additional, Handley, Lori H., additional, Newberry, J. Scott, additional, Bick, David P., additional, Schroeder, Molly C., additional, Brown, Donna M., additional, Birch, Camille L., additional, Levy, Shawn E., additional, Boone, Braden E., additional, Dorset, Dan C., additional, Jones, Angela L., additional, Manolio, Teri A., additional, Mulvihill, John J., additional, Wise, Anastasia L., additional, Dayal, Jyoti G., additional, Eckstein, David J., additional, Krasnewich, Donna M., additional, Loomis, Carson R., additional, Mamounas, Laura A., additional, Iglesias, Brenda, additional, Martin, Casey, additional, Koeller, David M., additional, Metz, Thomas O., additional, Ashley, Euan A., additional, Fisher, Paul G., additional, Bernstein, Jonathan A., additional, Wheeler, Matt T., additional, Zornio, Patricia A., additional, Waggott, Daryl M., additional, Dries, Annika M., additional, Kohler, Jennefer N., additional, Dipple, Katrina M., additional, Nelson, Stan F., additional, Palmer, Christina G.S., additional, Vilain, Eric, additional, Allard, Patrick, additional, Dell Angelica, Esteban C., additional, Lee, Hane, additional, Sinsheimer, Janet S., additional, Papp, Jeanette C., additional, Dorrani, Naghmeh, additional, Herzog, Matthew R., additional, Barseghyan, Hayk, additional, Adams, David R., additional, Adams, Christopher J., additional, Burke, Elizabeth A., additional, Chao, Katherine R., additional, Davids, Mariska, additional, Draper, David D., additional, Estwick, Tyra, additional, Frisby, Trevor S., additional, Frost, Kate, additional, Gahl, William A., additional, Gartner, Valerie, additional, Godfrey, Rena A., additional, Goheen, Mitchell, additional, Golas, Gretchen A., additional, Gordon, Mary G., additional, Groden, Catherine A., additional, Gropman, Andrea L., additional, Hackbarth, Mary E., additional, Hardee, Isabel, additional, Johnston, Jean M., additional, Koehler, Alanna E., additional, Latham, Lea, additional, Latour, Yvonne L., additional, Lau, Chyau Yueh C., additional, Lee, Paul R., additional, Levy, Denise J., additional, Liebendorder, Adam P., additional, Macnamara, Ellen F., additional, Maduro, Valerie V., additional, Malicdan, May V., additional, Markello, Thomas C., additional, McCarty, Alexandra J., additional, Murphy, Jennifer L., additional, Nehrebecky, Michele E., additional, Novacic, Donna, additional, Pusey, Barbara N., additional, Sadozai, Sarah, additional, Schaffer, Katherine E., additional, Sharma, Prashant, additional, Soldatos, Ariane G., additional, Thomas, Sara P., additional, Tifft, Cynthia J., additional, Tolman, Nathanial J., additional, Toro, Camilo, additional, Valivullah, Zaheer M., additional, Wahl, Colleen E., additional, Warburton, Mike, additional, Weech, Alec A., additional, Wolfe, Lynne A., additional, Yu, Guoyun, additional, Hamid, Rizwan, additional, Newman, John H., additional, Phillips, John A., additional, and Cogan, Joy D., additional

Published
2016
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34. Health Care Infrastructure for Financially Sustainable Clinical Genomics

Author

Lennerz, Jochen K., primary, McLaughlin, Heather M., additional, Baron, Jason M., additional, Rasmussen, David, additional, Sumbada Shin, Meini, additional, Berners-Lee, Nancy, additional, Miller Batten, Julie, additional, Swoboda, Kathryn J., additional, Gala, Manish K., additional, Winter, Harland S., additional, Schmahmann, Jeremy D., additional, Sweetser, David A., additional, Boswell, Marianne, additional, Pacula, Maciej, additional, Stenzinger, Albrecht, additional, Le, Long P., additional, Hynes, William, additional, Rehm, Heidi L., additional, Klibanski, Anne, additional, Black-Schaffer, Stephen W., additional, Golden, Jeffrey A., additional, Louis, David N., additional, Weiss, Scott T., additional, and Iafrate, A. John, additional

