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Your search keyword '"Olimpio, C."' showing total 19 results
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19 results on '"Olimpio, C."'

1. Classification of variants of reduced penetrance in high-penetrance cancer susceptibility genes: Framework for genetics clinicians and clinical scientists by CanVIG-UK (Cancer Variant Interpretation Group-UK)

Author

Turnbull, C., Garrett, A., Loong, L., Choi, S., Torr, B., Allen, S., Durkie, M., Callaway, A., Drummond, J., Burghel, G.J., Robinson, R., Berry, I.R., Wallace, A.J., Eccles, D.M., Tischkowitz, M., Ellard, S., Hanson, H., Baple, E., Evans, D.G., Woodward, E., Lalloo, F., Samant, S., Lucassen, A., Znaczko, A., Shaw, A., Ansari, A., Kumar, A., Donaldson, A., Murray, A., Ross, A., Taylor-Beadling, A., Taylor, A., Innes, A., Brady, A., Kulkarni, A., Hogg, A.C., Bowden, A. Ramsay, Hadonou, A., Coad, B., McIldowie, B., Speight, B., DeSouza, B., Mullaney, B., McKenna, C., Brewer, C., Olimpio, C., Clabby, C., Crosby, C., Jenkins, C., Armstrong, C., Bowles, C., Brooks, C., Byrne, C., Maurer, C., Baralle, D., Chubb, D., Stobo, D., Moore, D., O'Sullivan, D., Donnelly, D., Randhawa, D., Halliday, D., Atkinson, E., Rauter, E., Johnston, E., Maher, E., Sofianopoulou, E., Petrides, E., McRonald, F., Pelz, F., Frayling, I., Corbett, G., Rea, G., Clouston, H., Powell, H., Williamson, H., Carley, H., Thomas, H.J.W., Tomlinson, I., Cook, J., Hoyle, J., Tellez, J., Whitworth, J., Williams, J., Murray, J., Campbell, J., Tolmie, J., Field, J., Mason, J., Burn, J., Bruty, J., Callaway, J., Grant, J., Del Rey Jimenez, J., Pagan, J., VanCampen, J., Barwell, J., Monahan, K., Tatton-Brown, K., Ong, K.R., Murphy, K., Andrews, K., Mokretar, K., Cadoo, K., Smith, K., Baker, K., Brown, K., Reay, K., McKay Bounford, K., Bradshaw, K., Russell, K., Stone, K., Snape, K., Crookes, L., Reed, L., Taggart, L., Yarram, L., Cobbold, L., Walker, L., Hawkes, L., Busby, L., Izatt, L., Kiely, L., Hughes, L., Side, L., Sarkies, L., Greenhalgh, K.-L., Shanmugasundaram, M., Duff, M., Bartlett, M., Watson, M., Owens, M., Bradford, M., Huxley, M., Slean, M., Ryten, M., Smith, M., Ahmed, M., Roberts, N., O'Brien, C., Middleton, O., Tarpey, P., Logan, P., Dean, P., May, P., Brace, P., Tredwell, R., Harrison, R., Hart, R., Kirk, R., Martin, R., Nyanhete, R., Wright, R., Davidson, R., Cleaver, R., Talukdar, S., Butler, S., Sampson, J., Ribeiro, S., Dell, S., Mackenzie, S., Hegarty, S., Albaba, S., McKee, S., Palmer-Smith, S., Heggarty, S., MacParland, S., Greville-Heygate, S., Daniels, S., Prapa, S., Abbs, S., Tennant, S., Hardy, S., MacMahon, S., McVeigh, T., Foo, T., Bedenham, T., Cranston, T., McDevitt, T., Clowes, V., Tripathi, V., McConnell, V., Woodwaer, N., Wallis, Y., Kemp, Z., Mullan, G., Pierson, L., Rainey, L., Joyce, C., Timbs, A., Reuther, A.-M., Frugtniet, B., Husher, C., Lawn, C., Corbett, C., Nocera-Jijon, D., Reay, D., Cross, E., Ryan, F., Lindsay, H., Oliver, J., Dring, J., Spiers, J., Harper, J., Ciucias, K., Connolly, L., Tsang, M., Brown, R., Shepherd, S., Begum, S., Tadiso, T., Linton-Willoughby, T., Heppell, H., Sahan, K., Worrillow, L., Allen, Z., Watt, C., Hegarty, M., Mitchell, R., Coles, R., Nickless, G., Cojocaru, E., Doal, I., Sava, F., McCarthy, C., Jeeneea, R., Goudie, D., McConachie, M., Botosneanu, S., Kavanaugh, G., Sherlaw, C., Tsoulaki, O., Forde, C., Petley, E., Jones, A.-B., Oprych, K., Pryde, S., Hyder, Z., Elkhateeb, N., Braham, R., Hanington, L., Huntley, C., Irving, R., Sadan, A., Ramos, M., Elliot, C., Wren, D., Lobo, D., McLean, J., May, D., Kearney, L., Campbell, T., Asakura, K., Alwadi, L., O’Shea, R., Gabriel, J., Chiecchio, L., Bowman, P., Sutton, L.A., Walsh, C., Cloke, V., Ucanok, D., Davies, J., Pleasance, B., Maguire, E., Whaite, A., Best, S., Westbury, S., Logan, A., Navarajasegaran, D., Bench, A., Wightman, P., Cartwright, A., Higgs, E., J.Bott, Whitehouse, H., Stevens, J., Martin, D., Dunlop, J., Thomas, S., Sau, C., Farndon, S., Coleman, N., Angelini, P., Massey, H., Rowlands, C., Garcia-Petit, C., Gillespie, K., Alder, A., Middleton, E., Cassidy, C., Orfali, N., Webb, A., Luharia, A., Walker, N., Charlton, J., Andreou, A., Peddie, J., Khan, M., Wilkinson, L., Bezuidenhout, H., Edis, M., Callard, A., Ostrowski, P., Moverley, P., Bean, K., Dunne, A., Moleirinho, A., Waller, S., Cox, K., Greensmith, L., Brittle, A., Gossan, N., Freestone, L., Shak, C., Langford, T., Clinch, Y., Livesey, H., Borland, S., Joshi, A., Wall, K., Whitworth, A., Wilsdon, A., Edgerley, K., Pugh, S., Chrysochoidi, N., Mutch, S., McMullan, C., Johnston, Y., Muraru, M., May, A., Begum, R., Smith, C., Patel, R., Bhatnagar, I., Brown, D., Willan, J., Taylor, S., Jones, K., Ramsden, C., Taiwo, O., Jaudzemaite, J., Sharmin, R., Young, L., O’Dubhshlaine, C., McSorley, L., Rodriguez, I. Abreu, Lillis, S., Alexopoulos, P., Mortensson, E., Kingham, L., Moore, R., Kosicka-Slawinska, M., Aslam, S., Wells, R., Carter, A., Warren, H., Rolf, E., Reed, H., Pearce, L., Lock, D., Ali, F., Kolozi, A., White, N., Wood, D., Hayden, C., Garrett, Alice, Allen, Sophie, Durkie, Miranda, Burghel, George J., Robinson, Rachel, Callaway, Alison, Field, Joanne, Frugtniet, Bethan, Palmer-Smith, Sheila, Grant, Jonathan, Pagan, Judith, McDevitt, Trudi, Rowlands, Charlie F., McVeigh, Terri, Hanson, Helen, and Turnbull, Clare

