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2. The impact of clinical genome sequencing in a global population with suspected rare genetic disease

Author

Thorpe, Erin, Williams, Taylor, Shaw, Chad, Chekalin, Evgenii, Ortega, Julia, Robinson, Keisha, Button, Jason, Jones, Marilyn C., Campo, Miguel del, Basel, Donald, McCarrier, Julie, Keppen, Laura Davis, Royer, Erin, Foster-Bonds, Romina, Duenas-Roque, Milagros M., Urraca, Nora, Bosfield, Kerri, Brown, Chester W., Lydigsen, Holly, Mroczkowski, Henry J., Ward, Jewell, Sirchia, Fabio, Giorgio, Elisa, Vaux, Keith, Salguero, Hildegard Peña, Lumaka, Aimé, Mubungu, Gerrye, Makay, Prince, Ngole, Mamy, Lukusa, Prosper Tshilobo, Vanderver, Adeline, Muirhead, Kayla, Sherbini, Omar, Lah, Melissa D., Anderson, Katelynn, Bazalar-Montoya, Jeny, Rodriguez, Richard S., Cornejo-Olivas, Mario, Milla-Neyra, Karina, Shinawi, Marwan, Magoulas, Pilar, Henry, Duncan, Gibson, Kate, Wiafe, Samuel, Jayakar, Parul, Salyakina, Daria, Masser-Frye, Diane, Serize, Arturo, Perez, Jorge E., Taylor, Alan, Shenbagam, Shruti, Abou Tayoun, Ahmad, Malhotra, Alka, Bennett, Maren, Rajan, Vani, Avecilla, James, Warren, Andrew, Arseneault, Max, Kalista, Tasha, Crawford, Ali, Ajay, Subramanian S., Perry, Denise L., Belmont, John, and Taft, Ryan J.

Published
2024
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3. Whole genome sequencing for the diagnosis of neurological repeat expansion disorders in the UK: a retrospective diagnostic accuracy and prospective clinical validation study

Author

McDonagh, Ellen M, Rueda, Antonio, Polychronopoulos, Dimitris, Chan, Georgia, Angus-Leppan, Heather, Bhatia, Kailash P, Davison, James E, Festenstein, Richard, Fratta, Pietro, Giunti, Paola, Howard, Robin, Venkata, Laxmi, Laurá, Matilde, McEntagart, Meriel, Menzies, Lara, Morris, Huw, Reilly, Mary M, Robinson, Robert, Rosser, Elisabeth, Faravelli, Francesca, Schrag, Anette, Schott, Jonathan M, Warner, Thomas T, Wood, Nicholas W, Bourn, David, Eggleton, Kelly, Labrum, Robyn, Twiss, Philip, Abbs, Stephen, Santos, Liana, Almheiri, Ghareesa, Sheikh, Isabella, Vandrovcova, Jana, Patch, Christine, Taylor Tavares, Ana Lisa, Hyder, Zerin, Need, Anna, Brittain, Helen, Baple, Emma, Moutsianas, Loukas, Deshpande, Viraj, Perry, Denise L, Ajay, Subramanian S., Chawla, Aditi, Rajan, Vani, Oprych, Kathryn, Chinnery, Patrick F, Douglas, Angela, Wilson, Gill, Ellard, Sian, Temple, I Karen, Mumford, Andrew, McMullan, Dom, Naresh, Kikkeri, Flinter, Frances A, Taylor, Jenny C, Greenhalgh, Lynn, Newman, William, Brennan, Paul, Sayer, John A, Raymond, F Lucy, Chitty, Lyn S, Ambrose, John C., Arumugam, Prabhu, Bleda, Marta, Boardman-Pretty, Freya, Boissiere, Jeanne M., Boustred, Christopher R., Craig, Clare E.H., de Burca, Anna, Devereau, Andrew, Elgar, Greg, Foulger, Rebecca E., Furió-Tarí, Pedro, Hackett, Joanne, Halai, Dina, Hamblin, Angela, Henderson, Shirley, Holman, James, Hubbard, Tim J.P., Jackson, Rob, Jones, Louise J., Kayikci, Melis, Lahnstein, Lea, Lawson, Kay, Leigh, Sarah E.A., Leong, Ivonne U.S., Lopez, Javier F., Maleady-Crowe, Fiona, Mason, Joanne, Mueller, Michael, Murugaesu, Nirupa, Odhams, Chris A., Perez-Gil, Daniel, Pullinger, John, Rahim, Tahrima, Riesgo-Ferreiro, Pablo, Rogers, Tim, Ryten, Mina, Savage, Kevin, Sawant, Kushmita, Siddiq, Afshan, Sieghart, Alexander, Smedley, Damian, Sosinsky, Alona, Spooner, William, Stevens, Helen E., Stuckey, Alexander, Sultana, Razvan, Thompson, Simon R., Tregidgo, Carolyn, Walsh, Emma, Watters, Sarah A., Welland, Matthew J., Williams, Eleanor, Witkowska, Katarzyna, Wood, Suzanne M., Zarowiecki, Magdalena, Ibañez, Kristina, Polke, James, Hagelstrom, R Tanner, Dolzhenko, Egor, Pasko, Dorota, Thomas, Ellen Rachel Amy, Daugherty, Louise C, Kasperaviciute, Dalia, Smith, Katherine R, Deans, Zandra C, Hill, Sue, Fowler, Tom, Scott, Richard H, Hardy, John, Houlden, Henry, Rendon, Augusto, Caulfield, Mark J, Eberle, Michael A, Taft, Ryan J, and Tucci, Arianna