Published
2016
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35. Clinical Sequencing Exploratory Research Consortium: Accelerating Evidence-Based Practice of Genomic Medicine

Author

Green, Robert C., primary, Goddard, Katrina A.B., additional, Jarvik, Gail P., additional, Amendola, Laura M., additional, Appelbaum, Paul S., additional, Berg, Jonathan S., additional, Bernhardt, Barbara A., additional, Biesecker, Leslie G., additional, Biswas, Sawona, additional, Blout, Carrie L., additional, Bowling, Kevin M., additional, Brothers, Kyle B., additional, Burke, Wylie, additional, Caga-anan, Charlisse F., additional, Chinnaiyan, Arul M., additional, Chung, Wendy K., additional, Clayton, Ellen W., additional, Cooper, Gregory M., additional, East, Kelly, additional, Evans, James P., additional, Fullerton, Stephanie M., additional, Garraway, Levi A., additional, Garrett, Jeremy R., additional, Gray, Stacy W., additional, Henderson, Gail E., additional, Hindorff, Lucia A., additional, Holm, Ingrid A., additional, Lewis, Michelle Huckaby, additional, Hutter, Carolyn M., additional, Janne, Pasi A., additional, Joffe, Steven, additional, Kaufman, David, additional, Knoppers, Bartha M., additional, Koenig, Barbara A., additional, Krantz, Ian D., additional, Manolio, Teri A., additional, McCullough, Laurence, additional, McEwen, Jean, additional, McGuire, Amy, additional, Muzny, Donna, additional, Myers, Richard M., additional, Nickerson, Deborah A., additional, Ou, Jeffrey, additional, Parsons, Donald W., additional, Petersen, Gloria M., additional, Plon, Sharon E., additional, Rehm, Heidi L., additional, Roberts, J. Scott, additional, Robinson, Dan, additional, Salama, Joseph S., additional, Scollon, Sarah, additional, Sharp, Richard R., additional, Shirts, Brian, additional, Spinner, Nancy B., additional, Tabor, Holly K., additional, Tarczy-Hornoch, Peter, additional, Veenstra, David L., additional, Wagle, Nikhil, additional, Weck, Karen, additional, Wilfond, Benjamin S., additional, Wilhelmsen, Kirk, additional, Wolf, Susan M., additional, Wynn, Julia, additional, Yu, Joon-Ho, additional, Amaral, Michelle, additional, Amendola, Laura, additional, Aronson, Samuel J., additional, Arora, Shubhangi, additional, Azzariti, Danielle R., additional, Barsh, Greg S., additional, Bebin, E.M., additional, Biesecker, Barbara B., additional, Brown, Brian L., additional, Burt, Amber A., additional, Byers, Peter H., additional, Calikoglu, Muge G., additional, Carlson, Sara J., additional, Chahin, Nizar, additional, Christensen, Kurt D., additional, Chung, Wendy, additional, Cirino, Allison L., additional, Clayton, Ellen, additional, Conlin, Laura K., additional, Cooper, Greg M., additional, Crosslin, David R., additional, Davis, James V., additional, Davis, Kelly, additional, Deardorff, Matthew A., additional, Devkota, Batsal, additional, De Vries, Raymond, additional, Diamond, Pamela, additional, Dorschner, Michael O., additional, Dugan, Noreen P., additional, Dukhovny, Dmitry, additional, Dulik, Matthew C., additional, East, Kelly M., additional, Rivera-Munoz, Edgar A., additional, Evans, Barbara, additional, Everett, Jessica, additional, Exe, Nicole, additional, Fan, Zheng, additional, Feuerman, Lindsay Z., additional, Filipski, Kelly, additional, Finnila, Candice R., additional, Fishler, Kristen, additional, Ghrundmeier, Bob, additional, Giles, Karen, additional, Gilmore, Marian J., additional, Girnary, Zahra S., additional, Goddard, Katrina, additional, Gonsalves, Steven, additional, Gordon, Adam S., additional, Gornick, Michele C., additional, Grady, William M., additional, Gray, David E., additional, Green, Robert, additional, Greenwood, Robert