Published
2025
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2. Quantifying prediction of pathogenicity for within-codon concordance (PM5) using 7541 functional classifications of BRCA1 and MSH2 missense variants

Author

Samant, S., Lucassen, A., Znaczko, A., Shaw, A., Ansari, A., Kumar, A., Donaldson, A., Murray, A., Ross, A., Taylor-Beadling, A., Taylor, A., Innes, A., Brady, A., Kulkarni, A., Hogg, A.-C., Bowden, A. Ramsay, Hadonou, A., Coad, B., McIldowie, B., Speight, B., DeSouza, B., Mullaney, B., McKenna, C., Brewer, C., Olimpio, C., Clabby, C., Crosby, C., Jenkins, C., Armstrong, C., Bowles, C., Brooks, C., Byrne, C., Maurer, C., Baralle, D., Chubb, D., Stobo, D., Moore, D., O'Sullivan, D., Donnelly, D., Randhawa, D., Halliday, D., Atkinson, E., Baple, E., Rauter, E., Johnston, E., Woodward, E., Maher, E., Sofianopoulou, E., Petrides, E., Lalloo, F., McRonald, F., Pelz, F., Frayling, I., Evans, G., Corbett, G., Rea, G., Clouston, H., Powell, H., Williamson, H., Carley, H., Thomas, H.J.W., Tomlinson, I., Cook, J., Hoyle, J., Tellez, J., Whitworth, J., Williams, J., Murray, J., Campbell, J., Tolmie, J., Field, J., Mason, J., Burn, J., Bruty, J., Callaway, J., Grant, J., Del Rey Jimenez, J., Pagan, J., VanCampen, J., Barwell, J., Monahan, K., Tatton-Brown, K., Ong, K.-R., Murphy, K., Andrews, K., Mokretar, K., Cadoo, K., Smith, K., Baker, K., Brown, K., Reay, K., McKay Bounford, K., Bradshaw, K., Russell, K., Stone, K., Snape, K., Crookes, L., Reed, L., Taggart, L., Yarram, L., Cobbold, L., Walker, L., Hawkes, L., Busby, L., Izatt, L., Kiely, L., Hughes, L., Side, L., Sarkies, L., Greenhalgh, K.-L., Shanmugasundaram, M., Duff, M., Bartlett, M., Watson, M., Owens, M., Bradford, M., Huxley, M., Slean, M., Ryten, M., Smith, M., Ahmed, M., Roberts, N., O'Brien, C., Middleton, O., Tarpey, P., Logan, P., Dean, P., May, P., Brace, P., Tredwell, R., Harrison, R., Hart, R., Kirk, R., Martin, R., Nyanhete, R., Wright, R., Davidson, R., Cleaver, R., Talukdar, S., Butler, S., Sampson, J., Ribeiro, S., Dell, S., Mackenzie, S., Hegarty, S., Albaba, S., McKee, S., Palmer-Smith, S., Heggarty, S., MacParland, S., Greville-Heygate, S., Daniels, S., Prapa, S., Abbs, S., Tennant, S., Hardy, S., MacMahon, S., McVeigh, T., Foo, T., Bedenham, T., Cranston, T., McDevitt, T., Clowes, V., Tripathi, V., McConnell, V., Woodwaer, N., Wallis, Y., Kemp, Z., Mullan, G., Pierson, L., Rainey, L., Joyce, C., Timbs, A., Reuther, A.-M., Frugtniet, B., Husher, C., Lawn, C., Corbett, C., Nocera-Jijon, D., Reay, D., Cross, E., Ryan, F., Lindsay, H., Oliver, J., Dring, J., Spiers, J., Harper, J., Ciucias, K., Connolly, L., Tsang, M., Brown, R., Shepherd, S., Begum, S., Tadiso, T., Linton-Willoughby, T., Heppell, H., Sahan, K., Worrillow, L., Allen, Z., Barlett, M., Watt, C., Hegarty, M., Loong, Lucy, Cubuk, Cankut, Choi, Subin, Allen, Sophie, Torr, Beth, Garrett, Alice, Loveday, Chey, Durkie, Miranda, Callaway, Alison, Burghel, George J., Drummond, James, Robinson, Rachel, Berry, Ian R., Wallace, Andrew, Eccles, Diana M., Tischkowitz, Marc, Ellard, Sian, Ware, James S., Hanson, Helen, and Turnbull, Clare

Published
2022
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3. TEFM variants impair mitochondrial transcription causing childhood-onset neurological disease

