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1. Assessing the quality and value of metabolic chart data for capturing core outcomes for pediatric medium-chain acyl-CoA dehydrogenase (MCAD) deficiency

Author

Iverson, Ryan, Taljaard, Monica, Geraghty, Michael T., Pugliese, Michael, Tingley, Kylie, Coyle, Doug, Kronick, Jonathan B., Wilson, Kumanan, Austin, Valerie, Brunel-Guitton, Catherine, Buhas, Daniela, Butcher, Nancy J., Chan, Alicia K. J., Dyack, Sarah, Goobie, Sharan, Greenberg, Cheryl R., Jain-Ghai, Shailly, Inbar-Feigenberg, Michal, Karp, Natalya, Kozenko, Mariya, Langley, Erica, Lines, Matthew, Little, Julian, MacKenzie, Jennifer, Maranda, Bruno, Mercimek-Andrews, Saadet, Mhanni, Aizeddin, Mitchell, John J., Nagy, Laura, Offringa, Martin, Pender, Amy, Potter, Murray, Prasad, Chitra, Ratko, Suzanne, Salvarinova, Ramona, Schulze, Andreas, Siriwardena, Komudi, Sondheimer, Neal, Sparkes, Rebecca, Stockler-Ipsiroglu, Sylvia, Tapscott, Kendra, Trakadis, Yannis, Turner, Lesley, Van Karnebeek, Clara, Vandersteen, Anthony, Walia, Jagdeep S., Wilson, Brenda J., Yu, Andrea C., Potter, Beth K., and Chakraborty, Pranesh

Published
2024
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2. Clinical study of ferredoxin-reductase-related mitochondriopathy: Genotype-phenotype correlation and proposal of ancestry-based carrier screening in the Mexican population

Author

Campbell, Teresa, Slone, Jesse, Metzger, Hallie, Liu, Wensheng, Sacharow, Stephanie, Yang, Amy, Moosajee, Mariya, La Morgia, Chiara, Carelli, Valerio, Palombo, Flavia, Lines, Matthew A., Innes, A. Micheil, Levy, Rebecca J., Neilson, Derek, Longo, Nicola, and Huang, Taosheng

Published
2024
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4. Partial Loss of USP9X Function Leads to a Male Neurodevelopmental and Behavioral Disorder Converging on Transforming Growth Factor β Signaling.

Author

Johnson, Brett V, Kumar, Raman, Oishi, Sabrina, Alexander, Suzy, Kasherman, Maria, Vega, Michelle Sanchez, Ivancevic, Atma, Gardner, Alison, Domingo, Deepti, Corbett, Mark, Parnell, Euan, Yoon, Sehyoun, Oh, Tracey, Lines, Matthew, Lefroy, Henrietta, Kini, Usha, Van Allen, Margot, Grønborg, Sabine, Mercier, Sandra, Küry, Sébastien, Bézieau, Stéphane, Pasquier, Laurent, Raynaud, Martine, Afenjar, Alexandra, Billette de Villemeur, Thierry, Keren, Boris, Désir, Julie, Van Maldergem, Lionel, Marangoni, Martina, Dikow, Nicola, Koolen, David A, VanHasselt, Peter M, Weiss, Marjan, Zwijnenburg, Petra, Sa, Joaquim, Reis, Claudia Falcao, López-Otín, Carlos, Santiago-Fernández, Olaya, Fernández-Jaén, Alberto, Rauch, Anita, Steindl, Katharina, Joset, Pascal, Goldstein, Amy, Madan-Khetarpal, Suneeta, Infante, Elena, Zackai, Elaine, Mcdougall, Carey, Narayanan, Vinodh, Ramsey, Keri, Mercimek-Andrews, Saadet, Pena, Loren, Shashi, Vandana, Undiagnosed Diseases Network, Schoch, Kelly, Sullivan, Jennifer A, Pinto E Vairo, Filippo, Pichurin, Pavel N, Ewing, Sarah A, Barnett, Sarah S, Klee, Eric W, Perry, M Scott, Koenig, Mary Kay, Keegan, Catherine E, Schuette, Jane L, Asher, Stephanie, Perilla-Young, Yezmin, Smith, Laurie D, Rosenfeld, Jill A, Bhoj, Elizabeth, Kaplan, Paige, Li, Dong, Oegema, Renske, van Binsbergen, Ellen, van der Zwaag, Bert, Smeland, Marie Falkenberg, Cutcutache, Ioana, Page, Matthew, Armstrong, Martin, Lin, Angela E, Steeves, Marcie A, Hollander, Nicolette den, Hoffer, Mariëtte JV, Reijnders, Margot RF, Demirdas, Serwet, Koboldt, Daniel C, Bartholomew, Dennis, Mosher, Theresa Mihalic, Hickey, Scott E, Shieh, Christine, Sanchez-Lara, Pedro A, Graham, John M, Tezcan, Kamer, Schaefer, GB, Danylchuk, Noelle R, Asamoah, Alexander, Jackson, Kelly E, Yachelevich, Naomi, Au, Margaret, Pérez-Jurado, Luis A, and Kleefstra, Tjitske

Subjects
Undiagnosed Diseases Network, Animals, Humans, Mice, Ubiquitin Thiolesterase, Transforming Growth Factor beta, Developmental Disabilities, Signal Transduction, Phenotype, Female, Male, Haploinsufficiency, Intellectual Disability, Brain malformation, Deubiquitylating enzyme, Hippocampus, Neurodevelopmental disorder, TGFβ, USP9X, Congenital Structural Anomalies, Genetics, Neurosciences, Pediatric, Mental Health, Behavioral and Social Science, Brain Disorders, Clinical Research, 2.1 Biological and endogenous factors, Aetiology, Neurological, TGF beta, Biological Sciences, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry
Abstract

BackgroundThe X-chromosome gene USP9X encodes a deubiquitylating enzyme that has been associated with neurodevelopmental disorders primarily in female subjects. USP9X escapes X inactivation, and in female subjects de novo heterozygous copy number loss or truncating mutations cause haploinsufficiency culminating in a recognizable syndrome with intellectual disability and signature brain and congenital abnormalities. In contrast, the involvement of USP9X in male neurodevelopmental disorders remains tentative.MethodsWe used clinically recommended guidelines to collect and interrogate the pathogenicity of 44 USP9X variants associated with neurodevelopmental disorders in males. Functional studies in patient-derived cell lines and mice were used to determine mechanisms of pathology.ResultsTwelve missense variants showed strong evidence of pathogenicity. We define a characteristic phenotype of the central nervous system (white matter disturbances, thin corpus callosum, and widened ventricles); global delay with significant alteration of speech, language, and behavior; hypotonia; joint hypermobility; visual system defects; and other common congenital and dysmorphic features. Comparison of in silico and phenotypical features align additional variants of unknown significance with likely pathogenicity. In support of partial loss-of-function mechanisms, using patient-derived cell lines, we show loss of only specific USP9X substrates that regulate neurodevelopmental signaling pathways and a united defect in transforming growth factor β signaling. In addition, we find correlates of the male phenotype in Usp9x brain-specific knockout mice, and further resolve loss of hippocampal-dependent learning and memory.ConclusionsOur data demonstrate the involvement of USP9X variants in a distinctive neurodevelopmental and behavioral syndrome in male subjects and identify plausible mechanisms of pathogenesis centered on disrupted transforming growth factor β signaling and hippocampal function.