Published
2022
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4. Best practices for the interpretation and reporting of clinical whole genome sequencing

Author

Austin-Tse, Christina A., Jobanputra, Vaidehi, Perry, Denise L., Bick, David, Taft, Ryan J., Venner, Eric, Gibbs, Richard A., Young, Ted, Barnett, Sarah, Belmont, John W., Boczek, Nicole, Chowdhury, Shimul, Ellsworth, Katarzyna A., Guha, Saurav, Kulkarni, Shashikant, Marcou, Cherisse, Meng, Linyan, Murdock, David R., Rehman, Atteeq U., Spiteri, Elizabeth, Thomas-Wilson, Amanda, Kearney, Hutton M., and Rehm, Heidi L.

Published
2022
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5. Phenotypic and Imaging Spectrum Associated With WDR45

Author

Adang, Laura A., Pizzino, Amy, Malhotra, Alka, Dubbs, Holly, Williams, Catherine, Sherbini, Omar, Anttonen, Anna-Kaisa, Lesca, Gaetan, Linnankivi, Tarja, Laurencin, Chloé, Milh, Matthieu, Perrine, Charles, Schaaf, Christian P., Poulat, Anne-Lise, Ville, Dorothee, Hagelstrom, Tanner, Perry, Denise L., Taft, Ryan J., Goldstein, Amy, Vossough, Arastoo, Helbig, Ingo, and Vanderver, Adeline

Published
2020
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6. Pathogenic variants in USP7 cause a neurodevelopmental disorder with speech delays, altered behavior, and neurologic anomalies

Author

Fountain, Michael D., Oleson, David S., Rech, Megan E., Segebrecht, Lara, Hunter, Jill V., McCarthy, John M., Lupo, Philip J., Holtgrewe, Manuel, Moran, Rocio, Rosenfeld, Jill A., Isidor, Bertrand, Le Caignec, Cédric, Saenz, Margarita S., Pedersen, Robert C., Morgan, Thomas M., Pfotenhauer, Jean P., Xia, Fan, Bi, Weimin, Kang, Sung-Hae L., Patel, Ankita, Krantz, Ian D., Raible, Sarah E., Smith, Wendy, Cristian, Ingrid, Torti, Erin, Juusola, Jane, Millan, Francisca, Wentzensen, Ingrid M., Person, Richard E., Küry, Sébastien, Bézieau, Stéphane, Uguen, Kévin, Férec, Claude, Munnich, Arnold, van Haelst, Mieke, Lichtenbelt, Klaske D., van Gassen, Koen, Hagelstrom, Tanner, Chawla, Aditi, Perry, Denise L., Taft, Ryan J., Jones, Marilyn, Masser-Frye, Diane, Dyment, David, Venkateswaran, Sunita, Li, Chumei, Escobar, Luis F., Horn, Denise, Spillmann, Rebecca C., Peña, Loren, Wierzba, Jolanta, Strom, Tim M., Parenti, Ilaria, Kaiser, Frank J., Ehmke, Nadja, and Schaaf, Christian P.

