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1. EMILIN1 deficiency causes arterial tortuosity with osteopenia and connects impaired elastogenesis with defective collagen fibrillogenesis.

Author

Adamo, Christin S, Beyens, Aude, Schiavinato, Alvise, Keene, Douglas R, Tufa, Sara F, Mörgelin, Matthias, Brinckmann, Jürgen, Sasaki, Takako, Niehoff, Anja, Dreiner, Maren, Pottie, Lore, Muiño-Mosquera, Laura, Gulec, Elif Yilmaz, Gezdirici, Alper, Braghetta, Paola, Bonaldo, Paolo, Wagener, Raimund, Paulsson, Mats, Bornaun, Helen, De Rycke, Riet, De Bruyne, Michiel, Baeke, Femke, Devine, Walter P, Gangaram, Balram, Tam, Allison, Balasubramanian, Meena, Ellard, Sian, Moore, Sandra, Symoens, Sofie, Shen, Joseph, Cole, Stacey, Schwarze, Ulrike, Holmes, Kathryn W, Hayflick, Susan J, Wiszniewski, Wojciech, Nampoothiri, Sheela, Davis, Elaine C, Sakai, Lynn Y, Sengle, Gerhard, and Callewaert, Bert

Subjects
Animals, Humans, Mice, Bone Diseases, Metabolic, Cutis Laxa, Collagen, Elastin, Extracellular Matrix Proteins, EFEMP2, EMILIN1, LOX, aortic aneurysm, arterial tortuosity, collagen, cutis laxa, elastic fiber, extracellular matrix, fracture, Rare Diseases, Pediatric, Congenital Structural Anomalies, 1.1 Normal biological development and functioning, 2.1 Biological and endogenous factors, Underpinning research, Aetiology, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract

EMILIN1 (elastin-microfibril-interface-located-protein-1) is a structural component of the elastic fiber network and localizes to the interface between the fibrillin microfibril scaffold and the elastin core. How EMILIN1 contributes to connective tissue integrity is not fully understood. Here, we report bi-allelic EMILIN1 loss-of-function variants causative for an entity combining cutis laxa, arterial tortuosity, aneurysm formation, and bone fragility, resembling autosomal-recessive cutis laxa type 1B, due to EFEMP2 (FBLN4) deficiency. In both humans and mice, absence of EMILIN1 impairs EFEMP2 extracellular matrix deposition and LOX activity resulting in impaired elastogenesis, reduced collagen crosslinking, and aberrant growth factor signaling. Collagen fiber ultrastructure and histopathology in EMILIN1- or EFEMP2-deficient skin and aorta corroborate these findings and murine Emilin1-/- femora show abnormal trabecular bone formation and strength. Altogether, EMILIN1 connects elastic fiber network with collagen fibril formation, relevant for both bone and vascular tissue homeostasis.

Published
2022

2. Pantothenate kinase 2 interacts with PINK1 to regulate mitochondrial quality control via acetyl-CoA metabolism.

Author

Huang, Yunpeng, Wan, Zhihui, Tang, Yinglu, Xu, Junxuan, Laboret, Bretton, Nallamothu, Sree, Yang, Chenyu, Liu, Boxiang, Lu, Rongze, Lu, Bingwei, Feng, Juan, Cao, Jing, Hayflick, Susan, Wu, Zhihao, and Zhou, Bing

Subjects
Acetyl Coenzyme A, Animals, Drosophila, Drosophila Proteins, Mitochondria, Neurodegenerative Diseases, Parkinson Disease, Phosphotransferases (Alcohol Group Acceptor), Protein Kinases, Protein Serine-Threonine Kinases
Abstract

Human neurodegenerative disorders often exhibit similar pathologies, suggesting a shared aetiology. Key pathological features of Parkinsons disease (PD) are also observed in other neurodegenerative diseases. Pantothenate Kinase-Associated Neurodegeneration (PKAN) is caused by mutations in the human PANK2 gene, which catalyzes the initial step of de novo CoA synthesis. Here, we show that fumble (fbl), the human PANK2 homolog in Drosophila, interacts with PINK1 genetically. fbl and PINK1 mutants display similar mitochondrial abnormalities, and overexpression of mitochondrial Fbl rescues PINK1 loss-of-function (LOF) defects. Dietary vitamin B5 derivatives effectively rescue CoA/acetyl-CoA levels and mitochondrial function, reversing the PINK1 deficiency phenotype. Mechanistically, Fbl regulates Ref(2)P (p62/SQSTM1 homolog) by acetylation to promote mitophagy, whereas PINK1 regulates fbl translation by anchoring mRNA molecules to the outer mitochondrial membrane. In conclusion, Fbl (or PANK2) acts downstream of PINK1, regulating CoA/acetyl-CoA metabolism to promote mitophagy, uncovering a potential therapeutic intervention strategy in PD treatment.