Published
2020

5. PLPHP deficiency: clinical, genetic, biochemical, and mechanistic insights.

Author

Johnstone, Devon L, Al-Shekaili, Hilal H, Tarailo-Graovac, Maja, Wolf, Nicole I, Ivy, Autumn S, Demarest, Scott, Roussel, Yann, Ciapaite, Jolita, van Roermund, Carlo WT, Kernohan, Kristin D, Kosuta, Ceres, Ban, Kevin, Ito, Yoko, McBride, Skye, Al-Thihli, Khalid, Abdelrahim, Rana A, Koul, Roshan, Al Futaisi, Amna, Haaxma, Charlotte A, Olson, Heather, Sigurdardottir, Laufey Yr, Arnold, Georgianne L, Gerkes, Erica H, Boon, M, Heiner-Fokkema, M Rebecca, Noble, Sandra, Bosma, Marjolein, Jans, Judith, Koolen, David A, Kamsteeg, Erik-Jan, Drögemöller, Britt, Ross, Colin J, Majewski, Jacek, Cho, Megan T, Begtrup, Amber, Wasserman, Wyeth W, Bui, Tuan, Brimble, Elise, Violante, Sara, Houten, Sander M, Wevers, Ron A, van Faassen, Martijn, Kema, Ido P, Lepage, Nathalie, Lines, Matthew A, Dyment, David A, Wanders, Ronald JA, Verhoeven-Duif, Nanda, Ekker, Marc, Boycott, Kym M, Friedman, Jan M, Pena, Izabella A, and van Karnebeek, Clara DM

Subjects
Epilepsy, Neurosciences, Brain Disorders, Neurodegenerative, 2.1 Biological and endogenous factors, Aetiology, Neurological, Animals, Disease Models, Animal, Female, HEK293 Cells, Humans, Male, Phenotype, Proteins, Pyridoxal Phosphate, Pyridoxine, Vitamin B 6, Vitamin B 6 Deficiency, Zebrafish, PLPBP, PROSC, epilepsy, pyridoxine, vitamin B6-responsive epilepsy, Care4Rare Canada Consortium, PLPBP, PROSC, Medical and Health Sciences, Psychology and Cognitive Sciences, Neurology & Neurosurgery
Abstract

Biallelic pathogenic variants in PLPBP (formerly called PROSC) have recently been shown to cause a novel form of vitamin B6-dependent epilepsy, the pathophysiological basis of which is poorly understood. When left untreated, the disease can progress to status epilepticus and death in infancy. Here we present 12 previously undescribed patients and six novel pathogenic variants in PLPBP. Suspected clinical diagnoses prior to identification of PLPBP variants included mitochondrial encephalopathy (two patients), folinic acid-responsive epilepsy (one patient) and a movement disorder compatible with AADC deficiency (one patient). The encoded protein, PLPHP is believed to be crucial for B6 homeostasis. We modelled the pathogenicity of the variants and developed a clinical severity scoring system. The most severe phenotypes were associated with variants leading to loss of function of PLPBP or significantly affecting protein stability/PLP-binding. To explore the pathophysiology of this disease further, we developed the first zebrafish model of PLPHP deficiency using CRISPR/Cas9. Our model recapitulates the disease, with plpbp-/- larvae showing behavioural, biochemical, and electrophysiological signs of seizure activity by 10 days post-fertilization and early death by 16 days post-fertilization. Treatment with pyridoxine significantly improved the epileptic phenotype and extended lifespan in plpbp-/- animals. Larvae had disruptions in amino acid metabolism as well as GABA and catecholamine biosynthesis, indicating impairment of PLP-dependent enzymatic activities. Using mass spectrometry, we observed significant B6 vitamer level changes in plpbp-/- zebrafish, patient fibroblasts and PLPHP-deficient HEK293 cells. Additional studies in human cells and yeast provide the first empirical evidence that PLPHP is localized in mitochondria and may play a role in mitochondrial metabolism. These models provide new insights into disease mechanisms and can serve as a platform for drug discovery.

Published
2019

8. Partial Loss of USP9X Function Leads to a Male Neurodevelopmental and Behavioral Disorder Converging on Transforming Growth Factor β Signaling