Published
2019
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7. Copy-number variants in clinical genome sequencing: deployment and interpretation for rare and undiagnosed disease

Author

Gross, Andrew M., Ajay, Subramanian S., Rajan, Vani, Brown, Carolyn, Bluske, Krista, Burns, Nicole J., Chawla, Aditi, Coffey, Alison J., Malhotra, Alka, Scocchia, Alicia, Thorpe, Erin, Dzidic, Natasa, Hovanes, Karine, Sahoo, Trilochan, Dolzhenko, Egor, Lajoie, Bryan, Khouzam, Amirah, Chowdhury, Shimul, Belmont, John, Roller, Eric, Ivakhno, Sergii, Tanner, Stephen, McEachern, Julia, Hambuch, Tina, Eberle, Michael, Hagelstrom, R. Tanner, Bentley, David R., Perry, Denise L., and Taft, Ryan J.

Published
2019
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8. 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. Genome sequencing detects a balanced pericentric inversion with breakpoints that impact the DMD and upstream region of POU3F4 genes.

Author

Chandrasekhar, Anjana, Mroczkowski, Henry J., Urraca, Nora, Gross, Andrew, Bluske, Krista, Thorpe, Erin, Hagelstrom, R. Tanner, Schonberg, Steven A., Perry, Denise L., Taft, Ryan J., and Kesari, Akanchha

Abstract

We describe a family with two maternal half‐brothers both of whom presented with muscular dystrophy, autism spectrum disorder, developmental delay, and sensorineural hearing loss. The elder brother had onset of features at ~3 months of age, followed by clinical confirmation of muscular dystrophy at 3 years. Skeletal biopsy staining at 4.7 years showed an absence of dystrophin protein which prompted extensive molecular testing over 4 years that included gene panels, targeted single‐gene assays, arrays, and karyotyping, all of which failed to identify a clinically significant variant in the DMD gene. At 10 years of age, clinical whole‐genome sequencing (cWGS) was performed, which revealed a novel hemizygous ~50.7 Mb balanced pericentric inversion on chromosome X that disrupts the DMD gene in both siblings, consistent with the muscular dystrophy phenotype. This inversion also impacts the upstream regulatory region of POU3F4, structural rearrangements which are known to cause hearing loss. The unaffected mother is a heterozygous carrier for the pericentric inversion. This finding illustrates the ability of cWGS to detect a wide breadth of disease‐causing genomic variations including large genomic rearrangements. [ABSTRACT FROM AUTHOR]

Published
2024
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10. Clinical Sequencing Exploratory Research Consortium: Accelerating Evidence-Based Practice of Genomic Medicine

Author

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

Published
2016
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11. The smallest likely pathogenic duplication of a SOX9 enhancer identified to date in a family with 46,XX testicular differences of sex development.

Author

Sajan, Samin A., Brown, Carolyn M., Davis‐Keppen, Laura, Burns, Kaitlyn, Royer, Erin, Coleman, Jessica A. Cooley, Hilton, Benjamin A., DuPont, Barbara R., Perry, Denise L., Taft, Ryan J., and Kesari, Akanchha

Abstract

Copy number variants that duplicate distal upstream enhancer elements of the SOX9 gene cause 46,XX testicular differences of sex development (DSD) which is characterized by a 46,XX karyotype in an individual presenting with either ambiguous genitalia or genitalia with varying degrees of virilization, including those resembling typical male genitalia. Reported duplications in this region range in size from 24 to 780 kilobases (kb). Here we report a family with two affected individuals, the proband and his maternal uncle, harboring a 3.7 kb duplication of a SOX9 enhancer identified by clinical genome sequencing. Prior fluorescence in situ hybridization (FISH) for SRY and a multi‐gene panel for ambiguous genitalia were non‐diagnostic. The unaffected mother also carries this duplication, consistent with previously described incomplete penetrance. To our knowledge, this is the smallest duplication identified to‐date, most of which resides in a 5.2 kb region that has been previously shown to possess enhancer activity that promotes the expression of SOX9. The duplication was confirmed by quantitative‐PCR and shown to be in tandem by bidirectional Sanger sequencing breakpoint analysis. This finding highlights the importance of non‐coding variant interrogation in suspected genetic disorders. [ABSTRACT FROM AUTHOR]