Published
2022

5. Clinical implementation of RNA sequencing for Mendelian disease diagnostics

Author

Yépez, Vicente A., Gusic, Mirjana, Kopajtich, Robert, Mertes, Christian, Smith, Nicholas H., Alston, Charlotte L., Ban, Rui, Beblo, Skadi, Berutti, Riccardo, Blessing, Holger, Ciara, Elżbieta, Distelmaier, Felix, Freisinger, Peter, Häberle, Johannes, Hayflick, Susan J., Hempel, Maja, Itkis, Yulia S., Kishita, Yoshihito, Klopstock, Thomas, Krylova, Tatiana D., Lamperti, Costanza, Lenz, Dominic, Makowski, Christine, Mosegaard, Signe, Müller, Michaela F., Muñoz-Pujol, Gerard, Nadel, Agnieszka, Ohtake, Akira, Okazaki, Yasushi, Procopio, Elena, Schwarzmayr, Thomas, Smet, Joél, Staufner, Christian, Stenton, Sarah L., Strom, Tim M., Terrile, Caterina, Tort, Frederic, Van Coster, Rudy, Vanlander, Arnaud, Wagner, Matias, Xu, Manting, Fang, Fang, Ghezzi, Daniele, Mayr, Johannes A., Piekutowska-Abramczuk, Dorota, Ribes, Antonia, Rötig, Agnès, Taylor, Robert W., Wortmann, Saskia B., Murayama, Kei, Meitinger, Thomas, Gagneur, Julien, and Prokisch, Holger

Published
2022
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6. Safety and efficacy of deferiprone for pantothenate kinase-associated neurodegeneration: a randomised, double-blind, controlled trial and an open-label extension study

Author

Klopstock, Thomas, Tricta, Fernando, Neumayr, Lynne, Karin, Ivan, Zorzi, Giovanna, Fradette, Caroline, Kmieć, Tomasz, Büchner, Boriana, Steele, Hannah E, Horvath, Rita, Chinnery, Patrick F, Basu, Anna, Küpper, Clemens, Neuhofer, Christiane, Kálmán, Bernadette, Dušek, Petr, Yapici, Zuhal, Wilson, Ian, Zhao, Feng, Zibordi, Federica, Nardocci, Nardo, Aguilar, Christine, Hayflick, Susan J, Spino, Michael, Blamire, Andrew M, Hogarth, Penelope, and Vichinsky, Elliott

Published
2019
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7. Cardiac glycosides restore autophagy flux in an iPSC-derived neuronal model of WDR45 deficiency

Author

Papandreou, Apostolos, primary, Singh, Nivedita, additional, Gianfrancesco, Lorita, additional, Budinger, Dimitri, additional, Barwick, Katy, additional, Agrotis, Alexander, additional, Luft, Christin, additional, Shao, Ying, additional, Lenaerts, An-Sofie, additional, Gregory, Allison, additional, Jeong, Suh Young, additional, Hogarth, Penelope, additional, Hayflick, Susan, additional, Barral, Serena, additional, Kriston-Vizi, Janos, additional, Gissen, Paul, additional, Kurian, Manju A, additional, and Ketteler, Robin, additional

Published
2024
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8. Emerging variants, unique phenotypes, and transcriptomic signatures: an integrated study of COASY‐associated diseases.

Author

Cavestro, Chiara, Morra, Francesca, Legati, Andrea, D'Amato, Marco, Nasca, Alessia, Iuso, Arcangela, Lubarr, Naomi, Morrison, Jennifer L., Wheeler, Patricia G., Serra‐Juhé, Clara, Rodríguez‐Santiago, Benjamín, Turón‐Viñas, Eulalia, Prouteau, Clement, Barth, Magalie, Hayflick, Susan J., Ghezzi, Daniele, Tiranti, Valeria, and Di Meo, Ivano

Subjects
PHENOTYPES, EPILEPSY, CELL communication, COENZYME A, AUTISM spectrum disorders, TRANSCRIPTOMES
Abstract

Objective: COASY, the gene encoding the bifunctional enzyme CoA synthase, which catalyzes the last two reactions of cellular de novo coenzyme A (CoA) biosynthesis, has been linked to two exceedingly rare autosomal recessive disorders, such as COASY protein‐associated neurodegeneration (CoPAN), a form of neurodegeneration with brain iron accumulation (NBIA), and pontocerebellar hypoplasia type 12 (PCH12). We aimed to expand the phenotypic spectrum and gain insights into the pathogenesis of COASY‐related disorders. Methods: Patients were identified through targeted or exome sequencing. To unravel the molecular mechanisms of disease, RNA sequencing, bioenergetic analysis, and quantification of critical proteins were performed on fibroblasts. Results: We identified five new individuals harboring novel COASY variants. While one case exhibited classical CoPAN features, the others displayed atypical symptoms such as deafness, language and autism spectrum disorders, brain atrophy, and microcephaly. All patients experienced epilepsy, highlighting its potential frequency in COASY‐related disorders. Fibroblast transcriptomic profiling unveiled dysregulated expression in genes associated with mitochondrial respiration, responses to oxidative stress, transmembrane transport, various cellular signaling pathways, and protein translation, modification, and trafficking. Bioenergetic analysis revealed impaired mitochondrial oxygen consumption in COASY fibroblasts. Despite comparable total CoA levels to control cells, the amounts of mitochondrial 4′‐phosphopantetheinylated proteins were significantly reduced in COASY patients. Interpretation: These results not only extend the clinical phenotype associated with COASY variants but also suggest a continuum between CoPAN and PCH12. The intricate interplay of altered cellular processes and signaling pathways provides valuable insights for further research into the pathogenesis of COASY‐associated diseases. [ABSTRACT FROM AUTHOR]