Author

Pena, Loren, Shashi, Vandana, Schoch, Kelly, Sullivan, Jennifer A., Acosta, Maria T., Adams, David R., Aday, Aaron, Alejandro, Mercedes E., Allard, Patrick, Ashley, Euan A., Azamian, Mahshid S., Bacino, Carlos A., Bademci, Guney, Baker, Eva, Balasubramanyam, Ashok, Baldridge, Dustin, Barbouth, Deborah, Batzli, Gabriel F., Beggs, Alan H., Bellen, Hugo J., Bernstein, Jonathan A., Berry, Gerard T., Bican, Anna, Bick, David P., Birch, Camille L., Bivona, Stephanie, Bonnenmann, Carsten, Bonner, Devon, Boone, Braden E., Bostwick, Bret L., Briere, Lauren C., Brokamp, Elly, Brown, Donna M., Brush, Matthew, Burke, Elizabeth A., Burrage, Lindsay C., Butte, Manish J., Carrasquillo, Olveen, Peter Chang, Ta Chen, Chao, Hsiao-Tuan, Clark, Gary D., Coakley, Terra R., Cobban, Laurel A., Cogan, Joy D., Cole, F. Sessions, Colley, Heather A., Cooper, Cynthia M., Cope, Heidi, Craigen, William J., D'Souza, Precilla, Dasari, Surendra, Davids, Mariska, Davidson, Jean M., Dayal, Jyoti G., Dell'Angelica, Esteban C., Dhar, Shweta U., Dorrani, Naghmeh, Dorset, Daniel C., Douine, Emilie D., Draper, David D., Dries, Annika M., Duncan, Laura, Eckstein, David J., Emrick, Lisa T., Eng, Christine M., Enns, Gregory M., Esteves, Cecilia, Estwick, Tyra, Fernandez, Liliana, Ferreira, Carlos, Fieg, Elizabeth L., Fisher, Paul G., Fogel, Brent L., Forghani, Irman, Friedman, Noah D., Gahl, William A., Godfrey, Rena A., Goldman, Alica M., Goldstein, David B., Gourdine, Jean-Philippe F., Grajewski, Alana, Groden, Catherine A., Gropman, Andrea L., Haendel, Melissa, Hamid, Rizwan, Hanchard, Neil A., High, Frances, Holm, Ingrid A., Hom, Jason, Huang, Alden, Huang, Yong, Isasi, Rosario, Jamal, Fariha, Jiang, Yong-hui, Johnston, Jean M., Jones, Angela L., Karaviti, Lefkothea, Kelley, Emily G., Koeller, David M., Kohane, Isaac S., Kohler, Jennefer N., Krakow, Deborah, Krasnewich, Donna M., Korrick, Susan, Koziura, Mary, Krier, Joel B., Kyle, Jennifer E., Lalani, Seema R., Lam, Byron, Lanpher, Brendan C., Lanza, Ian R., Lau, C. Christopher, Lazar, Jozef, LeBlanc, Kimberly, Lee, Brendan H., Lee, Hane, Levitt, Roy, Levy, Shawn E., Lewis, Richard A., Lincoln, Sharyn A., Liu, Pengfei, Liu, Xue Zhong, Loo, Sandra K., Loscalzo, Joseph, Maas, Richard L., Macnamara, Ellen F., MacRae, Calum A., Maduro, Valerie V., Majcherska, Marta M., Malicdan, May Christine V., Mamounas, Laura A., Manolio, Teri A., Markello, Thomas C., Marom, Ronit, Martin, Martin G., Martínez-Agosto, Julian A., Marwaha, Shruti, May, Thomas, McCauley, Jacob, McConkie-Rosell, Allyn, McCormack, Colleen E., McCray, Alexa T., Merker, Jason D., Metz, Thomas O., Might, Matthew, Morava-Kozicz, Eva, Moretti, Paolo M., Morimoto, Marie, Mulvihill, John J., Murdock, David R., Nath, Avi, Nelson, Stan F., Newberry, J. Scott, Newman, John H., Nicholas, Sarah K., Novacic, Donna, Oglesbee, Devin, Orengo, James P., Pak, Stephen, Pallais, J. Carl, Palmer, Christina GS., Papp, Jeanette C., Parker, Neil H., Phillips, John A., III, Posey, Jennifer E., Postlethwait, John H., Potocki, Lorraine, Pusey, Barbara N., Renteri, Genecee, Reuter, Chloe M., Rives, Lynette, Robertson, Amy K., Rodan, Lance H., Rosenfeld, Jill A., Rowley, Robb K., Sacco, Ralph, Sampson, Jacinda B., Samson, Susan L., Saporta, Mario, Schaechter, Judy, Schedl, Timothy, Scott, Daryl A., Shakachite, Lisa, Sharma, Prashant, Shields, Kathleen, Shin, Jimann, Signer, Rebecca, Sillari, Catherine H., Silverman, Edwin K., Sinsheimer, Janet S., Smith, Kevin S., Solnica-Krezel, Lilianna, Spillmann, Rebecca C., Stoler, Joan M., Stong, Nicholas, Sweetser, David A., Tamburro, Cecelia P., Tan, Queenie K.-G., Tekin, Mustafa, Telischi, Fred, Thorson, Willa, Tifft, Cynthia J., Toro, Camilo, Tran, Alyssa A., Urv, Tiina K., Vogel, Tiphanie P., Waggott, Daryl M., Wahl, Colleen E., Walley, Nicole M., Walsh, Chris A., Walker, Melissa, Wambach, Jennifer, Wan, Jijun, Wang, Lee-kai, Wangler, Michael F., Ward, Patricia A., Waters, Katrina M., Webb-Robertson, Bobbie-Jo M., Wegner, Daniel, Westerfield, Monte, Wheeler, Matthew T., Wise, Anastasia L., Wolfe, Lynne A., Woods, Jeremy D., Worthey, Elizabeth A., Yamamoto, Shinya, Yang, John, Yoon, Amanda J., Yu, Guoyun, Zastrow, Diane B., Zhao, Chunli, Zuchner, Stephan, Gahl, William, Johnson, Brett V., Kumar, Raman, Oishi, Sabrina, Alexander, Suzy, Kasherman, Maria, Vega, Michelle Sanchez, Ivancevic, Atma, Gardner, Alison, Domingo, Deepti, Corbett, Mark, Parnell, Euan, Yoon, Sehyoun, Oh, Tracey, Lines, Matthew, Lefroy, Henrietta, Kini, Usha, Van Allen, Margot, Grønborg, Sabine, Mercier, Sandra, Küry, Sébastien, Bézieau, Stéphane, Pasquier, Laurent, Raynaud, Martine, Afenjar, Alexandra, Billette de Villemeur, Thierry, Keren, Boris, Désir, Julie, Van Maldergem, Lionel, Marangoni, Martina, Dikow, Nicola, Koolen, David A., VanHasselt, Peter M., Weiss, Marjan, Zwijnenburg, Petra, Sa, Joaquim, Reis, Claudia Falcao, López-Otín, Carlos, Santiago-Fernández, Olaya, Fernández-Jaén, Alberto, Rauch, Anita, Steindl, Katharina, Joset, Pascal, Goldstein, Amy, Madan-Khetarpal, Suneeta, Infante, Elena, Zackai, Elaine, Mcdougall, Carey, Narayanan, Vinodh, Ramsey, Keri, Mercimek-Andrews, Saadet, Pinto e Vairo, Filippo, Pichurin, Pavel N., Ewing, Sarah A., Barnett, Sarah S., Klee, Eric W., Perry, M. Scott, Koenig, Mary Kay, Keegan, Catherine E., Schuette, Jane L., Asher, Stephanie, Perilla-Young, Yezmin, Smith, Laurie D., Bhoj, Elizabeth, Kaplan, Paige, Li, Dong, Oegema, Renske, van Binsbergen, Ellen, van der Zwaag, Bert, Smeland, Marie Falkenberg, Cutcutache, Ioana, Page, Matthew, Armstrong, Martin, Lin, Angela E., Steeves, Marcie A., Hollander, Nicolette den, Hoffer, Mariëtte J.V., Reijnders, Margot R.F., Demirdas, Serwet, Koboldt, Daniel C., Bartholomew, Dennis, Mosher, Theresa Mihalic, Hickey, Scott E., Shieh, Christine, Sanchez-Lara, Pedro A., Graham, John M., Jr., Tezcan, Kamer, Schaefer, G.B., Danylchuk, Noelle R., Asamoah, Alexander, Jackson, Kelly E., Yachelevich, Naomi, Au, Margaret, Pérez-Jurado, Luis A., Kleefstra, Tjitske, Penzes, Peter, Wood, Stephen A., Burne, Thomas, Pierson, Tyler Mark, Piper, Michael, Gécz, Jozef, and Jolly, Lachlan A.