S., additional, Gutierrez, Amanda M., additional, Han, Paul, additional, Hart, Ragan, additional, Heagerty, Patrick, additional, Hensman, Naomi, additional, Hiatt, Susan M., additional, Himes, Patricia, additional, Hisama, Fuki M., additional, Ho, Carolyn Y., additional, Hoffman-Andrews, Lily B., additional, Hong, Celine, additional, Horike-Pyne, Martha J., additional, Hull, Sara, additional, Jamal, Seema, additional, Jensen, Brian C., additional, Joffe, Steve, additional, Johnston, Jennifer, additional, Karavite, Dean, additional, Kauffman, Tia L., additional, Kaufman, Dave, additional, Kelley, Whitley, additional, Kim, Jerry H., additional, Kirby, Christine, additional, Klein, William, additional, Knoppers, Bartha, additional, Kong, Sek Won, additional, Krantz, Ian, additional, Krier, Joel B., additional, Lamb, Neil E., additional, Lambert, Michele P., additional, Le, Lan Q., additional, Lebo, Matthew S., additional, Lee, Alexander, additional, Lee, Kaitlyn B., additional, Lennon, Niall, additional, Leo, Michael C., additional, Leppig, Kathleen A., additional, Lewis, Katie, additional, Lewis, Michelle, additional, Lindeman, Neal I., additional, Lockhart, Nicole, additional, Lonigro, Bob, additional, Lose, Edward J., additional, Lupo, Philip J., additional, Rodriguez, Laura Lyman, additional, Lynch, Frances, additional, Machini, Kalotina, additional, MacRae, Calum, additional, Marchuk, Daniel S., additional, Martinez, Josue N., additional, Masino, Aaron, additional, McLaughlin, Heather M., additional, McMullen, Carmit, additional, Mieczkowski, Piotr A., additional, Miller, Jeff, additional, Miller, Victoria A., additional, Mody, Rajen, additional, Mooney, Sean D., additional, Moore, Elizabeth G., additional, Morris, Elissa, additional, Murray, Michael, additional, Ng, David, additional, Oliver, Nelly M., additional, Parsons, Will, additional, Patrick, Donald L., additional, Pennington, Jeffrey, additional, Perry, Denise L., additional, Petersen, Gloria, additional, Plon, Sharon, additional, Porter, Katie, additional, Powell, Bradford C., additional, Punj, Sumit, additional, Breitkopf, Carmen Radecki, additional, Raesz-Martinez, Robin A., additional, Raskind, Wendy H., additional, Reigar, Dean A., additional, Reiss, Jacob A., additional, Rich, Carla A., additional, Richards, Carolyn Sue, additional, Rini, Christine, additional, Roberts, Scott, additional, Robertson, Peggy D., additional, Robinson, Jill O., additional, Robinson, Marguerite E., additional, Roche, Myra I., additional, Romasko, Edward J., additional, Rosenthal, Elisabeth A., additional, Salama, Joseph, additional, Scarano, Maria I., additional, Schneider, Jennifer, additional, Seidman, Christine E., additional, Seifert, Bryce A., additional, Shirts, Brian H., additional, Sholl, Lynette M., additional, Siddiqui, Javed, additional, Silverman, Elian, additional, Simmons, Shirley, additional, Simons, Janae V., additional, Skinner, Debra, additional, Stoffel, Elena, additional, Strande, Natasha T., additional, Sunyaev, Shamil, additional, Sybert, Virginia P., additional, Taber, Jennifer, additional, Taylor, Deanne M., additional, Tilley, Christian R., additional, Tomlinson, Ashley, additional, Trinidad, Susan, additional, Tsai, Ellen, additional, Ubel, Peter, additional, Van Allen, Eliezer M., additional, Vassy, Jason L., additional, Vats, Pankaj, additional, Vetter, Victoria L., additional, Vries, Raymond D., additional, Walser, Sarah A., additional, Walsh, Rebecca C., additional, Werner-Lin, Allison, additional, Whittle, Jana, additional, Wilfond, Ben, additional, Wilhelmsen, Kirk C., additional, Yang, Yaping, additional, Young, Carol, additional, and Zikmund-Fisher, Brian J., additional