Published
2024
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10. Cardiac glycosides restore autophagy flux in an iPSC-derived neuronal model of WDR45 deficiency

Author

Papandreou, Apostolos, primary, Singh, Nivedita, additional, Gianfrancesco, Lorita, additional, Budinger, Dimitri, additional, Barwick, Katy, additional, Agrotis, Alexander, additional, Luft, Christin, additional, Shao, Ying, additional, Lenaerts, An-Sofie, additional, Gregory, Allison, additional, Jeong, Suh Young, additional, Hogarth, Penelope, additional, Hayflick, Susan, additional, Barral, Serena, additional, Kriston-Vizi, Janos, additional, Gissen, Paul, additional, Kurian, Manju A. A, additional, and Ketteler, Robin, additional

Published
2023
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11. A burning question from the first international BPAN symposium: is restoration of autophagy a promising therapeutic strategy for BPAN?

Author

Mollereau, Bertrand, primary, Hayflick, Susan J, additional, Escalante, Ricardo, additional, Mauthe, Mario, additional, Papandreou, Apostolos, additional, Iuso, Arcangela, additional, Celle, Marion, additional, Aniorte, Sahra, additional, Issa, Abdul Raouf, additional, Lasserre, Jean Paul, additional, Lesca, Gaetan, additional, Thobois, Stéphane, additional, Burger, Pauline, additional, and Walter, Ludivine, additional

Published
2023
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16. MECR Mutations Cause Childhood-Onset Dystonia and Optic Atrophy, a Mitochondrial Fatty Acid Synthesis Disorder

Author

Bamshad, Michael J., Leal, Suzanne M., Nickerson, Deborah A., Anderson, Peter, Annable, Marcus, Blue, Elizabeth Marchani, Buckingham, Kati J., Chin, Jennifer, Chong, Jessica X., Cornejo, Rodolfo, Jr., Davis, Colleen P., Frazar, Christopher, He, Zongxiao, Jarvik, Gail P., Jimenez, Guillaume, Johanson, Eric, Kolar, Tom, Krauter, Stephanie A., Luksic, Daniel, Marvin, Colby T., McGee, Sean, McGoldrick, Daniel J., Patterson, Karynne, Perez, Marcos, Phillips, Sam W., Pijoan, Jessica, Robertson, Peggy D., Santos-Cortez, Regie, Shankar, Aditi, Slattery, Krystal, Shively, Kathryn M., Siegel, Deborah L., Smith, Joshua D., Tackett, Monica, Wang, Gao, Wegener, Marc, Weiss, Jeffrey M., Wernick, Riana I., Wheeler, Marsha M., Yi, Qian, Heimer, Gali, Kerätär, Juha M., Riley, Lisa G., Balasubramaniam, Shanti, Eyal, Eran, Pietikäinen, Laura P., Hiltunen, J. Kalervo, Marek-Yagel, Dina, Hamada, Jeffrey, Gregory, Allison, Rogers, Caleb, Hogarth, Penelope, Nance, Martha A., Shalva, Nechama, Veber, Alvit, Tzadok, Michal, Nissenkorn, Andreea, Tonduti, Davide, Renaldo, Florence, Kraoua, Ichraf, Panteghini, Celeste, Valletta, Lorella, Garavaglia, Barbara, Cowley, Mark J., Gayevskiy, Velimir, Roscioli, Tony, Silberstein, Jonathon M., Hoffmann, Chen, Raas-Rothschild, Annick, Tiranti, Valeria, Anikster, Yair, Christodoulou, John, Kastaniotis, Alexander J., Ben-Zeev, Bruria, and Hayflick, Susan J.

Published
2016
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17. 4′‐Phosphopantetheine corrects CoA, iron, and dopamine metabolic defects in mammalian models of PKAN

Author

Jeong, Suh Young, Hogarth, Penelope, Placzek, Andrew, Gregory, Allison M, Fox, Rachel, Zhen, Dolly, Hamada, Jeffrey, van der Zwaag, Marianne, Lambrechts, Roald, Jin, Haihong, Nilsen, Aaron, Cobb, Jared, Pham, Thao, Gray, Nora, Ralle, Martina, Duffy, Megan, Schwanemann, Leila, Rai, Puneet, Freed, Alison, Wakeman, Katrina, Woltjer, Randall L, Sibon, Ody CM, and Hayflick, Susan J

Published
2019
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19. A burning question from the first international BPAN symposium: is restoration of autophagy a promising therapeutic strategy for BPAN?