Author

Van Haute, L, O'Connor, E, Diaz-Maldonado, H, Munro, B, Polavarapu, K, Hock, DH, Arunachal, G, Athanasiou-Fragkouli, A, Bardhan, M, Barth, M, Bonneau, D, Brunetti-Pierri, N, Cappuccio, G, Caruana, NJ, Dominik, N, Goel, H, Helman, G, Houlden, H, Lenaers, G, Mention, K, Murphy, D, Nandeesh, B, Olimpio, C, Powell, CA, Preethish-Kumar, V, Procaccio, V, Rius, R, Rebelo-Guiomar, P, Simons, C, Vengalil, S, Zaki, MS, Ziegler, A, Thorburn, DR, Stroud, DA, Maroofian, R, Christodoulou, J, Gustafsson, C, Nalini, A, Lochmueller, H, Minczuk, M, Horvath, R, Van Haute, L, O'Connor, E, Diaz-Maldonado, H, Munro, B, Polavarapu, K, Hock, DH, Arunachal, G, Athanasiou-Fragkouli, A, Bardhan, M, Barth, M, Bonneau, D, Brunetti-Pierri, N, Cappuccio, G, Caruana, NJ, Dominik, N, Goel, H, Helman, G, Houlden, H, Lenaers, G, Mention, K, Murphy, D, Nandeesh, B, Olimpio, C, Powell, CA, Preethish-Kumar, V, Procaccio, V, Rius, R, Rebelo-Guiomar, P, Simons, C, Vengalil, S, Zaki, MS, Ziegler, A, Thorburn, DR, Stroud, DA, Maroofian, R, Christodoulou, J, Gustafsson, C, Nalini, A, Lochmueller, H, Minczuk, M, and Horvath, R

Abstract

Mutations in the mitochondrial or nuclear genomes are associated with a diverse group of human disorders characterized by impaired mitochondrial respiration. Within this group, an increasing number of mutations have been identified in nuclear genes involved in mitochondrial RNA biology. The TEFM gene encodes the mitochondrial transcription elongation factor responsible for enhancing the processivity of mitochondrial RNA polymerase, POLRMT. We report for the first time that TEFM variants are associated with mitochondrial respiratory chain deficiency and a wide range of clinical presentations including mitochondrial myopathy with a treatable neuromuscular transmission defect. Mechanistically, we show muscle and primary fibroblasts from the affected individuals have reduced levels of promoter distal mitochondrial RNA transcripts. Finally, tefm knockdown in zebrafish embryos resulted in neuromuscular junction abnormalities and abnormal mitochondrial function, strengthening the genotype-phenotype correlation. Our study highlights that TEFM regulates mitochondrial transcription elongation and its defect results in variable, tissue-specific neurological and neuromuscular symptoms.

Published
2023

4. Quantifying prediction of pathogenicity for within-codon concordance (PM5) using 7541 functional classifications of BRCA1 and MSH2 missense variants

Author

Loong, Lucy, primary, Cubuk, Cankut, additional, Choi, Subin, additional, Allen, Sophie, additional, Torr, Beth, additional, Garrett, Alice, additional, Loveday, Chey, additional, Durkie, Miranda, additional, Callaway, Alison, additional, Burghel, George J., additional, Drummond, James, additional, Robinson, Rachel, additional, Berry, Ian R., additional, Wallace, Andrew, additional, Eccles, Diana M., additional, Tischkowitz, Marc, additional, Ellard, Sian, additional, Ware, James S., additional, Hanson, Helen, additional, Turnbull, Clare, additional, Samant, S., additional, Lucassen, A., additional, Znaczko, A., additional, Shaw, A., additional, Ansari, A., additional, Kumar, A., additional, Donaldson, A., additional, Murray, A., additional, Ross, A., additional, Taylor-Beadling, A., additional, Taylor, A., additional, Innes, A., additional, Brady, A., additional, Kulkarni, A., additional, Hogg, A.-C., additional, Bowden, A. Ramsay, additional, Hadonou, A., additional, Coad, B., additional, McIldowie, B., additional, Speight, B., additional, DeSouza, B., additional, Mullaney, B., additional, McKenna, C., additional, Brewer, C., additional, Olimpio, C., additional, Clabby, C., additional, Crosby, C., additional, Jenkins, C., additional, Armstrong, C., additional, Bowles, C., additional, Brooks, C., additional, Byrne, C., additional, Maurer, C., additional, Baralle, D., additional, Chubb, D., additional, Stobo, D., additional, Moore, D., additional, O'Sullivan, D., additional, Donnelly, D., additional, Randhawa, D., additional, Halliday, D., additional, Atkinson, E., additional, Baple, E., additional, Rauter, E., additional, Johnston, E., additional, Woodward, E., additional, Maher, E., additional, Sofianopoulou, E., additional, Petrides, E., additional, Lalloo, F., additional, McRonald, F., additional, Pelz, F., additional, Frayling, I., additional, Evans, G., additional, Corbett, G., additional, Rea, G., additional, Clouston, H., additional, Powell, H., additional, Williamson, H., additional, Carley, H., additional, Thomas, H.J.W., additional, Tomlinson, I., additional, Cook, J., additional, Hoyle, J., additional, Tellez, J., additional, Whitworth, J., additional, Williams, J., additional, Murray, J., additional, Campbell, J., additional, Tolmie, J., additional, Field, J., additional, Mason, J., additional, Burn, J., additional, Bruty, J., additional, Callaway, J., additional, Grant, J., additional, Del Rey Jimenez, J., additional, Pagan, J., additional, VanCampen, J., additional, Barwell, J., additional, Monahan, K., additional, Tatton-Brown, K., additional, Ong, K.-R., additional, Murphy, K., additional, Andrews, K., additional, Mokretar, K., additional, Cadoo, K., additional, Smith, K., additional, Baker, K., additional, Brown, K., additional, Reay, K., additional, McKay Bounford, K., additional, Bradshaw, K., additional, Russell, K., additional, Stone, K., additional, Snape, K., additional, Crookes, L., additional, Reed, L., additional, Taggart, L., additional, Yarram, L., additional, Cobbold, L., additional, Walker, L., additional, Hawkes, L., additional, Busby, L., additional, Izatt, L., additional, Kiely, L., additional, Hughes, L., additional, Side, L., additional, Sarkies, L., additional, Greenhalgh, K.-L., additional, Shanmugasundaram, M., additional, Duff, M., additional, Bartlett, M., additional, Watson, M., additional, Owens, M., additional, Bradford, M., additional, Huxley, M., additional, Slean, M., additional, Ryten, M., additional, Smith, M., additional, Ahmed, M., additional, Roberts, N., additional, O'Brien, C., additional, Middleton, O., additional, Tarpey, P., additional, Logan, P., additional, Dean, P., additional, May, P., additional, Brace, P., additional, Tredwell, R., additional, Harrison, R., additional, Hart, R., additional, Kirk, R., additional, Martin, R., additional, Nyanhete, R., additional, Wright, R., additional, Davidson, R., additional, Cleaver, R., additional, Talukdar, S., additional, Butler, S., additional, Sampson, J., additional, Ribeiro, S., additional, Dell, S., additional, Mackenzie, S., additional, Hegarty, S., additional, Albaba, S., additional, McKee, S., additional, Palmer-Smith, S., additional, Heggarty, S., additional, MacParland, S., additional, Greville-Heygate, S., additional, Daniels, S., additional, Prapa, S., additional, Abbs, S., additional, Tennant, S., additional, Hardy, S., additional, MacMahon, S., additional, McVeigh, T., additional, Foo, T., additional, Bedenham, T., additional, Cranston, T., additional, McDevitt, T., additional, Clowes, V., additional, Tripathi, V., additional, McConnell, V., additional, Woodwaer, N., additional, Wallis, Y., additional, Kemp, Z., additional, Mullan, G., additional, Pierson, L., additional, Rainey, L., additional, Joyce, C., additional, Timbs, A., additional, Reuther, A.-M., additional, Frugtniet, B., additional, Husher, C., additional, Lawn, C., additional, Corbett, C., additional, Nocera-Jijon, D., additional, Reay, D., additional, Cross, E., additional, Ryan, F., additional, Lindsay, H., additional, Oliver, J., additional, Dring, J., additional, Spiers, J., additional, Harper, J., additional, Ciucias, K., additional, Connolly, L., additional, Tsang, M., additional, Brown, R., additional, Shepherd, S., additional, Begum, S., additional, Tadiso, T., additional, Linton-Willoughby, T., additional, Heppell, H., additional, Sahan, K., additional, Worrillow, L., additional, Allen, Z., additional, Barlett, M., additional, Watt, C., additional, and Hegarty, M., additional