Published
2023
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13. Reactive gene curation to support interpretation and reporting of a clinical genome test for rare disease: Experience from over 1,000 cases

Author

Brown, Carolyn, Brown, Matthew P., Buchanan, Amanda, Burns, Brendan, Burns, Nicole J., Chandrasekhar, Anjana, Chawla, Aditi, Golden-Grant, Katie, Kesari, Akanchha, Malhotra, Alka, Milewski, Becky, Sajan, Samin A., Schlachetzki, Zinayida, Schmidt, Sarah, Thomas, Brittany, Thorpe, Erin, Clause, Amanda R., Taylor, Julie P., Rajkumar, Revathi, Bluske, Krista, Bennett, Maren, Amendola, Laura M., Bentley, David R., Taft, Ryan J., Perry, Denise L., and Coffey, Alison J.

Published
2023
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15. Inactivation of AMMECR1 is associated with growth, bone, and heart alterations

Author

Moysés‐Oliveira, Mariana, Giannuzzi, Giuliana, Fish, Richard J., Rosenfeld, Jill A., Petit, Florence, Soares, Maria de Fatima, Kulikowski, Leslie Domenici, Di‐Battista, Adriana, Zamariolli, Malú, Xia, Fan, Liehr, Thomas, Kosyakova, Nadezda, Carvalheira, Gianna, Parker, Michael, Seaby, Eleanor G., Ennis, Sarah, Gilbert, Rodney D., Hagelstrom, R. Tanner, Cremona, Maria L., Li, Wenhui L., Malhotra, Alka, Chandrasekhar, Anjana, Perry, Denise L., Taft, Ryan J., McCarrier, Julie, Basel, Donald G., Andrieux, Joris, Stumpp, Taiza, Antunes, Fernanda, Pereira, Gustavo José, Neerman‐Arbez, Marguerite, Meloni, Vera Ayres, Drummond‐Borg, Margaret, Melaragno, Maria Isabel, and Reymond, Alexandre

Published
2018
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18. PERCHING syndrome: Clinical presentation in the first African patient confirmed by clinical whole genome sequencing.

Author

Makay, Prince, Mubungu, Gerrye, Mupuala, Aimée, Bluske, Krista, Brown, Carolyn, Schmidt, Sarah A., Ngole, Mamy, Fuanani, Patrick, Perry, Denise L., Lukusa, Prosper, Devriendt, Koenraad, Taft, Ryan J., and Lumaka, Aimé

Abstract

PERCHING syndrome is a rare multisystem developmental disorder caused by autosomal recessive (AR) variants (truncating and missense) in the Kelch‐like family member 7 gene (KLHL7). We report the first phenotypic and molecular description of PERCHING syndrome in a patient from Central Africa. The patient presented multiple dysmorphic features in addition to neurological, respiratory, gastroenteric, and dysautonomic disorders. Clinical Whole Genome Sequencing in the proband and his mother identified two novel heterozygous variants in the KLHL7 gene, including a maternally inherited intronic variant (NM_001031710.2:c.793 + 5G > C) classified as Variant of Uncertain Significance and a frameshift stop gain variant (NM_001031710.2:c.944delG; p.Ser315ThrfsTer23) of unknown inheritance classified as likely pathogenic. Although the diagnosis was only evoked after genomic testing, the review of published patients suggests that this disease could be clinically recognizable and maybe considered as an encephalopathy. Our report will allow expanding the phenotypic and molecular spectrum of Perching syndrome. [ABSTRACT FROM AUTHOR]

Published
2022
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19. A clinical laboratory's experience using GeneMatcher—Building stronger gene–disease relationships.

Author

Taylor, Julie P., Malhotra, Alka, Burns, Nicole J., Clause, Amanda R., Brown, Carolyn M., Burns, Brendan T., Chandrasekhar, Anjana, Schlachetzki, Zinayida, Bennett, Maren, Thorpe, Erin, Taft, Ryan J., Perry, Denise L., and Coffey, Alison J.