Author

Fondation Groupam, European Commission, Ministerio de Ciencia e Innovación (España), Agencia Estatal de Investigación (España), Mollereau, Bertrand, Hayflick, Susan J., Escalante, Ricardo, Mauthe, Mario, Papandreou, Apostolos, Luso, Arcangela, Celle, Marion, Aniorte, Sahra, Raouf Issa, Abdul, Lasserre, Jean Paul, Lesca, Gaetan, Thobois, Stéphane, Burger, Pauline, Fondation Groupam, European Commission, Ministerio de Ciencia e Innovación (España), Agencia Estatal de Investigación (España), Mollereau, Bertrand, Hayflick, Susan J., Escalante, Ricardo, Mauthe, Mario, Papandreou, Apostolos, Luso, Arcangela, Celle, Marion, Aniorte, Sahra, Raouf Issa, Abdul, Lasserre, Jean Paul, Lesca, Gaetan, Thobois, Stéphane, and Burger, Pauline

Abstract

Beta-propeller protein-associated neurodegeneration (BPAN) is a rare neurodegenerative disease associated with severe cognitive and motor deficits. BPAN pathophysiology and phenotypic spectrum are still emerging due to the fact that mutations in the WDR45 (WD repeat domain 45) gene, a regulator of macroautophagy/autophagy, were only identified a decade ago. In the first international symposium dedicated to BPAN, which was held in Lyon, France, a panel of international speakers, including several researchers from the autophagy community, presented their work on human patients, cellular and animal models, carrying WDR45 mutations and their homologs. Autophagy researchers found an opportunity to explore the defective function of autophagy mechanisms associated with WDR45 mutations, which underlie neuronal dysfunction and early death. Importantly, BPAN is one of the few human monogenic neurological diseases targeting a regulator of autophagy, which raises the possibility that it is a relevant model to directly assess the roles of autophagy in neurodegeneration and to develop autophagy restorative therapeutic strategies for more common disorders.

Published
2023

25. Exome Sequence Reveals Mutations in CoA Synthase as a Cause of Neurodegeneration with Brain Iron Accumulation

Author

Dusi, Sabrina, Valletta, Lorella, Haack, Tobias B., Tsuchiya, Yugo, Venco, Paola, Pasqualato, Sebastiano, Goffrini, Paola, Tigano, Marco, Demchenko, Nikita, Wieland, Thomas, Schwarzmayr, Thomas, Strom, Tim M., Invernizzi, Federica, Garavaglia, Barbara, Gregory, Allison, Sanford, Lynn, Hamada, Jeffrey, Bettencourt, Conceição, Houlden, Henry, Chiapparini, Luisa, Zorzi, Giovanna, Kurian, Manju A., Nardocci, Nardo, Prokisch, Holger, Hayflick, Susan, Gout, Ivan, and Tiranti, Valeria

Published
2014
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27. Copy Number Variation Analysis in 98 Individuals with PHACE Syndrome

Author

Siegel, Dawn H., Shieh, Joseph T.C., Kwon, Eun-kyung, Baselga, Eulalia, Blei, Francine, Cordisco, Maria, Dobyns, William B., Duffy, Kelly J., Garzon, Maria C., Gibbs, David L., Grimmer, Johannes F., Hayflick, Susan J., Krol, Alfons L., Kwok, Pui-Yan, Lorier, Rachel, Matter, Andrea, McWeeney, Shannon, Metry, Denise, Mitchell, Sheri, Pope, Elena, Santoro, Jennifer L., Stevenson, David A., Bayrak-Toydemir, Pinar, Wilmot, Beth, Worthey, Elizabeth A., Frieden, Ilona J., Drolet, Beth A., and Broeckel, Ulrich

Published
2013
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30. EMILIN1 deficiency causes arterial tortuosity with osteopenia and connects impaired elastogenesis with defective collagen fibrillogenesis

Author

Adamo, Christin S., Beyens, Aude, Schiavinato, Alvise, Keene, Douglas R., Tufa, Sara F., Morgelin, Matthias, Brinckmann, Jurgen, Sasaki, Takako, Niehoff, Anja, Dreiner, Maren, Pottie, Lore, Muino-Mosquera, Laura, Gulec, Elif Yilmaz, Gezdirici, Alper, Braghetta, Paola, Bonaldo, Paolo, Wagener, Raimund, Paulsson, Mats, Bornaun, Helen, De Rycke, Riet, De Bruyne, Michiel, Baeke, Femke, Devine, Walter P., Gangaram, Balram, Tam, Allison, Balasubramanian, Meena, Ellard, Sian, Moore, Sandra, Symoens, Sofie, Shen, Joseph, Cole, Stacey, Schwarze, Ulrike, Holmes, Kathryn W., Hayflick, Susan J., Wiszniewski, Wojciech, Nampoothiri, Sheela, Davis, Elaine C., Sakai, Lynn Y., Sengle, Gerhard, Callewaert, Bert, Adamo, Christin S., Beyens, Aude, Schiavinato, Alvise, Keene, Douglas R., Tufa, Sara F., Morgelin, Matthias, Brinckmann, Jurgen, Sasaki, Takako, Niehoff, Anja, Dreiner, Maren, Pottie, Lore, Muino-Mosquera, Laura, Gulec, Elif Yilmaz, Gezdirici, Alper, Braghetta, Paola, Bonaldo, Paolo, Wagener, Raimund, Paulsson, Mats, Bornaun, Helen, De Rycke, Riet, De Bruyne, Michiel, Baeke, Femke, Devine, Walter P., Gangaram, Balram, Tam, Allison, Balasubramanian, Meena, Ellard, Sian, Moore, Sandra, Symoens, Sofie, Shen, Joseph, Cole, Stacey, Schwarze, Ulrike, Holmes, Kathryn W., Hayflick, Susan J., Wiszniewski, Wojciech, Nampoothiri, Sheela, Davis, Elaine C., Sakai, Lynn Y., Sengle, Gerhard, and Callewaert, Bert