Published
2022
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5. Impact of postoperative non-steroidal anti-inflammatory drugs on adverse events after gastrointestinal surgery

Author

Chapman, S. J., Glasbey, J., Kelly, M., Khatri, C., Nepogodiev, D., Fitzgerald, J. E. F., Bhangu, A., Harrison, E. M., Adams, R., Patel, K., Retchless, A. R., Elsaddig, M., Curtis, A. E., McMahon, R., Mittapalli, D., Ferguson, L. A., Gentry, S. V., Kong, C. Y. N., Naqvi, Z., Amin, H., Chaudhry, B., Burke, J., Henderson, I., Trecarten, S., Clements, J. M., Drake, T. M., Wild, J. R. L., Venkatesh, H., Butters, N., Ahmeidat, H., Goergen, N., Black, D., Robertson, K., Jama, G. M., McGuire, S. A., Ahl, R., Suri, T. S., Kuo, R., Fadhlillah, M., Mills, H., Mitchell, R., Goodship, J., Tan, M., Barker, T., Wright, T., Mohamad, W., Hanna, N., Laing, G., Warnock, M. W. C., Baird-Fraser, P. R., Logan, T., Young, F. M., Fane De Salis, A. C., McHugh, R., Hickson, C., Paszkiewicz, J., Anderson, L. B., Neeson, D., Mohan, M., Narang, Y., Brophy, T., Punj, R., Majumdar, S., Kauser, S., Jong, G., Palkhi, E., Finch, D., Mitchell, H., Carter, N., Viyasar, T., Sammut, T., Cook, N., Powell, M. M., Horne, S., Allen, J. L. Y., Marshall, D., McIntyre, C., S Koh, D. T., Shi, J., Reid, T., Armugam, N. P., Luck, J., Fozard, T., OʼCallaghan, J., Copley, P. C., Tilliriou, V., Aiyer, R., Yazdi, A., Wiltshire, A., Blower, E., Jewitt, C., Cheung, L. K., Fourali, S., Rahimi, Y., Velho, R., Taylor, C., Satterthwaite, L., Eze, N. V., Johnston, J. P. M., McCain, R. S., Hess, E. C. F., Thumbadoo, R. P., Turner, E. J. H., Wookey, R., Morris, R., Gasteratos, K., Heywood, E., Simpson, S. J., Rai, Z., Kazzazi, D., Ducey, J., Livesey, M. J., Finan, C., Staunton, E., Haddad, S. D., Karanjia, R., Bokobza, I., Ahmed, M., Howell, J., Grainger, C., Woo, A., McDowall, M., Bulley, F., Keating, R., Tan, B., Sng, S., Brown, C., Aidoo-Micah, G., Champsi, A., Ellis, R., Darwazeh, S., Polson, R., Chan, J. Z., Chong, B. F. H. K., Park, J. H., Kong, C. Y., Mogan, Y. P., Stevens, S., Sekhon, H. K., McIntosh, R., Ochiltree, D. W., Jamieson, P. D., Naumann, D. N., Bowley, D. M., Howell, G., Clark, T., Dear, K., James, L., Upchurch, E., Wilson, H., Hughes, M., Modayur, S. M., Datta, U., Chen, J. H. C., Williams, L. J. L., Selby, J., Prabhudesai, A., Mahomed, K., Shah, H. A., Kong, K., Chandramoorthy, S., Marshall, L., De Kauwe, C., Rana, R., Patel, J., Pezas, T., Ma, J., Stohlner, V., Kinsella, M. S., Gardiner, S. N., Smith, R. A., Glover, M., Akinfala, M., Lee, J. Z. C., Aggarwal, V., Waters, S., Atif, M., Hill, M., Ramasubramoni, A., Jaffry, Z., Sagoo, H., Jeyakumar, J., Kosasih, S., Davis, J., Stanley, G. H. M., Nijran, J., Tang, I., Mehta, K., Fillery, A., Watson, N. F., Shah, D., Naidu, S., Grewal, T. K., Singh, P., Reissis, D., Marusza, C., Pettit, W., Timbrell, S., Woods, R., Phillips, J., Vaughan, R., Dean, S., Gibby, R., Jones, T. F., Rao, R., Torrance, H. D. T., Thirumal, V., McMahon, R. K., Yap, D., Shaw, A., Claireaux, H. A., Pang, Y. L., Narramore, R., Holmes, C., Caldwell, A., Daoub, A., Bibby, L., Hague, A. G., Sykes, M. C., Morar, P., Downes, G., Shah, S., Walimohamed, S., Alsulaimi, A., Biswas, V., Gnaneswaran, B., Davies, N., Narwani, V., Hernon, J., Jumbu, A., Ilyas, M., Johal, G., Atia, F., Williams, A., Chan, C., McAnelly, S., Evans, A., Chan, K. Y., Flegg, K., Carter, S., Coley, J., Khaw, R., Jayakody, N., Jones, B., Fawcett, N., Ghali, C., Jalundhwala, K., Ariyaratnam, P., Colville, H., Walls, M., Lindsay, J., Keane, M., Ban, V. S., Kambasha, C., Sait, S., Tahir, M., Tharakan, R., Voll, J., Shiwani, H., Al-Omran, Y., Hawash, A., McCaughan, V., Shatkar, V., Gohil, K., Greenhalgh, A., Higgins, E., Moody, T., Booth, M. B., Chan, W. H., Shanthakumaran, S., Maple, N., McNish, D., Shahin, B., Nicholas, J., McDermid, R., Narayan, P., Brodie, C., Hurrey, S., Panayi, V., Turner, B., Kopala, K., Winfield, Clayton S. A., Mohamud, A., Venkatesh, A., Hosein, S., Olimpio, C., Gkiousias, V., Kilgour, J. M., Cogbill, E., Ramcham, M., Carr, G., Bannerman, A., Grundy, L., White, S., Beamish, A., Neo, Y. N., Cragg, A. R., Perkins, A., Wynn-Hebden, A., Khan, T., Ali, M., Battersby, C. L. F., Pinto, R. S., Poon, S. S., Patel, M., Patel, P., Shafi, A. M. A., Vedage, D., Ghorbhanian, S., Klimach, S., Bradley, J., de Sausmarez, E., Hayward, P., Naqib, S., Flanigan, C., Shuttleworth, R. H. A., McElvanna, K., Shelton, B., Westbrook, N., Weir, A., Webb, P., Alam, M., Bhanderi, S., Roberts, C., Al-Shakarchi, J., Lu, M., Harvey, J., Chowdhury, M. U., McGow, C., Antoniou, I., Good, D. F., Gerasimova, N., Eragat, M., Pressler, N., Santos, C. R. D., Arshad, W., Patel, H. R., Kassim, Y., Jayaratne, N., Perera, A., Chandramoorthy, L., Quan, V., Ponweera, A., Tadjkarimi, J., Moyes, L., Metcalfe, C., Napier-Hemy, T, Bull, A., Jaffer, Y., Mushtaq, J., Warren, M., Jarrar, Z., Wickenden, R., Kang, M., Holohan, G., Isbister, T., Strachan, E., Varma, R., Simpson, R., Rajasekar, N., Panayiotou, H., Walsh, E., Thacoor, A., Willson, J. M. H., Mustafa, A., Barai, I., Menon, A., Soon, W. C., Thakrar, C., McCurdie, S., Carr, E. C. F., Westwood, K. J., Wardell, H., Weinberg, D., Craig, A. R. J., Khan, F. A. S., Mulla, A., Dann, P., Saleh, M., Pignatelli, I. C., Igbagiri, K. V., Panagoulas, E. V., Tilston, T. W., Thayaparan, A. J., Navaratnam, J., Aryasomayajula, S., Joji, N., Screen, R., Quinn, C., Harrison, R., Arnaout, A., McCartan, N., Allen, W., Gabriel, R., Hartelius, C. F., Makinde, M. L., Sivasubramaniam, S., Spreadborough, P., Lobo, R., Surendran, H., Couch, L., Butters, T., Beale, K., Markiewicz, O., Kennedy, E. D., Neely, D. M., Martin, A., Al-Moasseb, Z. H., Ong, K. K., Letchumanan, S., Lam, W. L., Yapp, L., Skelly, B. L., Stallard, S., Westhuizen, P. V. D., Rafferty, A. R., Lambert, A., Tay, Y. Z., Koshnow, Z., Elamin, O., Shah, A., Kim, E., English, W., Farrell, A., Sharma, J., Rowan, Chudek. D. K., Mullan, B., Brown, R. J., McCarter, J. A., Johnston, D., Symonds, C., Gatfield, W., Messenger, D., Knox, J. D., Jani, P., Trinquet, J., Naqvi, Z. B., Hussain, K., Jaffer, A., McAleer, E., Joshi, H., Cecil, E., Lochrane, A., Woolley, T., Marriott, P., Bolton, W., Balian, V., Scott, A. J., and Tan, Y. H.

Published
2014
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6. Classification of variants of reduced penetrance in high-penetrance cancer susceptibility genes: Framework for genetics clinicians and clinical scientists by CanVIG-UK (Cancer Variant Interpretation Group-UK)