Published
2020
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9. Mandibulofacial Dysostosis with Microcephaly: Mutation and Database Update

Author

Huang, Lijia, Vanstone, Megan R, Hartley, Taila, Osmond, Matthew, Barrowman, Nick, Allanson, Judith, Baker, Laura, Dabir, Tabib A, Dipple, Katrina M, Dobyns, William B, Estrella, Jane, Faghfoury, Hanna, Favaro, Francine P, Goel, Himanshu, Gregersen, Pernille A, Gripp, Karen W, Grix, Art, Guion‐Almeida, Maria‐Leine, Harr, Margaret H, Hudson, Cindy, Hunter, Alasdair GW, Johnson, John, Joss, Shelagh K, Kimball, Amy, Kini, Usha, Kline, Antonie D, Lauzon, Julie, Lildballe, Dorte L, López‐González, Vanesa, Martinezmoles, Johanna, Meldrum, Cliff, Mirzaa, Ghayda M, Morel, Chantal F, Morton, Jenny EV, Pyle, Louise C, Quintero‐Rivera, Fabiola, Richer, Julie, Scheuerle, Angela E, Schönewolf‐Greulich, Bitten, Shears, Deborah J, Silver, Josh, Smith, Amanda C, Temple, I Karen, Center, UCLA Clinical Genomics, de Kamp, Jiddeke M, Dijk, Fleur S, Vandersteen, Anthony M, White, Sue M, Zackai, Elaine H, Zou, Ruobing, Consortium, Care4Rare Canada, Bulman, Dennis E, Boycott, Kym M, and Lines, Matthew A

Subjects
Pediatric, Congenital Structural Anomalies, Rare Diseases, Genetics, Prevention, Human Genome, Neurosciences, Clinical Research, Dental/Oral and Craniofacial Disease, 2.1 Biological and endogenous factors, Aetiology, Congenital, Abnormalities, Multiple, Amino Acid Motifs, Databases, Genetic, Gene Expression, Haploinsufficiency, Hearing Loss, Humans, Intellectual Disability, Mandibulofacial Dysostosis, Microcephaly, Models, Molecular, Molecular Sequence Data, Mutation, Penetrance, Peptide Elongation Factors, Phenotype, Protein Structure, Secondary, Protein Structure, Tertiary, RNA Splicing, Ribonucleoprotein, U5 Small Nuclear, Spliceosomes, EFTUD2, mandibulofacial dysostosis with microcephaly, MFDM, mandibulofacial dysostosis Guion-Almeida type, mandibulofacial dysostosis, microcephaly, UCLA Clinical Genomics Center, Care4Rare Canada Consortium, Clinical Sciences, Genetics & Heredity
Abstract

Mandibulofacial dysostosis with microcephaly (MFDM) is a multiple malformation syndrome comprising microcephaly, craniofacial anomalies, hearing loss, dysmorphic features, and, in some cases, esophageal atresia. Haploinsufficiency of a spliceosomal GTPase, U5-116 kDa/EFTUD2, is responsible. Here, we review the molecular basis of MFDM in the 69 individuals described to date, and report mutations in 38 new individuals, bringing the total number of reported individuals to 107 individuals from 94 kindreds. Pathogenic EFTUD2 variants comprise 76 distinct mutations and seven microdeletions. Among point mutations, missense substitutions are infrequent (14 out of 76; 18%) relative to stop-gain (29 out of 76; 38%), and splicing (33 out of 76; 43%) mutations. Where known, mutation origin was de novo in 48 out of 64 individuals (75%), dominantly inherited in 12 out of 64 (19%), and due to proven germline mosaicism in four out of 64 (6%). Highly penetrant clinical features include, microcephaly, first and second arch craniofacial malformations, and hearing loss; esophageal atresia is present in an estimated ∼27%. Microcephaly is virtually universal in childhood, with some adults exhibiting late "catch-up" growth and normocephaly at maturity. Occasionally reported anomalies, include vestibular and ossicular malformations, reduced mouth opening, atrophy of cerebral white matter, structural brain malformations, and epibulbar dermoid. All reported EFTUD2 mutations can be found in the EFTUD2 mutation database (http://databases.lovd.nl/shared/genes/EFTUD2).

Published
2016

12. Clinical study of FDXR-related mitochondriopathy: genotype-phenotype correlation and proposal of ancestry-based carrier screening in the Mexican population

Author

Campbell, Teresa, primary, Slone, Jesse, additional, Metzger, Hallie, additional, Liu, Wensheng, additional, Sacharow, Stephanie, additional, Yang, Amy, additional, Moosajee, Mariya, additional, La Morgia, Chiara, additional, Carelli, Valerio, additional, Palombo, Flavia, additional, Lines, Matthew A., additional, Innes, A. Micheil, additional, Levy, Rebecca J., additional, Neilson, Derek, additional, Longo, Nicola, additional, and Huang, Taosheng, additional

Published
2023
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14. Severe Neonatal Presentation of Mitochondrial Citrate Carrier (SLC25A1) Deficiency

Author

FORGE Canada Consortium, Smith, Amanda, McBride, Skye, Marcadier, Julien L., Michaud, Jean, Al-Dirbashi, Osama Y., Schwartzentruber, Jeremy, Beaulieu, Chandree L., Katz, Sherri L., Majewski, Jacek, Bulman, Dennis E., Geraghty, Michael T., Harper, Mary-Ellen, Chakraborty, Pranesh, Lines, Matthew A., Baumgartner, Matthias R., Series editor, Patterson, Marc, Series editor, Rahman, Shamima, Series editor, Peters, Verena, Series editor, Morava, Eva, Editor-in-chief, Zschocke, Johannes, Series editor, and Baumgartner, Matthias, editor

Published
2016
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15. Detailed Biochemical and Bioenergetic Characterization of FBXL4-Related Encephalomyopathic Mitochondrial DNA Depletion

Author

Antoun, Ghadi, McBride, Skye, Vanstone, Jason R., Naas, Turaya, Michaud, Jean, Redpath, Stephanie, McMillan, Hugh J., Brophy, Jason, Daoud, Hussein, Chakraborty, Pranesh, Dyment, David, Holcik, Martin, Harper, Mary-Ellen, Lines, Matthew A., Baumgartner, Matthias, Series editor, Patterson, Marc, Series editor, Rahman, Shamima, Series editor, Peters, Verena, Series editor, Morava, Eva, Editor-in-chief, and Zschocke, Johannes, Series editor