Abstract

EMILIN1 (elastin-microfibril-interface-located-protein-1) is a structural component of the elastic fiber network and localizes to the inter-face between the fibrillin microfibril scaffold and the elastin core. How EMILIN1 contributes to connective tissue integrity is not fully understood. Here, we report bi-allelic EMILIN1 loss-of-function variants causative for an entity combining cutis laxa, arterial tortuosity, aneurysm formation, and bone fragility, resembling autosomal-recessive cutis laxa type 1B, due to EFEMP2 (FBLN4) deficiency. In both humans and mice, absence of EMILIN1 impairs EFEMP2 extracellular matrix deposition and LOX activity resulting in impaired elasto-genesis, reduced collagen crosslinking, and aberrant growth factor signaling. Collagen fiber ultrastructure and histopathology in EMILIN1-or EFEMP2-deficient skin and aorta corroborate these findings and murine Emilin1-/- femora show abnormal trabecular bone formation and strength. Altogether, EMILIN1 connects elastic fiber network with collagen fibril formation, relevant for both bone and vascular tissue homeostasis.

Published
2022

31. Therapeutics development for pantothenate kinase-associated neurodegeneration (PKAN)

Author

Hayflick, Susan and Hayflick, Susan

Abstract

Therapeutics Development for Pantothenate Kinase-Associated Neurodegeneration Lay summary For more than two decades, research has been underway to understand the biology of and develop treatments for PKAN, an ultra-rare genetic disease affecting children and adults. People with PKAN suffer from painful muscle spasms, stiffness, trouble controlling their movements, and blindness. The cause of PKAN is a mis-spelled gene that normally enables the body to use vitamin B5 to build other essential chemicals. Without a properly spelled gene, people with PKAN are unable to make those chemicals to preserve brain and eye health. Our work presented in this thesis has been focused on improving understanding of PKAN and the chemical pathways affected in this progressive disorder. We use that understanding to inspire new ideas to combat this chemical problem and potentially develop a treatment. Our work was provided hope for a way to bypass the PKAN problem, and we are currently focused on testing this idea in people with the disease.

Published
2022

32. Clinical implementation of RNA sequencing for Mendelian disease diagnostics

Author

Yépez, Vicente A, Gusic, Mirjana, Kopajtich, Robert, Mertes, Christian, Smith, Nicholas H, Alston, Charlotte L, Ban, Rui, Beblo, Skadi, Berutti, Riccardo, Blessing, Holger, Ciara, Elżbieta, Distelmaier, Felix, Freisinger, Peter, Häberle, Johannes; https://orcid.org/0000-0003-0635-091X, Hayflick, Susan J, Hempel, Maja, Itkis, Yulia S, Kishita, Yoshihito, Klopstock, Thomas; https://orcid.org/0000-0003-2805-4652, Krylova, Tatiana D, Lamperti, Costanza, Lenz, Dominic, Makowski, Christine, Mosegaard, Signe, Müller, Michaela F, Muñoz-Pujol, Gerard, Nadel, Agnieszka, Ohtake, Akira, Okazaki, Yasushi, Procopio, Elena, et al, Yépez, Vicente A, Gusic, Mirjana, Kopajtich, Robert, Mertes, Christian, Smith, Nicholas H, Alston, Charlotte L, Ban, Rui, Beblo, Skadi, Berutti, Riccardo, Blessing, Holger, Ciara, Elżbieta, Distelmaier, Felix, Freisinger, Peter, Häberle, Johannes; https://orcid.org/0000-0003-0635-091X, Hayflick, Susan J, Hempel, Maja, Itkis, Yulia S, Kishita, Yoshihito, Klopstock, Thomas; https://orcid.org/0000-0003-2805-4652, Krylova, Tatiana D, Lamperti, Costanza, Lenz, Dominic, Makowski, Christine, Mosegaard, Signe, Müller, Michaela F, Muñoz-Pujol, Gerard, Nadel, Agnieszka, Ohtake, Akira, Okazaki, Yasushi, Procopio, Elena, and et al