Author

Garrett, Alice, Allen, Sophie, Durkie, Miranda, Burghel, George J., Robinson, Rachel, Callaway, Alison, Field, Joanne, Frugtniet, Bethan, Palmer-Smith, Sheila, Grant, Jonathan, Pagan, Judith, McDevitt, Trudi, Rowlands, Charlie F., McVeigh, Terri, Hanson, Helen, Turnbull, Clare, Turnbull, C., Garrett, A., Loong, L., Choi, S., Torr, B., Allen, S., Durkie, M., Callaway, A., Drummond, J., Burghel, G.J., Robinson, R., Berry, I.R., Wallace, A.J., Eccles, D.M., Tischkowitz, M., Ellard, S., Hanson, H., Baple, E., Evans, D.G., Woodward, E., Lalloo, F., Samant, S., Lucassen, A., Znaczko, A., Shaw, A., Ansari, A., Kumar, A., Donaldson, A., Murray, A., Ross, A., Taylor-Beadling, A., Taylor, A., Innes, A., Brady, A., Kulkarni, A., Hogg, A.C., Bowden, A. Ramsay, Hadonou, A., Coad, B., McIldowie, B., Speight, B., DeSouza, B., Mullaney, B., McKenna, C., Brewer, C., Olimpio, C., Clabby, C., Crosby, C., Jenkins, C., Armstrong, C., Bowles, C., Brooks, C., Byrne, C., Maurer, C., Baralle, D., Chubb, D., Stobo, D., Moore, D., O'Sullivan, D., Donnelly, D., Randhawa, D., Halliday, D., Atkinson, E., Rauter, E., Johnston, E., Maher, E., Sofianopoulou, E., Petrides, E., McRonald, F., Pelz, F., Frayling, I., Corbett, G., Rea, G., Clouston, H., Powell, H., Williamson, H., Carley, H., Thomas, H.J.W., Tomlinson, I., Cook, J., Hoyle, J., Tellez, J., Whitworth, J., Williams, J., Murray, J., Campbell, J., Tolmie, J., Field, J., Mason, J., Burn, J., Bruty, J., Callaway, J., Grant, J., Del Rey Jimenez, J., Pagan, J., VanCampen, J., Barwell, J., Monahan, K., Tatton-Brown, K., Ong, K.R., Murphy, K., Andrews, K., Mokretar, K., Cadoo, K., Smith, K., Baker, K., Brown, K., Reay, K., McKay Bounford, K., Bradshaw, K., Russell, K., Stone, K., Snape, K., Crookes, L., Reed, L., Taggart, L., Yarram, L., Cobbold, L., Walker, L., Walker, L., Hawkes, L., Busby, L., Izatt, L., Kiely, L., Hughes, L., Side, L., Sarkies, L., Greenhalgh, K.-L., Shanmugasundaram, M., Duff, M., Bartlett, M., Watson, M., Owens, M., Bradford, M., Huxley, M., Slean, M., Ryten, M., Smith, M., Ahmed, M., Roberts, N., O'Brien, C., Middleton, O., Tarpey, P., Logan, P., Dean, P., May, P., Brace, P., Tredwell, R., Harrison, R., Hart, R., Kirk, R., Martin, R., Nyanhete, R., Wright, R., Martin, R., Davidson, R., Cleaver, R., Talukdar, S., Butler, S., Sampson, J., Ribeiro, S., Dell, S., Mackenzie, S., Hegarty, S., Albaba, S., McKee, S., Palmer-Smith, S., Heggarty, S., MacParland, S., Greville-Heygate, S., Daniels, S., Prapa, S., Abbs, S., Tennant, S., Hardy, S., MacMahon, S., McVeigh, T., Foo, T., Bedenham, T., Cranston, T., McDevitt, T., Clowes, V., Tripathi, V., McConnell, V., Woodwaer, N., Wallis, Y., Kemp, Z., Mullan, G., Pierson, L., Rainey, L., Joyce, C., Timbs, A., Reuther, A.-M., Frugtniet, B., DeSouza, B., Husher, C., Lawn, C., Corbett, C., Nocera-Jijon, D., Reay, D., Cross, E., Ryan, F., Lindsay, H., Oliver, J., Dring, J., Spiers, J., Harper, J., Ciucias, K., Connolly, L., Tsang, M., Brown, R., Shepherd, S., Begum, S., Daniels, S., Tadiso, T., Linton-Willoughby, T., Heppell, H., Sahan, K., Worrillow, L., Allen, Z., Watt, C., Hegarty, M., Mitchell, R., Coles, R., Nickless, G., Cojocaru, E., Doal, I., Sava, F., McCarthy, C., Jeeneea, R., Goudie, D., McConachie, M., Botosneanu, S., Kavanaugh, G., Russell, K., Sherlaw, C., Tsoulaki, O., Forde, C., Petley, E., Jones, A.-B., Oprych, K., Pryde, S., Hyder, Z., Elkhateeb, N., Braham, R., Hanington, L., Huntley, C., Irving, R., Sadan, A., Ramos, M., Elliot, C., Wren, D., Lobo, D., McLean, J., May, D., Kearney, L., Campbell, T., Asakura, K., Alwadi, L., O’Shea, R., Gabriel, J., Chiecchio, L., Bowman, P., Sutton, L.A., Walsh, C., Cloke, V., Ucanok, D., Davies, J., Pleasance, B., Maguire, E., Whaite, A., Best, S., Westbury, S., Logan, A., Navarajasegaran, D., Bench, A., Wightman, P., Cartwright, A., Higgs, E., J.Bott, Whitehouse, H., Stevens, J., Martin, D., Dunlop, J., Thomas, S., Sau, C., Farndon, S., Coleman, N., Angelini, P., Duff, M., Massey, H., Rowlands, C., Garcia-Petit, C., Gillespie, K., Alder, A., Middleton, E., Cassidy, C., Orfali, N., Webb, A., Luharia, A., Walker, N., Charlton, J., Andreou, A., Peddie, J., Khan, M., Wilkinson, L., Bezuidenhout, H., Edis, M., Callard, A., Ostrowski, P., Moverley, P., Bean, K., Dunne, A., Moleirinho, A., Waller, S., Cox, K., Greensmith, L., Brittle, A., Gossan, N., Freestone, L., Shak, C., Langford, T., Clinch, Y., Livesey, H., Borland, S., Joshi, A., Wall, K., Whitworth, A., Wilsdon, A., Edgerley, K., Pugh, S., Chrysochoidi, N., Mutch, S., McMullan, C., Johnston, Y., Muraru, M., May, A., Begum, R., Smith, C., Patel, R., Bhatnagar, I., Taylor, A., Brown, D., Willan, J., Taylor, S., Jones, K., Cox, K., Ramsden, C., Taiwo, O., Jaudzemaite, J., Sharmin, R., Young, L., O’Dubhshlaine, C., McSorley, L., Rodriguez, I. Abreu, Lillis, S., Alexopoulos, P., Mortensson, E., Kingham, L., Moore, R., Kosicka-Slawinska, M., Aslam, S., Wells, R., Carter, A., Warren, H., Rolf, E., Reed, H., Pearce, L., Lock, D., Ali, F., Kolozi, A., White, N., Wood, D., and Hayden, C.