Abstract

The use of whole‐genome sequencing (WGS) has accelerated the pace of gene discovery and highlighted the need for open and collaborative data sharing in the search for novel disease genes and variants. GeneMatcher (GM) is designed to facilitate connections between researchers, clinicians, health‐care providers, and others to help in the identification of additional patients with variants in the same candidate disease genes. The Illumina Clinical Services Laboratory offers a WGS test for patients with suspected rare and undiagnosed genetic disease and regularly submits potential candidate genes to GM to strengthen gene–disease relationships. We describe our experience with GM, including criteria for evaluation of candidate genes, and our workflow for the submission and review process. We have made 69 submissions, 36 of which are currently active. Ten percent of submissions have resulted in publications, with an additional 14 submissions part of ongoing collaborations and expected to result in a publication. [ABSTRACT FROM AUTHOR]

Published
2022
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20. Genome sequencing identifies three molecular diagnoses including a mosaic variant in the COL2A1 gene in an individual with Pol III-related leukodystrophy and Feingold syndrome.

Author

Muirhead, Kayla J., Clause, Amanda R., Schlachetzki, Zinayida, Dubbs, Holly, Perry, Denise L., Hagelstrom, R. Tanner, Taft, Ryan J., and Vanderver, Adeline

Subjects
DNA sequencing, LEUKODYSTROPHY, MOLECULAR diagnosis, MOSAICISM, SINGLE nucleotide polymorphisms, GENETIC counseling
Abstract

Undiagnosed genetic disease imposes a significant burden on families and health-care resources, especially in cases with a complex phenotype. Here we present a child with suspected leukodystrophy in the context of additional features, including hearing loss, clinodactyly, rotated thumbs, tapered fingers, and simplified palmar crease. Trio genome sequencing (GS) identified three molecular diagnoses in this individual: compound heterozygous missense variants associated with polymerase III (Pol III)-related leukodystrophy, a 4-Mb de novo copy-number loss including the MYCN gene associated with Feingold syndrome, and a mosaic single-nucleotide variant associated with COL2A1-related disorders. These variants fully account for the individual's features, but also illustrate the potential for superimposed and unclear contributions of multiple diagnoses to an individual's overall presentation. This report demonstrates the advantage of GS in detection of multiple variant types, including low-level mosaic variants, and emphasizes the need for comprehensive genetic analysis and detailed clinical phenotyping to provide individuals and their families with the maximum benefit for clinical care and genetic counseling. [ABSTRACT FROM AUTHOR]

Published
2021
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21. Mutations in PIGS, Encoding a GPI Transamidase, Cause a Neurological Syndrome Ranging from Fetal Akinesia to Epileptic Encephalopathy

Author

Nguyen, Thi Tuyet Mai, Murakami, Yoshiko, Wigby, Kristen M., Baratang, Nissan V., Rousseau, Justine, St-Denis, Anik, Rosenfeld, Jill A., Laniewski, Stephanie C., Jones, Julie, Iglesias, Alejandro D., Jones, Marilyn C., Masser-Frye, Diane, Scheuerle, Angela E., Perry, Denise L., Taft, Ryan J., Le Deist, Françoise, Thompson, Miles, Kinoshita, Taroh, and Campeau, Philippe M.

Published
2018
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22. De novo missense variants in LMBRD2 are associated with developmental and motor delays, brain structure abnormalities and dysmorphic features.

Author

Malhotra, Alka, Ziegler, Alban, Li Shu, Perrier, Renee, Amlie-Wolf, Louise, Wohler, Elizabeth, de Macena Sobreira, Nara Lygia, Colin, Estelle, Vanderver, Adeline, Sherbini, Omar, Stouffs, Katrien, Scalais, Emmanuel, Serretti, Alessandro, Barth, Magalie, Navet, Benjamin, Rollier, Paul, Hui Xi, Hua Wang, Hainan Zhang, and Perry, Denise L.

Abstract

Objective To determine the potential disease association between variants in LMBRD2 and complex multisystem neurological and developmental delay phenotypes. Methods Here we describe a series of de novo missense variants in LMBRD2 in 10 unrelated individuals with overlapping features. Exome sequencing or genome sequencing was performed on all individuals, and the cohort was assembled through GeneMatcher. Results LMBRD2 encodes an evolutionary ancient and widely expressed transmembrane protein with no known disease association, although two paralogues are involved in developmental and metabolic disorders. Exome or genome sequencing revealed rare de novo LMBRD2 missense variants in 10 individuals with developmental delay, intellectual disability, thin corpus callosum, microcephaly and seizures. We identified five unique variants and two recurrent variants, c.1448G>A (p.Arg483His) in three cases and c.367T>C (p.Trp123Arg) in two cases. All variants are absent from population allele frequency databases, and most are predicted to be deleterious by multiple in silico damage-prediction algorithms. Conclusion These findings indicate that rare de novo variants in LMBRD2 can lead to a previously unrecognised early-onset neurodevelopmental disorder. Further investigation of individuals harbouring LMBRD2 variants may lead to a better understanding of the function of this ubiquitously expressed gene. [ABSTRACT FROM AUTHOR]