Abstract

BACKGROUND: Lack of functional evidence hampers variant interpretation, leaving a large proportion of individuals with a suspected Mendelian disorder without genetic diagnosis after whole genome or whole exome sequencing (WES). Research studies advocate to further sequence transcriptomes to directly and systematically probe gene expression defects. However, collection of additional biopsies and establishment of lab workflows, analytical pipelines, and defined concepts in clinical interpretation of aberrant gene expression are still needed for adopting RNA sequencing (RNA-seq) in routine diagnostics. METHODS: We implemented an automated RNA-seq protocol and a computational workflow with which we analyzed skin fibroblasts of 303 individuals with a suspected mitochondrial disease that previously underwent WES. We also assessed through simulations how aberrant expression and mono-allelic expression tests depend on RNA-seq coverage. RESULTS: We detected on average 12,500 genes per sample including around 60% of all disease genes-a coverage substantially higher than with whole blood, supporting the use of skin biopsies. We prioritized genes demonstrating aberrant expression, aberrant splicing, or mono-allelic expression. The pipeline required less than 1 week from sample preparation to result reporting and provided a median of eight disease-associated genes per patient for inspection. A genetic diagnosis was established for 16% of the 205 WES-inconclusive cases. Detection of aberrant expression was a major contributor to diagnosis including instances of 50% reduction, which, together with mono-allelic expression, allowed for the diagnosis of dominant disorders caused by haploinsufficiency. Moreover, calling aberrant splicing and variants from RNA-seq data enabled detecting and validating splice-disrupting variants, of which the majority fell outside WES-covered regions. CONCLUSION: Together, these results show that streamlined experimental and computational processes can

Published
2022

33. Additional file 2 of Clinical implementation of RNA sequencing for Mendelian disease diagnostics

Author

Yépez, Vicente A., Gusic, Mirjana, Kopajtich, Robert, Mertes, Christian, Smith, Nicholas H., Alston, Charlotte L., Ban, Rui, Beblo, Skadi, Berutti, Riccardo, Blessing, Holger, Ciara, Elżbieta, Distelmaier, Felix, Freisinger, Peter, Häberle, Johannes, Hayflick, Susan J., Hempel, Maja, Itkis, Yulia S., Kishita, Yoshihito, Klopstock, Thomas, Krylova, Tatiana D., Lamperti, Costanza, Lenz, Dominic, Makowski, Christine, Mosegaard, Signe, Müller, Michaela F., Muñoz-Pujol, Gerard, Nadel, Agnieszka, Ohtake, Akira, Okazaki, Yasushi, Procopio, Elena, Schwarzmayr, Thomas, Smet, Joél, Staufner, Christian, Stenton, Sarah L., Strom, Tim M., Terrile, Caterina, Tort, Frederic, Van Coster, Rudy, Vanlander, Arnaud, Wagner, Matias, Xu, Manting, Fang, Fang, Ghezzi, Daniele, Mayr, Johannes A., Piekutowska-Abramczuk, Dorota, Ribes, Antonia, Rötig, Agnès, Taylor, Robert W., Wortmann, Saskia B., Murayama, Kei, Meitinger, Thomas, Gagneur, Julien, and Prokisch, Holger

Subjects
parasitic diseases, population characteristics, geographic locations, health care economics and organizations
Abstract

Additional file 2: Fig. S1. Overview of the study. Fig. S2. Quality control. Fig. S3. DNA-RNA sample matching. Fig. S4. Aberrant events per sample. Fig. S5. Rare variants among expression outliers. Fig. S6. Power analysis of overexpression outliers. Fig. S7. Power analysis of underexpression outliers with respect to biological coefficient of variation. Fig. S8. Cases with many mtDNA expression outliers. Fig. S9. Rare variants among splicing outliers. Fig. S10. Splicing prediction algorithms evaluation. Fig. S11. Complex pattern of aberrant splicing. Fig. S12. Analysis of variants called by RNA-seq. Fig. S13. Rare variants leading to outliers. Fig. S14. Diagnostic rate across cohorts.

Published
2022
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35. Contributors