Published
2016
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17. Danon Disease Due to a Novel LAMP2 Microduplication

Author

Lines, Matthew A., Hewson, Stacy, Halliday, William, Sabatini, Peter J. B., Stockley, Tracy, Dipchand, Anne I., Bowdin, Sarah, Siriwardena, Komudi, Zschocke, Johannes, Editor-in-chief, Gibson, K Michael, Editor-in-chief, Gibson, K. Michael, editor, Brown, Garry, editor, Morava, Eva, editor, and Peters, Verena, editor

Published
2014
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20. Clinico-radiological features, molecular spectrum, and identification of prognostic factors in developmental and epileptic encephalopathy due to inosine triphosphate pyrophosphatase (ITPase) deficiency

Author

Scala, Marcello, Wortmann, Saskia B., Kaya, Namik, Stellingwerff, Menno D., Pistorio, Angela, Glamuzina, Emma, van Karnebeek, Clara D., Skrypnyk, Cristina, Iwanicka-Pronicka, Katarzyna, Piekutowska-Abramczuk, Dorota, Ciara, Elżbieta, Tort, Frederic, Sheidley, Beth, Poduri, Annapurna, Jayakar, Parul, Jayakar, Anuj, Upadia, Jariya, Walano, Nicolette, Haack, Tobias B., Prokisch, Holger, Aldhalaan, Hesham, Karimiani, Ehsan G., Yildiz, Yilmaz, Ceylan, Ahmet C., Santiago-Sim, Teresa, Dameron, Amy, Yang, Hui, Toosi, Mehran B., Ashrafzadeh, Farah, Akhondian, Javad, Imannezhad, Shima, Mirzadeh, Hanieh S., Maqbool, Shazia, Farid, Aisha, Al-Muhaizea, Mohamed A., Alshwameen, Meznah O., Aldowsari, Lama, Alsagob, Maysoon, Alyousef, Ashwaq, AlMass, Rawan, AlHargan, Aljouhra, Alwadei, Ali H., AlRasheed, Maha M., Colak, Dilek, Alqudairy, Hanan, Khan, Sameena, Lines, Matthew A., García Cazorla, M. Ángeles, Ribes, Antonia, Morava, Eva, Bibi, Farah, Haider, Shahzad, Ferla, Matteo P., Taylor, Jenny C., Alsaif, Hessa S., Firdous, Abdulwahab, Hashem, Mais, Shashkin, Chingiz, Koneev, Kairgali, Kaiyrzhanov, Rauan, Efthymiou, Stephanie, Genomics, Queen Square, Schmitt-Mechelke, Thomas, Ziegler, Andreas, Issa, Mahmoud Y., Elbendary, Hasnaa M., Striano, Pasquale, Alkuraya, Fowzan S., Zaki, Maha S., Gleeson, Joseph G., Barakat, Tahsin Stefan, Bierau, Jorgen, van der Knaap, Marjo S., Maroofian, Reza, Houlden, Henry, Scala, Marcello, Wortmann, Saskia B., Kaya, Namik, Stellingwerff, Menno D., Pistorio, Angela, Glamuzina, Emma, van Karnebeek, Clara D., Skrypnyk, Cristina, Iwanicka-Pronicka, Katarzyna, Piekutowska-Abramczuk, Dorota, Ciara, Elżbieta, Tort, Frederic, Sheidley, Beth, Poduri, Annapurna, Jayakar, Parul, Jayakar, Anuj, Upadia, Jariya, Walano, Nicolette, Haack, Tobias B., Prokisch, Holger, Aldhalaan, Hesham, Karimiani, Ehsan G., Yildiz, Yilmaz, Ceylan, Ahmet C., Santiago-Sim, Teresa, Dameron, Amy, Yang, Hui, Toosi, Mehran B., Ashrafzadeh, Farah, Akhondian, Javad, Imannezhad, Shima, Mirzadeh, Hanieh S., Maqbool, Shazia, Farid, Aisha, Al-Muhaizea, Mohamed A., Alshwameen, Meznah O., Aldowsari, Lama, Alsagob, Maysoon, Alyousef, Ashwaq, AlMass, Rawan, AlHargan, Aljouhra, Alwadei, Ali H., AlRasheed, Maha M., Colak, Dilek, Alqudairy, Hanan, Khan, Sameena, Lines, Matthew A., García Cazorla, M. Ángeles, Ribes, Antonia, Morava, Eva, Bibi, Farah, Haider, Shahzad, Ferla, Matteo P., Taylor, Jenny C., Alsaif, Hessa S., Firdous, Abdulwahab, Hashem, Mais, Shashkin, Chingiz, Koneev, Kairgali, Kaiyrzhanov, Rauan, Efthymiou, Stephanie, Genomics, Queen Square, Schmitt-Mechelke, Thomas, Ziegler, Andreas, Issa, Mahmoud Y., Elbendary, Hasnaa M., Striano, Pasquale, Alkuraya, Fowzan S., Zaki, Maha S., Gleeson, Joseph G., Barakat, Tahsin Stefan, Bierau, Jorgen, van der Knaap, Marjo S., Maroofian, Reza, and Houlden, Henry

Abstract

Developmental and epileptic encephalopathy 35 (DEE 35) is a severe neurological condition caused by biallelic variants in ITPA, encoding inosine triphosphate pyrophosphatase, an essential enzyme in purine metabolism. We delineate the genotypic and phenotypic spectrum of DEE 35, analyzing possible predictors for adverse clinical outcomes. We investigated a cohort of 28 new patients and reviewed previously described cases, providing a comprehensive characterization of 40 subjects. Exome sequencing was performed to identify underlying ITPA pathogenic variants. Brain MRI (magnetic resonance imaging) scans were systematically analyzed to delineate the neuroradiological spectrum. Survival curves according to the Kaplan–Meier method and log-rank test were used to investigate outcome predictors in different subgroups of patients. We identified 18 distinct ITPA pathogenic variants, including 14 novel variants, and two deletions. All subjects showed profound developmental delay, microcephaly, and refractory epilepsy followed by neurodevelopmental regression. Brain MRI revision revealed a recurrent pattern of delayed myelination and restricted diffusion of early myelinating structures. Congenital microcephaly and cardiac involvement were statistically significant novel clinical predictors of adverse outcomes. We refined the molecular, clinical, and neuroradiological characterization of ITPase deficiency, and identified new clinical predictors which may have a potentially important impact on diagnosis, counseling, and follow-up of affected individuals.