Published
2016
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36. Performance of ACMG-AMP Variant-Interpretation Guidelines among Nine Laboratories in the Clinical Sequencing Exploratory Research Consortium

Author

Amendola, Laura M., primary, Jarvik, Gail P., additional, Leo, Michael C., additional, McLaughlin, Heather M., additional, Akkari, Yassmine, additional, Amaral, Michelle D., additional, Berg, Jonathan S., additional, Biswas, Sawona, additional, Bowling, Kevin M., additional, Conlin, Laura K., additional, Cooper, Greg M., additional, Dorschner, Michael O., additional, Dulik, Matthew C., additional, Ghazani, Arezou A., additional, Ghosh, Rajarshi, additional, Green, Robert C., additional, Hart, Ragan, additional, Horton, Carrie, additional, Johnston, Jennifer J., additional, Lebo, Matthew S., additional, Milosavljevic, Aleksandar, additional, Ou, Jeffrey, additional, Pak, Christine M., additional, Patel, Ronak Y., additional, Punj, Sumit, additional, Richards, Carolyn Sue, additional, Salama, Joseph, additional, Strande, Natasha T., additional, Yang, Yaping, additional, Plon, Sharon E., additional, Biesecker, Leslie G., additional, and Rehm, Heidi L., additional

Published
2016
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37. Results of clinical genetic testing of 2,912 probands with hypertrophic cardiomyopathy: expanded panels offer limited additional sensitivity

Author

Alfares, Ahmed A., primary, Kelly, Melissa A., additional, McDermott, Gregory, additional, Funke, Birgit H., additional, Lebo, Matthew S., additional, Baxter, Samantha B., additional, Shen, Jun, additional, McLaughlin, Heather M., additional, Clark, Eugene H., additional, Babb, Larry J., additional, Cox, Stephanie W., additional, DePalma, Steven R., additional, Ho, Carolyn Y., additional, Seidman, J.G., additional, Seidman, Christine E., additional, and Rehm, Heidi L., additional

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

Author

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

Abstract

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

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

Author

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

Abstract

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

Published
2014

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

Author

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

Published
2014
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41. Candidate exome capture identifies mutation of SDCCAG8 as the cause of a retinal-renal ciliopathy