Published
2021
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23. 'Not Tied Up Neatly with a Bow': Professionals’ Challenging Cases in Informed Consent for Genomic Sequencing

Author

Bernhardt, Barbara A., Perry, Denise L., Scollon, Sarah R., Skinner, Debra, Tomlinson, Ashley N., and Roche, Myra I.

Subjects
humanities
Abstract

As the use of genomic technology has expanded in research and clinical settings, issues surrounding informed consent for genome and exome sequencing have surfaced. Despite the importance of informed consent, little is known about the specific challenges that professionals encounter when consenting patients or research participants for genomic sequencing. We interviewed 29 genetic counselors and research coordinators with considerable experience obtaining informed consent for genomic sequencing to understand their experiences and perspectives. As part of this interview, 24 interviewees discussed an informed consent case they found particularly memorable or challenging. We analyzed these case examples to determine the primary issue or challenge represented by each case. Challenges fell into two domains: participant understanding, and facilitating decisions about testing or research participation. Challenges related to participant understanding included varying levels of general and genomic literacy, difficulty managing participant expectations, and contextual factors that impeded participant understanding. Challenges related to facilitating decision-making included complicated family dynamics such as disagreement or coercion, situations in which it was unclear whether sequencing research would be a good use of participant time or resources, and situations in which the professional experienced disagreement or discomfort with participant decisions. The issues highlighted in these case examples are instructive in preparing genetics professionals to obtain informed consent for genomic sequencing.

Published
2016
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25. Participants and Study Decliners’ Perspectives About the Risks of Participating in a Clinical Trial of Whole Genome Sequencing.

Author

Robinson, Jill Oliver, Carroll, Thomas M., Feuerman, Lindsay Z., Perry, Denise L., Hoffman-Andrews, Lily, Walsh, Rebecca C., Christensen, Kurt D., Green, Robert C., and McGuire, Amy L.

Subjects
NUCLEOTIDE sequencing, CLINICAL trials, INFORMED consent (Medical law), SOCIAL impact, MEDICAL ethics
Abstract

An increasing number of individuals are being recruited to whole genome sequencing (WGS) research. When asked hypothetically, the majority of the public express willingness to participate in this type of research, yet little is known about how many individuals will actually consent to research participation or what they perceive the risks to be. The MedSeq Project is a clinical trial exploring WGS in clinical care. We documented primary reason(s) for declining participation and reviewed audio-recorded informed consent sessions to identify participants’ concerns. Of 514 individuals recruited, 173 (34%) actively declined, 205 (40%) enrolled, and the remaining 136 (26%) were ineligible, unresponsive or waitlisted. Although the majority of active decliners cited logistical barriers, 40% cited risks related to the ethical, legal, and social implications (ELSI) of WGS research. Participants similarly discussed ELSI-related concerns but felt the potential benefits of participation outweighed the risks. Findings provide insight into the perspectives of potential WGS research participants and identify potential barriers to participation. [ABSTRACT FROM AUTHOR]

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

Author

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

Subjects
3. Good health
Abstract

Despite rapid technical progress and demonstrable effectiveness for some types of diagnosis and therapy, much remains to be learned about clinical genome and exome sequencing (CGES) and its role within the practice of medicine. The Clinical Sequencing Exploratory Research (CSER) consortium includes 18 extramural research projects, one National Human Genome Research Institute (NHGRI) intramural project, and a coordinating center funded by the NHGRI and National Cancer Institute. The consortium is exploring analytic and clinical validity and utility, as well as the ethical, legal, and social implications of sequencing via multidisciplinary approaches; it has thus far recruited 5,577 participants across a spectrum of symptomatic and healthy children and adults by utilizing both germline and cancer sequencing. The CSER consortium is analyzing data and creating publically available procedures and tools related to participant preferences and consent, variant classification, disclosure and management of primary and secondary findings, health outcomes, and integration with electronic health records. Future research directions will refine measures of clinical utility of CGES in both germline and somatic testing, evaluate the use of CGES for screening in healthy individuals, explore the penetrance of pathogenic variants through extensive phenotyping, reduce discordances in public databases of genes and variants, examine social and ethnic disparities in the provision of genomics services, explore regulatory issues, and estimate the value and downstream costs of sequencing. The CSER consortium has established a shared community of research sites by using diverse approaches to pursue the evidence-based development of best practices in genomic medicine.