Published
2022

22. Next-generation sequencing for diagnosis of rare diseases in the neonatal intensive care unit

Author

Daoud, Hussein, Luco, Stephanie M., Li, Rui, Bareke, Eric, Beaulieu, Chandree, Jarinova, Olga, Carson, Nancy, Nikkel, Sarah M., Graham, Gail E., Richer, Julie, Armour, Christine, Bulman, Dennis E., Chakraborty, Pranesh, Geraghty, Michael, Lines, Matthew A., Lacaze-Masmonteil, Thierry, Majewski, Jacek, Boycott, Kym M., and Dyment, David A.

Subjects
Newborn infants -- Health aspects, Rare diseases -- Diagnosis, Neonatal intensive care units -- Management, Company business management, Health
Abstract

Background: Rare diseases often present in the first days and weeks of life and may require complex management in the setting of a neonatal intensive care unit (NICU). Exhaustive consultations and traditional genetic or metabolic investigations are costly and often fail to arrive at a final diagnosis when no recognizable syndrome is suspected. For this pilot project, we assessed the feasibility of next-generation sequencing as a tool to improve the diagnosis of rare diseases in newborns in the NICU. Methods: We retrospectively identified and prospectively recruited newborns and infants admitted to the NICU of the Children's Hospital of Eastern Ontario and the Ottawa Hospital, General Campus, who had been referred to the medical genetics or metabolics inpatient consult service and had features suggesting an underlying genetic or metabolic condition. DNA from the newborns and parents was enriched for a panel of clinically relevant genes and sequenced on a MiSeq sequencing platform (Illumina Inc.). The data were interpreted with a standard informatics pipeline and reported to care providers, who assessed the importance of genotype-phenotype correlations. Results: Of 20 newborns studied, 8 received a diagnosis on the basis of next-generation sequencing (diagnostic rate 40%). The diagnoses were renal tubular dysgenesis, SCN1Arelated encephalopathy syndrome, myotubular myopathy, FTO deficiency syndrome, cranio-ectodermal dysplasia, congenital myasthenic syndrome, autosomal dominant intellectual disability syndrome type 7 and Denys-Drash syndrome. Interpretation: This pilot study highlighted the potential of next-generation sequencing to deliver molecular diagnoses rapidly with a high success rate. With broader use, this approach has the potential to alter health care delivery in the NICU., A rare disease is defined by a prevalence of less than 1 in 2000 individuals. (1) However, when considered in aggregate, 1%-2% of Canadians will manifest a rare disease in [...]

Published
2016
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23. Clinico‐radiological features, molecular spectrum, and identification of prognostic factors in developmental and epileptic encephalopathy due to inosine triphosphate pyrophosphatase (ITPase) deficiency

Author

Scala, Marcello, primary, Wortmann, Saskia B., additional, Kaya, Namik, additional, Stellingwerff, Menno D., additional, Pistorio, Angela, additional, Glamuzina, Emma, additional, Karnebeek, Clara D., additional, Skrypnyk, Cristina, additional, Iwanicka‐Pronicka, Katarzyna, additional, Piekutowska‐Abramczuk, Dorota, additional, Ciara, Elżbieta, additional, Tort, Frederic, additional, Sheidley, Beth, additional, Poduri, Annapurna, additional, Jayakar, Parul, additional, Jayakar, Anuj, additional, Upadia, Jariya, additional, Walano, Nicolette, additional, Haack, Tobias B., additional, Prokisch, Holger, additional, Aldhalaan, Hesham, additional, Karimiani, Ehsan G., additional, Yildiz, Yilmaz, additional, Ceylan, Ahmet C., additional, Santiago‐Sim, Teresa, additional, Dameron, Amy, additional, Yang, Hui, additional, Toosi, Mehran B., additional, Ashrafzadeh, Farah, additional, Akhondian, Javad, additional, Imannezhad, Shima, additional, Mirzadeh, Hanieh S., additional, Maqbool, Shazia, additional, Farid, Aisha, additional, Al‐Muhaizea, Mohamed A., additional, Alshwameen, Meznah O., additional, Aldowsari, Lama, additional, Alsagob, Maysoon, additional, Alyousef, Ashwaq, additional, AlMass, Rawan, additional, AlHargan, Aljouhra, additional, Alwadei, Ali H., additional, AlRasheed, Maha M., additional, Colak, Dilek, additional, Alqudairy, Hanan, additional, Khan, Sameena, additional, Lines, Matthew A., additional, García Cazorla, M. Ángeles, additional, Ribes, Antonia, additional, Morava, Eva, additional, Bibi, Farah, additional, Haider, Shahzad, additional, Ferla, Matteo P., additional, Taylor, Jenny C., additional, Alsaif, Hessa S., additional, Firdous, Abdulwahab, additional, Hashem, Mais, additional, Shashkin, Chingiz, additional, Koneev, Kairgali, additional, Kaiyrzhanov, Rauan, additional, Efthymiou, Stephanie, additional, Genomics, Queen Square, additional, Schmitt‐Mechelke, Thomas, additional, Ziegler, Andreas, additional, Issa, Mahmoud Y., additional, Elbendary, Hasnaa M., additional, Striano, Pasquale, additional, Alkuraya, Fowzan S., additional, Zaki, Maha S., additional, Gleeson, Joseph G., additional, Barakat, Tahsin Stefan, additional, Bierau, Jorgen, additional, Knaap, Marjo S., additional, Maroofian, Reza, additional, and Houlden, Henry, additional

Published
2022
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26. Detailed Biochemical and Bioenergetic Characterization of FBXL4-Related Encephalomyopathic Mitochondrial DNA Depletion

Author

Antoun, Ghadi, primary, McBride, Skye, additional, Vanstone, Jason R., additional, Naas, Turaya, additional, Michaud, Jean, additional, Redpath, Stephanie, additional, McMillan, Hugh J., additional, Brophy, Jason, additional, Daoud, Hussein, additional, Chakraborty, Pranesh, additional, Dyment, David, additional, Holcik, Martin, additional, Harper, Mary-Ellen, additional, and Lines, Matthew A., additional

Published
2015
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27. Congenital sucrase-isomaltase deficiency: identification of a common Inuit founder mutation

Author

Marcadier, Julien L., Boland, Margaret, Scott, C. Ronald, Issa, Kheirie, Wu, Zaining, McIntyre, Adam D., Hegele, Robert A., Geraghty, Michael T., and Lines, Matthew A.