Author

Otto, Edgar A., Hurd, Toby W., Airik, Rannar, Chaki, Moumita, Zhou, Weibin, Stoetzel, Corinne, Patil, Suresh B., Levy, Shawn, Ghosh, Amiya K., Murga-Zamalloa, Carlos A., van Reeuwijk, Jeroen, Letteboer, Stef J. F., Sang, Liyun, Giles, Rachel H., Liu, Qin, Coene, Karlien L. M., Estrada-Cuzcano, Alejandro, Collin, Rob W. J., McLaughlin, Heather M., Held, Susanne, Kasanuki, Jennifer M., Ramaswami, Gokul, Conte, Jinny, Lopez, Irma, Washburn, Joseph, MacDonald, James, Hu, Jinghua, Yamashita, Yukiko, Maher, Eamonn R., Guay-Woodford, Lisa M., Neumann, Hartmut P. H., Obermueller, Nicholas, Koenekoop, Robert K., Bergmann, Carsten, Bei, Xiaoshu, Lewis, Richard A., Katsanis, Nicholas, Lopes, Vanda, Williams, David S., Lyons, Robert H., Dang, Chi V., Brito, Daniela A., Dias, Monica Bettencourt, Zhang, Xinmin, Cavalcoli, James D., Nuernberg, Gudrun, Nuernberg, Peter, Pierce, Eric A., Jackson, Peter K., Antignac, Corinne, Saunier, Sophie, Roepman, Ronald, Dollfus, Helene, Khanna, Hemant, Hildebrandt, Friedhelm, Otto, Edgar A., Hurd, Toby W., Airik, Rannar, Chaki, Moumita, Zhou, Weibin, Stoetzel, Corinne, Patil, Suresh B., Levy, Shawn, Ghosh, Amiya K., Murga-Zamalloa, Carlos A., van Reeuwijk, Jeroen, Letteboer, Stef J. F., Sang, Liyun, Giles, Rachel H., Liu, Qin, Coene, Karlien L. M., Estrada-Cuzcano, Alejandro, Collin, Rob W. J., McLaughlin, Heather M., Held, Susanne, Kasanuki, Jennifer M., Ramaswami, Gokul, Conte, Jinny, Lopez, Irma, Washburn, Joseph, MacDonald, James, Hu, Jinghua, Yamashita, Yukiko, Maher, Eamonn R., Guay-Woodford, Lisa M., Neumann, Hartmut P. H., Obermueller, Nicholas, Koenekoop, Robert K., Bergmann, Carsten, Bei, Xiaoshu, Lewis, Richard A., Katsanis, Nicholas, Lopes, Vanda, Williams, David S., Lyons, Robert H., Dang, Chi V., Brito, Daniela A., Dias, Monica Bettencourt, Zhang, Xinmin, Cavalcoli, James D., Nuernberg, Gudrun, Nuernberg, Peter, Pierce, Eric A., Jackson, Peter K., Antignac, Corinne, Saunier, Sophie, Roepman, Ronald, Dollfus, Helene, Khanna, Hemant, and Hildebrandt, Friedhelm

Abstract

Nephronophthisis-related ciliopathies (NPHP-RC) are recessive disorders that feature dysplasia or degeneration occurring preferentially in the kidney, retina and cerebellum. Here we combined homozygosity mapping with candidate gene analysis by performing 'ciliopathy candidate exome capture' followed by massively parallel sequencing. We identified 12 different truncating mutations of SDCCAG8 (serologically defined colon cancer antigen 8, also known as CCCAP) in 10 families affected by NPHP-RC. We show that SDCCAG8 is localized at both centrioles and interacts directly with OFD1 (oral-facial-digital syndrome 1), which is associated with NPHP-RC. Depletion of sdccag8 causes kidney cysts and a body axis defect in zebrafish and induces cell polarity defects in three-dimensional renal cell cultures. This work identifies loss of SDCCAG8 function as a cause of a retinal-renal ciliopathy and validates exome capture analysis for broadly heterogeneous single-gene disorders.

Published
2010

44. Candidate exome capture identifies mutation of SDCCAG8 as the cause of a retinal-renal ciliopathy

Author

Otto, Edgar A, primary, Hurd, Toby W, additional, Airik, Rannar, additional, Chaki, Moumita, additional, Zhou, Weibin, additional, Stoetzel, Corinne, additional, Patil, Suresh B, additional, Levy, Shawn, additional, Ghosh, Amiya K, additional, Murga-Zamalloa, Carlos A, additional, van Reeuwijk, Jeroen, additional, Letteboer, Stef J F, additional, Sang, Liyun, additional, Giles, Rachel H, additional, Liu, Qin, additional, Coene, Karlien L M, additional, Estrada-Cuzcano, Alejandro, additional, Collin, Rob W J, additional, McLaughlin, Heather M, additional, Held, Susanne, additional, Kasanuki, Jennifer M, additional, Ramaswami, Gokul, additional, Conte, Jinny, additional, Lopez, Irma, additional, Washburn, Joseph, additional, MacDonald, James, additional, Hu, Jinghua, additional, Yamashita, Yukiko, additional, Maher, Eamonn R, additional, Guay-Woodford, Lisa M, additional, Neumann, Hartmut P H, additional, Obermüller, Nicholas, additional, Koenekoop, Robert K, additional, Bergmann, Carsten, additional, Bei, Xiaoshu, additional, Lewis, Richard A, additional, Katsanis, Nicholas, additional, Lopes, Vanda, additional, Williams, David S, additional, Lyons, Robert H, additional, Dang, Chi V, additional, Brito, Daniela A, additional, Dias, Mónica Bettencourt, additional, Zhang, Xinmin, additional, Cavalcoli, James D, additional, Nürnberg, Gudrun, additional, Nürnberg, Peter, additional, Pierce, Eric A, additional, Jackson, Peter K, additional, Antignac, Corinne, additional, Saunier, Sophie, additional, Roepman, Ronald, additional, Dollfus, Helene, additional, Khanna, Hemant, additional, and Hildebrandt, Friedhelm, additional