27. Development of a comprehensive cardiovascular disease genetic risk assessment test.

Author

Amendola LM, Coffey AJ, Lowry J, Avecilla J, Malhotra A, Chawla A, Thacker S, Taylor JP, Rajkumar R, Brown CM, Golden-Grant K, Hejja R, Lee JA, Medrano P, Milewski B, Mullen F, Walker A, Huertez-Vasquez A, Longoni M, Perry DL, Hostin D, Ajay SS, Kesari A, Strom SP, Margulies E, Belmont J, Lanfear DE, and Taft RJ

Abstract

Background: Despite monogenic and polygenic contributions to cardiovascular disease (CVD), genetic testing is not widely adopted, and current tests are limited by the breadth of surveyed conditions and interpretation burden., Methods: We developed a comprehensive clinical genome CVD test with semi-automated interpretation. Monogenic conditions and risk alleles were selected based on the strength of disease association and evidence for increased disease risk, respectively. Non-CVD secondary findings genes, pharmacogenomic (PGx) variants and CVD polygenic risk scores (PRS) were assessed for inclusion. Test performance was modeled using 2,594 genomes from the 1000 Genomes Project, and further investigated in 20 previously tested individuals., Results: The CVD genome test is composed of a panel of 215 CVD gene-disease pairs, 35 non-CVD secondary findings genes, 4 risk alleles or genotypes, 10 PGx genes and a PRS for coronary artery disease. Modeling of test performance using samples from the 1000 Genomes Project revealed ~6% of individuals with a monogenic finding in a CVD-associated gene, 6% with a risk allele finding, ~1% with a non-CVD secondary finding, and 93% with CVD-associated PGx variants. Assessment of blinded clinical samples showed complete concordance with prior testing. An average of 4 variants were reviewed per case, with interpretation and reporting time ranging from 9-96 min., Conclusions: A genome sequencing based CVD genetic risk assessment can provide comprehensive genetic disease and genetic risk information to patients with CVD. The semi-automated and limited interpretation burden suggest that this testing approach could be scaled to support population-level initiatives.

Published
2024
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28. Effect of Whole-Genome Sequencing on the Clinical Management of Acutely Ill Infants With Suspected Genetic Disease: A Randomized Clinical Trial.

Author

Krantz ID, Medne L, Weatherly JM, Wild KT, Biswas S, Devkota B, Hartman T, Brunelli L, Fishler KP, Abdul-Rahman O, Euteneuer JC, Hoover D, Dimmock D, Cleary J, Farnaes L, Knight J, Schwarz AJ, Vargas-Shiraishi OM, Wigby K, Zadeh N, Shinawi M, Wambach JA, Baldridge D, Cole FS, Wegner DJ, Urraca N, Holtrop S, Mostafavi R, Mroczkowski HJ, Pivnick EK, Ward JC, Talati A, Brown CW, Belmont JW, Ortega JL, Robinson KD, Brocklehurst WT, Perry DL, Ajay SS, Hagelstrom RT, Bennett M, Rajan V, and Taft RJ

Subjects
Female, Humans, Infant, Infant, Newborn, Male, Outcome Assessment, Health Care, Acute Disease, Genetic Diseases, Inborn, Whole Genome Sequencing
Abstract