Abstract

Current practice is to report and manage likely pathogenic/pathogenic variants in a given cancer susceptibility gene as though having equivalent penetrance, despite increasing evidence of intervariant variability in risk associations. Using existing variant interpretation approaches, largely based on full-penetrance models, variants in which reduced penetrance is suspected may be classified inconsistently and/or as variants of uncertain significance. We aimed to develop a national consensus approach for such variants within the Cancer Variant Interpretation Group UK (CanVIG-UK) multidisciplinary network.

Published
2025
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7. Quantifying prediction of pathogenicity for within-codon concordance (PM5) using 7541 functional classifications of BRCA1and MSH2missense variants

Author

Loong, Lucy, Cubuk, Cankut, Choi, Subin, Allen, Sophie, Torr, Beth, Garrett, Alice, Loveday, Chey, Durkie, Miranda, Callaway, Alison, Burghel, George J., Drummond, James, Robinson, Rachel, Berry, Ian R., Wallace, Andrew, Eccles, Diana M., Tischkowitz, Marc, Ellard, Sian, Ware, James S., Hanson, Helen, Turnbull, Clare, Samant, S., Lucassen, A., Znaczko, A., Shaw, A., Ansari, A., Kumar, A., Donaldson, A., Murray, A., Ross, A., Taylor-Beadling, A., Taylor, A., Innes, A., Brady, A., Kulkarni, A., Hogg, A.-C., Bowden, A. Ramsay, Hadonou, A., Coad, B., McIldowie, B., Speight, B., DeSouza, B., Mullaney, B., McKenna, C., Brewer, C., Olimpio, C., Clabby, C., Crosby, C., Jenkins, C., Armstrong, C., Bowles, C., Brooks, C., Byrne, C., Maurer, C., Baralle, D., Chubb, D., Stobo, D., Moore, D., O'Sullivan, D., Donnelly, D., Randhawa, D., Halliday, D., Atkinson, E., Baple, E., Rauter, E., Johnston, E., Woodward, E., Maher, E., Sofianopoulou, E., Petrides, E., Lalloo, F., McRonald, F., Pelz, F., Frayling, I., Evans, G., Corbett, G., Rea, G., Clouston, H., Powell, H., Williamson, H., Carley, H., Thomas, H.J.W., Tomlinson, I., Cook, J., Hoyle, J., Tellez, J., Whitworth, J., Williams, J., Murray, J., Campbell, J., Tolmie, J., Field, J., Mason, J., Burn, J., Bruty, J., Callaway, J., Grant, J., Del Rey Jimenez, J., Pagan, J., VanCampen, J., Barwell, J., Monahan, K., Tatton-Brown, K., Ong, K.-R., Murphy, K., Andrews, K., Mokretar, K., Cadoo, K., Smith, K., Baker, K., Brown, K., Reay, K., McKay Bounford, K., Bradshaw, K., Russell, K., Stone, K., Snape, K., Crookes, L., Reed, L., Taggart, L., Yarram, L., Cobbold, L., Walker, L., Walker, L., Hawkes, L., Busby, L., Izatt, L., Kiely, L., Hughes, L., Side, L., Sarkies, L., Greenhalgh, K.-L., Shanmugasundaram, M., Duff, M., Bartlett, M., Watson, M., Owens, M., Bradford, M., Huxley, M., Slean, M., Ryten, M., Smith, M., Ahmed, M., Roberts, N., O'Brien, C., Middleton, O., Tarpey, P., Logan, P., Dean, P., May, P., Brace, P., Tredwell, R., Harrison, R., Hart, R., Kirk, R., Martin, R., Nyanhete, R., Wright, R., Martin, R., Davidson, R., Cleaver, R., Talukdar, S., Butler, S., Sampson, J., Ribeiro, S., Dell, S., Mackenzie, S., Hegarty, S., Albaba, S., McKee, S., Palmer-Smith, S., Heggarty, S., MacParland, S., Greville-Heygate, S., Daniels, S., Prapa, S., Abbs, S., Tennant, S., Hardy, S., MacMahon, S., McVeigh, T., Foo, T., Bedenham, T., Cranston, T., McDevitt, T., Clowes, V., Tripathi, V., McConnell, V., Woodwaer, N., Wallis, Y., Kemp, Z., Mullan, G., Pierson, L., Rainey, L., Joyce, C., Timbs, A., Reuther, A.-M., Frugtniet, B., DeSouza, B., Husher, C., Lawn, C., Corbett, C., Nocera-Jijon, D., Reay, D., Cross, E., Ryan, F., Lindsay, H., Oliver, J., Dring, J., Spiers, J., Harper, J., Ciucias, K., Connolly, L., Tsang, M., Brown, R., Shepherd, S., Begum, S., Daniels, S., Tadiso, T., Linton-Willoughby, T., Heppell, H., Sahan, K., Worrillow, L., Allen, Z., Barlett, M., Watt, C., and Hegarty, M.

Abstract

Conditions and thresholds applied for evidence weighting of within-codon concordance (PM5) for pathogenicity vary widely between laboratories and expert groups. Because of the sparseness of available clinical classifications, there is little evidence for variation in practice.