Published
2010
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45. A systematic approach to the reporting of medically relevant findings from whole genome sequencing.

Author

McLaughlin, Heather M., Ceyhan-Birsoy, Ozge, Christensen, Kurt D., Kohane, Isaac S., Krier, Joel, Lane, William J., Lautenbach, Denise, Lebo, Matthew S., Machini, Kalotina, MacRae, Calum, Azzariti, Danielle R., Murray, Michael F., Seidman, Christine E., Vassy, Jason L., Green, Robert C., and Rehm, Heidi L.

Subjects
*GENOMES, *INCIDENTAL findings (Medicine), *NUCLEOTIDE sequencing, *CLINICAL medicine, *DIAGNOSIS
Abstract

Background: The MedSeq Project is a randomized clinical trial developing approaches to assess the impact of integrating genome sequencing into clinical medicine. To facilitate the return of results of potential medical relevance to physicians and patients participating in the MedSeq Project, we sought to develop a reporting approach for the effective communication of such findings. Methods: Genome sequencing was performed on the Illumina HiSeq platform. Variants were filtered, interpreted, and validated according to methods developed by the Laboratory for Molecular Medicine and consistent with current professional guidelines. The GeneInsight software suite, which is integrated with the Partners HealthCare electronic health record, was used for variant curation, report drafting, and delivery. Results: We developed a concise 5-6 page Genome Report (GR) featuring a single-page summary of results of potential medical relevance with additional pages containing structured variant, gene, and disease information along with supporting evidence for reported variants and brief descriptions of associated diseases and clinical implications. The GR is formatted to provide a succinct summary of genomic findings, enabling physicians to take appropriate steps for disease diagnosis, prevention, and management in their patients. Conclusions: Our experience highlights important considerations for the reporting of results of potential medical relevance and provides a framework for interpretation and reporting practices in clinical genome sequencing. [ABSTRACT FROM AUTHOR]

Published
2014
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46. The MedSeq Project: a randomized trial of integrating whole genome sequencing into clinical medicine.

Author

Vassy, Jason L., Lautenbach, Denise M., McLaughlin, Heather M., Sek Won Kong, Christensen, Kurt D., Krier, Joel, Kohane, Isaac S., Feuerman, Lindsay Z., Blumenthal-Barby, Jennifer, Roberts, J. Scott, Lehmann, Lisa Soleymani, Ho, Carolyn Y., Ubel, Peter A., MacRae, Calum A., Seidman, Christine E., Murray, Michael F., McGuire, Amy L., Rehm, Heidi L., and Green, Robert C.