Author

Ajjuri, Rami R., primary, Ali, Yousuf, additional, Arena, Giuseppe, additional, Ashizawa, Tetsuo, additional, Auburger, Georg, additional, Bagchi, Devika P., additional, Baldo, Barbara, additional, Baxter, Sally L., additional, Berman, Robert F., additional, Binder, Lester I., additional, Blackstone, Craig, additional, Breda, Carlo, additional, Brotchie, Jonathan M., additional, Burton, Edward A., additional, Calderon, Diany Paola, additional, Caldwell, Guy A., additional, Caldwell, Kim A., additional, Cenci, M. Angela, additional, Chen, Jianmin, additional, Chesselet, Marie-Francoise, additional, Collins-Praino, Lyndsey E., additional, Colosimo, Carlo, additional, Combs, Benjamin, additional, Correa, Mercè, additional, D’Adamo, Maria Cristina, additional, Dai, Helena, additional, Datta, Debkanya, additional, DeAndrade, Mark P., additional, Dietrich, Paula, additional, Dragatsis, Ioannis, additional, Eidelberg, David, additional, El-Khamisy, Sherif F., additional, Evinger, Craig L., additional, Fassier, Coralie, additional, Figiel, Maciej, additional, Fox, Susan H., additional, Francardo, Veronica, additional, Freeman, Amanda A.H., additional, Frucht, Steven, additional, Gardiner, John, additional, Giasson, Benoit, additional, Giorgini, Flaviano, additional, Gispert, Suzana, additional, González-Cabo, Pilar, additional, Gradinaru, Viviana, additional, Hall, Marleshia, additional, Hama, Hiroko, additional, Handforth, Adrian, additional, Hayflick, Susan, additional, Hazan, Jamilé, additional, Hedera, Peter, additional, Heiman, Gary A., additional, Herrup, Karl, additional, Hess, Ellen J., additional, Hickey, Patrick, additional, Himmelstein, Diana S., additional, Hoekstra, Pieter J., additional, Houart, Corinne, additional, Hunsaker, Michael Ryan, additional, Iderberg, Hanna, additional, Jackson-Lewis, Vernic, additional, Jankovic, Joseph, additional, Jinnah, H.A., additional, Joensuu, Tarja, additional, Johnston, Tom M., additional, Josephs, Keith A., additional, Kanaan, Nicholas M., additional, Khodakhah, Kamran, additional, Kim, Kwang-Soo, additional, Klinker, F., additional, Kooner, Gurdeep S., additional, Kopra, Outi, additional, Kotzbauer, Paul T., additional, Kozina, Elena, additional, Krismer, Florian, additional, Krzyzosiak, Wlodzimierz J., additional, Kuruvilla, Korah P., additional, Kuzdas, Daniela, additional, Kyriacou, Charalambos P., additional, Leavitt, Blair R., additional, LeDoux, Mark S., additional, Lehesjoki, Anna-Elina, additional, Lester, Deranda, additional, Lewis, Jada, additional, Li, Jiali, additional, Liebetanz, D., additional, Lindgren, Hanna, additional, Mallucci, Giovanna R., additional, Mann, Amandeep, additional, Margolis, Russell L., additional, Mason, Robert P., additional, Mazarei, Gelareh, additional, McDonald, Michael P., additional, Melki, Judith, additional, Méneret, Aurélie, additional, Moscovich, Mariana, additional, Neuner, Irene, additional, O’Donnell, Janis M., additional, Oleas, Janneth, additional, Ondo, William G., additional, Opal, Puneet, additional, Orr, Harry T., additional, Ozdowski, Emily F., additional, Pandolfo, Massimo, additional, Paschou, Peristera, additional, Pascual, Juan M., additional, Patel, Amar, additional, Patel, Neepa, additional, Peres, João N., additional, Pessia, Mauro, additional, Petersén, Åsa, additional, Petrucci, Simona, additional, Pfeiffer, Ronald F., additional, Phielipp, Nicolás M., additional, Pienaar, Ilse Sanet, additional, Pittenger, Christopher, additional, Plummer, Mark R., additional, Podurgiel, Samantha, additional, Przedborski, Serge, additional, Puschmann, Andreas, additional, Reiter, Lawrence T., additional, Ren, Yan, additional, Renvoisé, Benoît, additional, Rose, Samuel J., additional, Ross, Owen A., additional, Roze, Emmanuel, additional, Ruan, Kai, additional, Rudnicki, Dobrila D., additional, Sahara, Naruhiko, additional, Sako, Wataru, additional, Salamone, John D., additional, Sanyal, Subhabrata, additional, Saunders, Thomas L., additional, Schneider, Susanne A., additional, Schulte, Eva C., additional, Schwartzer, Jared J., additional, Sherwood, Nina T., additional, Sibon, Ody, additional, Smeyne, Richard J., additional, Stacy, Mark, additional, Starr, Philip, additional, Staveley, Brian E., additional, Stefanova, Nadia, additional, Subramony, S.H., additional, Swann, Nicole, additional, Switonski, Pawel M., additional, Szlachcic, Wojciech J., additional, Tai, Kwok-Keung, additional, Tiranti, Valeria, additional, Truong, Daniel D., additional, Tyynismaa, Henna, additional, Uluğ, Aziz M., additional, Valente, Enza M., additional, Van Gerpen, Jay A., additional, Vázquez-Manrique, Rafael P., additional, Vemula, Satya, additional, Vidailhet, Marie, additional, Walker, Ruth H., additional, Ward, Sarah M., additional, Wells, Owen S., additional, Wenning, Gregor K., additional, Willet, Kathleen A., additional, Winkelmann, Juliane, additional, Wszolek, Zbigniew K., additional, Xiao, Jianfeng, additional, Yang, X. William, additional, Ylikallio, Emil, additional, Yokoi, Fumiaki, additional, Yue, Zhenyu, additional, and Zhai, R. Grace, additional

Published
2015
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38. Mitochondrial DNA analysis from exome sequencing data improves diagnostic yield in neurological diseases

Author

Poole, Olivia V, Pizzamiglio, Chiara, Murphy, David, Falabella, Micol, Macken, William L, Bugiardini, Enrico, Woodward, Cathy E, Labrum, Robyn, Efthymiou, Stephanie, Salpietro, Vincenzo, Chelban, Viorica, Kaiyrzhanov, Rauan, Maroofian, Reza, Synaps, Group, Aguennouz, M'Hammed, Di Rosa, Gabriella, Amato, Anthony A, Gregory, Allison, Hayflick, Susan J, Jonvik, Hallgeir, Wood, Nicholas, Houlden, Henry, Vandrovcova, Jana, Hanna, Michael G, Pittman, Alan, and Pitceathly, Robert D S