Importance: Whole-genome sequencing (WGS) shows promise as a first-line genetic test for acutely ill infants, but widespread adoption and implementation requires evidence of an effect on clinical management., Objective: To determine the effect of WGS on clinical management in a racially and ethnically diverse and geographically distributed population of acutely ill infants in the US., Design, Setting, and Participants: This randomized, time-delayed clinical trial enrolled participants from September 11, 2017, to April 30, 2019, with an observation period extending to July 2, 2019. The study was conducted at 5 US academic medical centers and affiliated children's hospitals. Participants included infants aged between 0 and 120 days who were admitted to an intensive care unit with a suspected genetic disease. Data were analyzed from January 14 to August 20, 2020., Interventions: Patients were randomized to receive clinical WGS results 15 days (early) or 60 days (delayed) after enrollment, with the observation period extending to 90 days. Usual care was continued throughout the study., Main Outcomes and Measures: The main outcome was the difference in the proportion of infants in the early and delayed groups who received a change of management (COM) 60 days after enrollment. Additional outcome measures included WGS diagnostic efficacy, within-group COM at 90 days, length of hospital stay, and mortality., Results: A total of 354 infants were randomized to the early (n = 176) or delayed (n = 178) arms. The mean participant age was 15 days (IQR, 7-32 days); 201 participants (56.8%) were boys; 19 (5.4%) were Asian; 47 (13.3%) were Black; 250 (70.6%) were White; and 38 (10.7%) were of other race. At 60 days, twice as many infants in the early group vs the delayed group received a COM (34 of 161 [21.1%; 95% CI, 15.1%-28.2%] vs 17 of 165 [10.3%; 95% CI, 6.1%-16.0%]; P = .009; odds ratio, 2.3; 95% CI, 1.22-4.32) and a molecular diagnosis (55 of 176 [31.0%; 95% CI, 24.5%-38.7%] vs 27 of 178 [15.0%; 95% CI, 10.2%-21.3%]; P < .001). At 90 days, the delayed group showed a doubling of COM (to 45 of 161 [28.0%; 95% CI, 21.2%-35.6%]) and diagnostic efficacy (to 56 of 178 [31.0%; 95% CI, 24.7%-38.8%]). The most frequent COMs across the observation window were subspecialty referrals (39 of 354; 11%), surgery or other invasive procedures (17 of 354; 4%), condition-specific medications (9 of 354; 2%), or other supportive alterations in medication (12 of 354; 3%). No differences in length of stay or survival were observed., Conclusions and Relevance: In this randomized clinical trial, for acutely ill infants in an intensive care unit, introduction of WGS was associated with a significant increase in focused clinical management compared with usual care. Access to first-line WGS may reduce health care disparities by enabling diagnostic equity. These data support WGS adoption and implementation in this population., Trail Registration: ClinicalTrials.gov Identifier: NCT03290469.

Published
2021
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29. Disclosing genetic risk for Alzheimer's dementia to individuals with mild cognitive impairment.

Author

Christensen KD, Karlawish J, Roberts JS, Uhlmann WR, Harkins K, Wood EM, Obisesan TO, Le LQ, Cupples LA, Zoltick ES, Johnson MS, Bradbury MK, Waterston LB, Chen CA, Feldman S, Perry DL, and Green RC

Abstract

Introduction: The safety of predicting conversion from mild cognitive impairment (MCI) to Alzheimer's disease (AD) dementia using apolipoprotein E ( APOE ) genotyping is unknown., Methods: We randomized 114 individuals with MCI to receive estimates of 3-year risk of conversion to AD dementia informed by APOE genotyping (disclosure arm) or not (non-disclosure arm) in a non-inferiority clinical trial. Primary outcomes were anxiety and depression scores. Secondary outcomes included other psychological measures., Results: Upper confidence limits for randomization arm differences were 2.3 on the State Trait Anxiety Index and 0.5 on the Geriatric Depression Scale, below non-inferiority margins of 3.3 and 1.0. Moreover, mean scores were lower in the disclosure arm than non-disclosure arm for test-related positive impact (difference: -1.9, indicating more positive feelings) and AD concern (difference: -0.3)., Discussion: Providing genetic information to individuals with MCI about imminent risk for AD does not increase risks of anxiety or depression and may provide psychological benefits., Competing Interests: Robert Green receives compensation for advising AIA, Applied Therapeutics, Biggs Institute, Helix, Humanity, Verily, and Veritas, and is a cofounder with equity in Genome Medical., (© 2020 The Authors. Alzheimer's & Dementia: Translational Research & Clinical Interventions published by Wiley Periodicals, Inc. on behalf of Alzheimer's Association.)

Published
2020
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