Abstract

Background: Whole genome sequencing (WGS) is already being used in certain clinical and research settings, but its impact on patient well-being, health-care utilization, and clinical decision-making remains largely unstudied. It is also unknown how best to communicate sequencing results to physicians and patients to improve health. We describe the design of the MedSeq Project: the first randomized trials of WGS in clinical care. Methods/Design: This pair of randomized controlled trials compares WGS to standard of care in two clinical contexts: (a) disease-specific genomic medicine in a cardiomyopathy clinic and (b) general genomic medicine in primary care. We are recruiting 8 to 12 cardiologists, 8 to 12 primary care physicians, and approximately 200 of their patients. Patient participants in both the cardiology and primary care trials are randomly assigned to receive a family history assessment with or without WGS. Our laboratory delivers a genome report to physician participants that balances the needs to enhance understandability of genomic information and to convey its complexity. We provide an educational curriculum for physician participants and offer them a hotline to genetics professionals for guidance in interpreting and managing their patients' genome reports. Using varied data sources, including surveys, semi-structured interviews, and review of clinical data, we measure the attitudes, behaviors and outcomes of physician and patient participants at multiple time points before and after the disclosure of these results. Discussion: The impact of emerging sequencing technologies on patient care is unclear. We have designed a process of interpreting WGS results and delivering them to physicians in a way that anticipates how we envision genomic medicine will evolve in the near future. That is, our WGS report provides clinically relevant information while communicating the complexity and uncertainty of WGS results to physicians and, through physicians, to their patients. This project will not only illuminate the impact of integrating genomic medicine into the clinical care of patients but also inform the design of future studies. [ABSTRACT FROM AUTHOR]

Published
2014
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47. A survey of current practices for genomic sequencing test interpretation and reporting processes in US laboratories

Author

O’Daniel, Julianne M., McLaughlin, Heather M., Amendola, Laura M., Bale, Sherri J., Berg, Jonathan S., Bick, David, Bowling, Kevin M., Chao, Elizabeth C., Chung, Wendy K., Conlin, Laura K., Cooper, Gregory M., Das, Soma, Deignan, Joshua L., Dorschner, Michael O., Evans, James P., Ghazani, Arezou A., Goddard, Katrina A., Gornick, Michele, Farwell Hagman, Kelly D., Hambuch, Tina, Hegde, Madhuri, Hindorff, Lucia A., Holm, Ingrid A., Jarvik, Gail P., Johnson, Amy Knight, Mighion, Lindsey, Morra, Massimo, Plon, Sharon E., Punj, Sumit, Richards, C. Sue, Santani, Avni, Shirts, Brian H., Spinner, Nancy B., Tang, Sha, Weck, Karen E., Wolf, Susan M., Yang, Yaping, and Rehm, Heidi L.

Subjects
exome sequencing, genome sequencing, laboratory standards, genetic testing, clinical reporting
Abstract

PURPOSE While the diagnostic success of genomic sequencing expands, the complexity of this testing should not be overlooked. Numerous laboratory processes are required to support the identification, interpretation and reporting of clinically significant variants. This study aimed to examine workflow and reporting procedures among US laboratories to highlight shared practices and identify areas in need of standardization. METHODS Surveys and follow-up interviews were conducted with laboratories offering exome and/or genome sequencing, to support a research program or for routine clinical services. The 73-item survey elicited multiple choice and free text responses, later clarified with phone interviews. RESULTS Twenty-one laboratories participated. Practices highly concordant across all groups included: consent documentation, multi-person case review, and enabling patient opt-out of incidental or secondary findings analysis. Noted divergence included use of phenotypic data to inform case analysis and interpretation, and reporting of case-specific quality metrics and methods. Few laboratory policies detailed procedures for data reanalysis, data sharing or patient access to data. CONCLUSION This study provides an overview of practices and policies of experienced exome and genome sequencing laboratories. The results enable broader consideration of which practices are becoming standard approaches, where divergence remains, and areas development of best practice guidelines may be helpful.

Published
2016
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48. Compound heterozygosity of predicted loss-of-function DES variants in a family with recessive desminopathy.

Author

McLaughlin, Heather M., Kelly, Melissa A., Hawley, Pamela P., Darras, Basil T., Funke, Birgit, and Picker, Jonathan

Subjects
*CARDIOMYOPATHIES, *HETEROZYGOSITY, *MUSCLE diseases, *ETIOLOGY of diseases, *GENES
Abstract