Subjects
Adult, Male, 0301 basic medicine, Mitochondrial DNA, Mitochondrial Diseases, Adolescent, Disease, Brief Communication, DNA, Mitochondrial, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Exome Sequencing, Humans, Medicine, Exome sequencing, Aged, Aged, 80 and over, Genetics, business.industry, Middle Aged, Phenotype, Mtdna mutations, 030104 developmental biology, Neurology, Child, Preschool, Neurology (clinical), Nervous System Diseases, Brief Communications, business, 030217 neurology & neurosurgery
Abstract

A rapidly expanding catalog of neurogenetic disorders has encouraged a diagnostic shift towards early clinical whole exome sequencing (WES). Adult primary mitochondrial diseases (PMDs) frequently exhibit neurological manifestations that overlap with other nervous system disorders. However, mitochondrial DNA (mtDNA) is not routinely analyzed in standard clinical WES bioinformatic pipelines. We reanalyzed 11,424 exomes, enriched with neurological diseases, for pathogenic mtDNA variants. Twenty-four different mtDNA mutations were detected in 64 exomes, 11 of which were considered disease causing based on the associated clinical phenotypes. These findings highlight the diagnostic uplifts gained by analyzing mtDNA from WES data in neurological diseases. ANN NEUROL 2021;89:1240-1247.

Published
2021

42. Clinical implementation of RNA sequencing for Mendelian disease diagnostics

Author

Yépez, Vicente A., primary, Gusic, Mirjana, additional, Kopajtich, Robert, additional, Mertes, Christian, additional, Smith, Nicholas H., additional, Alston, Charlotte L., additional, Ban, Rui, additional, Beblo, Skadi, additional, Berutti, Riccardo, additional, Blessing, Holger, additional, Ciara, Elżbieta, additional, Distelmaier, Felix, additional, Freisinger, Peter, additional, Häberle, Johannes, additional, Hayflick, Susan J., additional, Hempel, Maja, additional, Itkis, Yulia S., additional, Kishita, Yoshihito, additional, Klopstock, Thomas, additional, Krylova, Tatiana D., additional, Lamperti, Costanza, additional, Lenz, Dominic, additional, Makowski, Christine C., additional, Mosegaard, Signe, additional, Müller, Michaela F., additional, Muñoz-Pujol, Gerard, additional, Nadel, Agnieszka, additional, Ohtake, Akira, additional, Okazaki, Yasushi, additional, Procopio, Elena, additional, Schwarzmayr, Thomas, additional, Smet, Joél, additional, Staufner, Christian, additional, Stenton, Sarah L., additional, Strom, Tim M., additional, Terrile, Caterina, additional, Tort, Frederic, additional, Van Coster, Rudy, additional, Vanlander, Arnaud, additional, Wagner, Matias, additional, Xu, Manting, additional, Fang, Fang, additional, Ghezzi, Daniele, additional, Mayr, Johannes A., additional, Piekutowska-Abramczuk, Dorota, additional, Ribes, Antonia, additional, Rötig, Agnès, additional, Taylor, Robert W., additional, Wortmann, Saskia B., additional, Murayama, Kei, additional, Meitinger, Thomas, additional, Gagneur, Julien, additional, and Prokisch, Holger, additional

Published
2021
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44. BPAN

Author

Haack, Tobias B., primary, Hogarth, Penny, additional, Gregory, Allison, additional, Prokisch, Holger, additional, and Hayflick, Susan J., additional

Published
2013
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47. Beta-propeller protein-associated neurodegeneration: a new X-linked dominant disorder with brain iron accumulation

Author

Hayflick, Susan J., Kruer, Michael C., Gregory, Allison, Haack, Tobias B., Kurian, Manju A., Houlden, Henry H., Anderson, James, Boddaert, Nathalie, Sanford, Lynn, Harik, Sami I., Dandu, Vasuki H., Nardocci, Nardo, Zorzi, Giovanna, Dunaway, Todd, Tarnopolsky, Mark, Skinner, Steven, Holden, Kenton R., Frucht, Steven, Hanspal, Era, Schrander-Stumpel, Connie, Mignot, Cyril, Héron, Delphine, Saunders, Dawn E., Kaminska, Margaret, Lin, Jean-Pierre, Lascelles, Karine, Cuno, Stephan M., Meyer, Esther, Garavaglia, Barbara, Bhatia, Kailash, de Silva, Rajith, Crisp, Sarah, Lunt, Peter, Carey, Martyn, Hardy, John, Meitinger, Thomas, Prokisch, Holger, and Hogarth, Penelope

Published
2013
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48. Genetic, clinical, and radiographic delineation of Hallervorden-Spatz syndrome

Author

Hayflick, Susan J., Westaway, Shawn K., Levinson, Barbara, Zhou, Bing, Johnson, Monique A., Ching, Katherine H.L., and Gitschier, Jane

Subjects
Nervous system -- Degeneration
Abstract

All patients with classic Hallervorden-Spatz syndrome and one-third of patients with atypical Hallervorden-Spatz syndrome have a mutation in the gene for pantothenate kinase 2. This causes a deficiency of this enzyme, which causes iron to accumulate in the body and degeneration of the nervous system. The classic form of this syndrome occurs at an early age and progresses rapidly whereas the atypical form occurs later and progresses slowly.

Published
2003

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