Subjects
Gene mutations -- Identification and classification, Deficiency diseases -- Genetic aspects, Hydrolases -- Properties, Enzymes -- Properties, Health
Abstract

Background: Congenital sucrase-isomaltase deficiency is a rare hereditary cause of chronic diarrhea in children. People with this condition lack the intestinal brush-border enzyme required for digestion of di- and oligosaccharides, including sucrose and isomaltose, leading to malabsorption. Although the condition is known to be highly prevalent (about 5%-10%) in several Inuit populations, the genetic basis for this has not been described. We sought to identify a common mutation for congenital sucrase-isomaltase deficiency in the Inuit population. Methods: We sequenced the sucrase-isomaltase gene, SI, in a single Inuit proband with congenital sucrase-isomaltase deficiency who had severe fermentative diarrhea and failure to thrive. We then genotyped a further 128 anonymized Inuit controls from a variety of locales in the Canadian Arctic to assess for a possible founder effect. Results: In the proband, we identified a novel, homozygous frameshift mutation, c.273_274delAG (p.Gly92Leufs*8), predicted to result in complete absence of a functional protein product. This change was very common among the Inuit controls, with an observed allele frequency of 17.2% (95% confidence interval [CI] 12.6%-21.8%). The predicted Hardy-Weinberg prevalence of congenital sucrase-isomaltase deficiency in Inuit people, based on this single founder allele, is 3.0% (95% CI 1.4%-4.5%), which is comparable with previous estimates. Interpretation: We found a common mutation, SI c.273_274delAG, to be responsible for the high prevalence of congenital sucrase-isomaltase deficiency among Inuit people. Targeted mutation testing for this allele should afford a simple and minimally invasive means of diagnosing this condition in Inuit patients with chronic diarrhea., Congenital sucrase-isomaltase deficiency (Online Mendelian Inheritance in Man database no. #222900; www.omim.org /entry/222900) is a rare autosomal recessive form of carbohydrate malabsorption caused by reduced or absent activity of sucrase-isomaltase, [...]

Published
2015
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30. Phenotypic spectrum of the recurrent TRPM3 p.(Val837Met) substitution in seven individuals with global developmental delay and hypotonia.

Author

Lines, Matthew A., Goldenberg, Paula, Wong, Ashley, Srivastava, Siddharth, Bayat, Allan, Hove, Hanne, Karstensen, Helena Gásdal, Anyane‐Yeboa, Kwame, Liao, Jun, Jiang, Nan, May, Alison, Guzman, Edwin, Morleo, Manuela, D'Arrigo, Stefano, Ciaccio, Claudia, Pantaleoni, Chiara, Castello, Raffaele, McKee, Shane, Ong, Jinfon, and Zibdeh‐Lough, Hana

Abstract

TRPM3 encodes a transient receptor potential cation channel of the melastatin family, expressed in the central nervous system and in peripheral sensory neurons of the dorsal root ganglia. The recurrent substitution in TRPM3: c.2509G>A, p.(Val837Met) has been associated with syndromic intellectual disability and seizures. In this report, we present the clinical and molecular features of seven previously unreported individuals, identified by exome sequencing, with the recurrent p.(Val837Met) variant and global developmental delay. Other shared clinical features included congenital hypotonia, dysmorphic facial features (broad forehead, deep‐set eyes, and down turned mouth), exotropia, and musculoskeletal issues (hip dysplasia, hip dislocation, scoliosis). Seizures were observed in two of seven individuals (febrile seizure in one and generalized tonic–clonic seizures with atonic drops in another), and epileptiform activity was observed in an additional two individuals. This report extends the number of affected individuals to 16 who are heterozygous for the de novo recurrent substitution p.(Val837Met). In contrast with the initial report, epilepsy was not a mandatory feature observed in this series. TRPM3 pathogenic variation should be considered in individuals with global developmental delays, moderate–severe intellectual disability with, or without, childhood‐onset epilepsy. [ABSTRACT FROM AUTHOR]

Published
2022
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33. Danon Disease Due to a Novel LAMP2 Microduplication

Author

Lines, Matthew A., primary, Hewson, Stacy, additional, Halliday, William, additional, Sabatini, Peter J. B., additional, Stockley, Tracy, additional, Dipchand, Anne I., additional, Bowdin, Sarah, additional, and Siriwardena, Komudi, additional

Published
2013
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35. Mutation in Eftud2 causes craniofacial defects in mice via mis-splicing of Mdm2 and increased P53

Author

Beauchamp, Marie-Claude, primary, Djedid, Anissa, additional, Bareke, Eric, additional, Merkuri, Fjodor, additional, Aber, Rachel, additional, Tam, Annie S, additional, Lines, Matthew A, additional, Boycott, Kym M, additional, Stirling, Peter C, additional, Fish, Jennifer L, additional, Majewski, Jacek, additional, and Jerome-Majewska, Loydie A, additional

Published
2021
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37. Mis-splicing ofMdm2leads to Increased P53-Activity and Craniofacial Defects in a MFDMEftud2Mutant Mouse Model

Author

Beauchamp, Marie-Claude, primary, Djedid, Anissa, additional, Bareke, Eric, additional, Merkuri, Fjodor, additional, Aber, Rachel, additional, Tam, Annie S., additional, Lines, Matthew A., additional, Boycott, Kym M., additional, Stirling, Peter C., additional, Fish, Jennifer L., additional, Majewski, Jacek, additional, and Jerome-Majewska, Loydie A., additional

Published
2020
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39. De novo substitutions of TRPM3 cause intellectual disability and epilepsy

Author

Genetica Klinische Genetica, Child Health, Genetica Sectie Genoomdiagnostiek, Dyment, David A., Terhal, Paulien A., Rustad, Cecilie F., Tveten, Kristian, Griffith, Christopher, Jayakar, Parul, Shinawi, Marwan, Ellingwood, Sara, Smith, Rosemarie, van Gassen, Koen, McWalter, Kirsty, Innes, A. Micheil, Lines, Matthew A., Genetica Klinische Genetica, Child Health, Genetica Sectie Genoomdiagnostiek, Dyment, David A., Terhal, Paulien A., Rustad, Cecilie F., Tveten, Kristian, Griffith, Christopher, Jayakar, Parul, Shinawi, Marwan, Ellingwood, Sara, Smith, Rosemarie, van Gassen, Koen, McWalter, Kirsty, Innes, A. Micheil, and Lines, Matthew A.