Background: Variants in the desmin gene (DES) are associated with desminopathy; a myofibrillar myopathy mainly characterized by muscle weakness, conduction block, and dilated cardiomyopathy. To date, only ~50 diseaseassociated variants have been described, and the majority of these lead to dominant-negative effects. However, the complete genotypic spectrum of desminopathy is not well established. Case presentation: Next-generation sequencing was performed on 51 cardiac disease genes in a proband with profound skeletal myopathy, dilated cardiomyopathy, and respiratory dysfunction. Our analyses revealed compound heterozygous DES variants, both of which are predicted to lead to a loss-of-function. Consistent with recessive inheritance, each variant was identified in an unaffected parent. Conclusions: This case report serves to broaden the variant spectrum of desminopathies and provides insight into the molecular mechanisms of desminopathy, supporting distinct dominant-negative and loss-of-function etiologies. [ABSTRACT FROM AUTHOR]

Published
2013
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49. A Loss-of-Function Variant in the Human Histidyl-t RNA Synthetase ( HARS) Gene is Neurotoxic In Vivo.

Author

Vester, Aimée, Velez‐Ruiz, Gisselle, McLaughlin, Heather M., NISC Comparative Sequencing Program, Lupski, James R., Talbot, Kevin, Vance, Jeffery M., Züchner, Stephan, Roda, Ricardo H., Fischbeck, Kenneth H., Biesecker, Leslie G., Nicholson, Garth, Beg, Asim A., and Antonellis, Anthony

Abstract

ABSTRACT Aminoacyl-t RNA synthetases ( ARSs) are ubiquitously expressed enzymes responsible for ligating amino acids to cognate t RNA molecules. Mutations in four genes encoding an ARS have been implicated in inherited peripheral neuropathy with an axonal pathology, suggesting that all ARS genes are relevant candidates for disease in patients with related phenotypes. Here, we present results from a mutation screen of the histidyl-t RNA synthetase ( HARS) gene in a large cohort of patients with peripheral neuropathy. These efforts revealed a rare missense variant (c.410G>A/p.Arg137Gln) that resides at a highly conserved amino acid, represents a loss-of-function allele when evaluated in yeast complementation assays, and is toxic to neurons when expressed in a worm model. In addition to the patient with peripheral neuropathy, p.Arg137Gln HARS was detected in three individuals by genome-wide exome sequencing. These findings suggest that HARS is the fifth ARS locus associated with axonal peripheral neuropathy. Implications for identifying ARS alleles in human populations and assessing them for a role in neurodegenerative phenotypes are discussed. [ABSTRACT FROM AUTHOR]

Published
2013
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50. Correction to: De novo variants in SNAP25cause an early-onset developmental and epileptic encephalopathy

Author

Klöckner, Chiara, Sticht, Heinrich, Zacher, Pia, Popp, Bernt, Babcock, Holly E., Bakker, Dewi P., Barwick, Katy, Bonfert, Michaela V., Bönnemann, Carsten G., Brilstra, Eva H., Chung, Wendy K., Clarke, Angus J., Devine, Patrick, Donkervoort, Sandra, Fraser, Jamie L., Friedman, Jennifer, Gates, Alyssa, Ghoumid, Jamal, Hobson, Emma, Horvath, Gabriella, Keller-Ramey, Jennifer, Keren, Boris, Kurian, Manju A., Lee, Virgina, Leppig, Kathleen A., Lundgren, Johan, McDonald, Marie T., McLaughlin, Heather M., McTague, Amy, Mefford, Heather C., Mignot, Cyril, Mikati, Mohamad A., Nava, Caroline, Raymond, F. Lucy, Sampson, Julian R., Sanchis-Juan, Alba, Shashi, Vandana, Shieh, Joseph T.C., Shinawi, Marwan, Slavotinek, Anne, Stödberg, Tommy, Stong, Nicholas, Sullivan, Jennifer A., Taylor, Ashley C., Toler, Tomi L., van den Boogaard, Marie-José, van der Crabben, Saskia N., van Gassen, Koen L.I., van Jaarsveld, Richard H., Van Ziffle, Jessica, Wadley, Alexandrea F., Wagner, Matias, Wigby, Kristen, Wortmann, Saskia B., Zarate, Yuri A., Møller, Rikke S., Lemke, Johannes R., and Platzer, Konrad

Published
2021
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