Published
2019

44. Autosomal dominant transmission of transient neonatal lactic acidosis: a case report.

Author

Mardian, Emily B., Lines, Matthew A., Moore, Gregory P., and Care4Rare Consortium

Subjects
LACTIC acidosis, BLOOD lactate, PYRUVATE carboxylase, MITOCHONDRIAL pathology, GENETIC disorders, INBORN errors of metabolism, NEWBORN infants, HYPERLACTATEMIA
Abstract

Background: Lactic acidosis is a common finding in neonates, in whom mitochondrial dysfunction is often secondary to tissue hypoperfusion, respiratory failure, and/or sepsis. Primary (non-physiological) lactic acidosis is comparatively rare, and suggests the presence of an inborn error of mitochondrial energy metabolism. Optimal medical management and accurate prognostication requires the correct determination of the etiology of lactic acidosis in a given patient. Unfortunately, genetic diagnoses are rare and highly variable for neonates presenting with primary lactic acidosis; individual case reports may offer the most promise for treatment considerations. The mitochondrion is a complex molecular machine incorporating the products of > 1000 distinct nuclear genes. Primary lactic acidoses are therefore characterized by high genetic heterogeneity and a specific genetic diagnosis currently remains out of reach in most cases. Most mitochondriopathies with neonatal onset follow autosomal recessive inheritance and carry a poor prognosis. Here we detail the case of a father and daughter with dominantly-inherited, resolving (i.e. transient) neonatal hyperlactatemia due to complex IV deficiency. We found no other published descriptions of benign transient complex IV deficiency with autosomal dominant inheritance.Case Presentation: Both individuals presented as neonates with unexplained, marked lactic acidosis suggesting a primary mitochondrial disorder. Within the first weeks of life, elevated blood lactate levels normalized. Their clinical and developmental outcomes were normal. Biochemical studies in the proband showed multiple abnormalities consistent with a complex IV respiratory chain defect. Cultured skin fibroblasts showed an elevated lactate-to-pyruvate ratio, deficient complex IV activity, and normal pyruvate dehydrogenase and pyruvate carboxylase activities. Whole-exome sequencing of the proband and both parents did not identify a causative mutation.Conclusion: We conclude that the proband and her father appear to have a dominant form of transient neonatal hyperlactatemia due to heterozygous changes in an as-yet unidentified gene. This transient neonatal complex IV deficiency should be considered in the differential diagnosis of primary neonatal hyperlactatemia; notable clinical features include autosomal-dominant inheritance and an apparently benign postnatal course. This report exemplifies the growing differential diagnosis for neonatal lactic acidosis and highlights the importance of both physician counselling and the use of family history in communicating with parents. [ABSTRACT FROM AUTHOR]

Published
2020
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46. FARS2 deficiency; new cases, review of clinical, biochemical, and molecular spectra, and variants interpretation based on structural, functional, and evolutionary significance

Author

Almannai, Mohammed, primary, Wang, Julia, additional, Dai, Hongzheng, additional, El-Hattab, Ayman W., additional, Faqeih, Eissa A., additional, Saleh, Mohammed A., additional, Al Asmari, Ali, additional, Alwadei, Ali H., additional, Aljadhai, Yaser I., additional, AlHashem, Amal, additional, Tabarki, Brahim, additional, Lines, Matthew A., additional, Grange, Dorothy K., additional, Benini, Ruba, additional, Alsaman, Abdulaziz S., additional, Mahmoud, Adel, additional, Katsonis, Panagiotis, additional, Lichtarge, Olivier, additional, and Wong, Lee-Jun C., additional

Published
2018
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47. Further delineation of the clinical spectrum of de novo TRIM8 truncating mutations

Author

Assoum, Mirna, primary, Lines, Matthew A., additional, Elpeleg, Orly, additional, Darmency, Véronique, additional, Whiting, Sharon, additional, Edvardson, Simon, additional, Devinsky, Orrin, additional, Heinzen, Erin, additional, Hernan, Rebecca Rose, additional, Antignac, Corinne, additional, Deleuze, Jean‐François, additional, Des Portes, Vincent, additional, Bertholet‐Thomas, Aurélie, additional, Belot, Alexandre, additional, Geller, Eric, additional, Lemesle, Martine, additional, Duffourd, Yannis, additional, Thauvin‐Robinet, Christel, additional, Thevenon, Julien, additional, Chung, Wendy, additional, Lowenstein, Daniel H., additional, and Faivre, Laurence, additional

Published
2018
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48. Diagnostic clarity of exome sequencing following negative comprehensive panel testing in the neonatal intensive care unit

Author

Kernohan, Kristin D., primary, Hartley, Taila, additional, Naumenko, Sergey, additional, Armour, Christine M., additional, Graham, Gail E., additional, Nikkel, Sarah M., additional, Lines, Matthew, additional, Geraghty, Michael T., additional, Richer, Julie, additional, Mears, Wendy, additional, Boycott, Kym M., additional, and Dyment, David A., additional

Published
2018
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49. Disturbed phospholipid metabolism in serine biosynthesis defects revealed by metabolomic profiling

Author

Glinton, Kevin E., primary, Benke, Paul J., additional, Lines, Matthew A., additional, Geraghty, Michael T., additional, Chakraborty, Pranesh, additional, Al-Dirbashi, Osama Y., additional, Jiang, Yi, additional, Kennedy, Adam D., additional, Grotewiel, Michael S., additional, Sutton, V. Reid, additional, Elsea, Sarah H., additional, and El-Hattab, Ayman W., additional

Published
2018
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50. Additional file 1: Figure S1. of Impaired activity of CCA-adding enzyme TRNT1 impacts OXPHOS complexes and cellular respiration in SIFD patient-derived fibroblasts

Author

Liwak-Muir, Urszula, Hapsatou Mamady, Turaya Naas, Quinlan Wylie, McBride, Skye, Lines, Matthew, Michaud, Jean, Baird, Stephen, Pranesh Chakraborty, and Holcik, Martin

Abstract

Immunofluorescent imaging of mitochondrial network in fibroblast cells. (Left) Nuclei are identified by Hoechst stain (red) and mitochondria are stained with an anti-Tom20 antibody (green). Representative images are shown. (Right) The mitochondria segment length was calculated as the pixel distance from between either the end of a mitochondria or a branch point or the crossing over of another mitochondria and is averaged for each cell using a custom Acapella script run in the Columbus software. From 100 to 200 cells were measured per well and averaged over 14 wells for three separate experiments. Figure S2. Electron microscopy images of additional control fibroblasts. The red box identifies the area enlarged on the right. Figure S3. Additional control fibroblasts for membrane potential assessment. Shown are immunofluorescence images of the mitochondrial membrane potential as monitored by the incorporation of the TMRE dye (red) and compared to the total mitochondrial stain as measured by MitoTracker (green). Nuclei are identified by Hoechst stain (blue).Figure S4. (A) Oxygen consumption rate (OCR) of three control fibroblasts as measured by micro-oximetry analysis. (B) Densitometry of western blot analysis of 5 OXPHOS proteins. The band intensities were determined using ImageJ software. The intensity of each band is shown relative to total protein (ns = not significant; * = p < 0.05; ** = p

Published
2016
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