Published
2022
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11. Anti-inflammatory properties of the novel antitumor agent yondelis (trabectedin): inhibition of macrophage differentiation and cytokine production

Author

Allavena, P, Signorelli, M, Chieppa, M, Erba, E, Bianchi, G, Marchesi, F, Olimpio, C, Bonardi, C, Garbi, A, Lissoni, A, de Braud, F, Jimeno, J, D'Incalci, M, Olimpio, CO, D'Incalci, M., SIGNORELLI, MAURO, BONARDI, CLAUDIA, GARBI, ANNALISA, LISSONI, ANDREA ALBERTO, Allavena, P, Signorelli, M, Chieppa, M, Erba, E, Bianchi, G, Marchesi, F, Olimpio, C, Bonardi, C, Garbi, A, Lissoni, A, de Braud, F, Jimeno, J, D'Incalci, M, Olimpio, CO, D'Incalci, M., SIGNORELLI, MAURO, BONARDI, CLAUDIA, GARBI, ANNALISA, and LISSONI, ANDREA ALBERTO

Abstract

Yondelis (Trabectedin) is a novel antitumor agent of marine origin extracted from the tunicate Ecteinascidia turbinata. This original compound is active against several human tumors including sarcoma and ovarian and breast adenocarcinoma, as evidenced in phase II clinical trials in advanced multitreated patients. Yondelis is a DNA minor groove binder that blocks cell cycle and interferes with inducible gene transcription in a selective manner. In this study, we investigated the immunomodulatory properties of Yondelis on leukocytes. Human blood monocytes were highly susceptible in vitro to its cytotoxic effect and underwent apoptosis at pharmacologically relevant concentrations (5 nmol/L), whereas lymphocytes were up to 5-fold less sensitive. Macrophages differentiated in vitro with macrophage colony-stimulating factor and tumor-associated macrophages (TAM), isolated from patients with ovarian cancer, were also susceptible. At subcytotoxic concentrations, Yondelis inhibited the in vitro differentiation of monocytes to macrophages. In tumor-treated patients, drug infusion caused a selective decrease of monocyte counts and of ex vivo macrophage differentiation. The in vitro production of two proinflammatory mediators, CCL2 and IL-6, was markedly reduced by Yondelis in monocytes, macrophages, TAM, and freshly isolated ovarian tumor cells. The chemokine CCL2 is the major determinant of monocyte recruitment at tumor sites, whereas IL-6 is a growth factor for ovarian tumors. In view of the protumor activity of TAM and of the strong association between chronic inflammation and cancer progression, the inhibitory effect of Yondelis on macrophage viability, differentiation, and cytokine production is likely to contribute to the antitumor activity of this agent in inflammation-associated human tumors.

Published
2005

13. Anti-inflammatory Properties of the Novel Antitumor Agent Yondelis (Trabectedin): Inhibition of Macrophage Differentiation and Cytokine Production

Author

Federica Marchesi, Claudia Bonardi, Chiara Omero Olimpio, Jose Jimeno, Marcello Chieppa, Filippo de Braud, Andrea Lissoni, Annalisa Garbi, Maurizio D'Incalci, Paola Allavena, Mauro Signorelli, Eugenio Erba, Giancarlo Bianchi, Allavena, P., Signorelli, M., Chieppa, M., Erba, E., Bianchi, G., Marchesi, F., Olimpio, C. O., Bonardi, C., Garbi, A., Lissoni, A., De Braud, F., Jimeno, J., D'Incalci, M., Allavena, P, Signorelli, M, Chieppa, M, Erba, E, Bianchi, G, Marchesi, F, Olimpio, C, Bonardi, C, Garbi, A, Lissoni, A, de Braud, F, Jimeno, J, and D'Incalci, M

Subjects
Cancer Research, Chemokine, Cell Survival, Macrophage, medicine.medical_treatment, Apoptosis, Dioxoles, Dioxole, Ecteinascidia turbinata, CCL2, Monocyte, Monocytes, Proinflammatory cytokine, Ovarian tumor, Tetrahydroisoquinolines, Tetrahydroisoquinoline, medicine, Humans, BIO/14 - FARMACOLOGIA, Antineoplastic Agents, Alkylating, Cytokine, Trabectedin, Isoquinoline, biology, Macrophages, Apoptosi, Cell Differentiation, Isoquinolines, biology.organism_classification, medicine.anatomical_structure, Oncology, Immunology, MED/06 - ONCOLOGIA MEDICA, biology.protein, Cancer research, Cytokines, Human, medicine.drug
Abstract

Yondelis (Trabectedin) is a novel antitumor agent of marine origin extracted from the tunicate Ecteinascidia turbinata. This original compound is active against several human tumors including sarcoma and ovarian and breast adenocarcinoma, as evidenced in phase II clinical trials in advanced multitreated patients. Yondelis is a DNA minor groove binder that blocks cell cycle and interferes with inducible gene transcription in a selective manner. In this study, we investigated the immunomodulatory properties of Yondelis on leukocytes. Human blood monocytes were highly susceptible in vitro to its cytotoxic effect and underwent apoptosis at pharmacologically relevant concentrations (5 nmol/L), whereas lymphocytes were up to 5-fold less sensitive. Macrophages differentiated in vitro with macrophage colony-stimulating factor and tumor-associated macrophages (TAM), isolated from patients with ovarian cancer, were also susceptible. At subcytotoxic concentrations, Yondelis inhibited the in vitro differentiation of monocytes to macrophages. In tumor-treated patients, drug infusion caused a selective decrease of monocyte counts and of ex vivo macrophage differentiation. The in vitro production of two proinflammatory mediators, CCL2 and IL-6, was markedly reduced by Yondelis in monocytes, macrophages, TAM, and freshly isolated ovarian tumor cells. The chemokine CCL2 is the major determinant of monocyte recruitment at tumor sites, whereas IL-6 is a growth factor for ovarian tumors. In view of the protumor activity of TAM and of the strong association between chronic inflammation and cancer progression, the inhibitory effect of Yondelis on macrophage viability, differentiation, and cytokine production is likely to contribute to the antitumor activity of this agent in inflammation-associated human tumors.

Published
2005
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14. Genomic reanalysis of a pan-European rare-disease resource yields new diagnoses.

Author

Laurie S, Steyaert W, de Boer E, Polavarapu K, Schuermans N, Sommer AK, Demidov G, Ellwanger K, Paramonov I, Thomas C, Aretz S, Baets J, Benetti E, Bullich G, Chinnery PF, Clayton-Smith J, Cohen E, Danis D, de Sainte Agathe JM, Denommé-Pichon AS, Diaz-Manera J, Efthymiou S, Faivre L, Fernandez-Callejo M, Freeberg M, Garcia-Pelaez J, Guillot-Noel L, Haack TB, Hanna M, Hengel H, Horvath R, Houlden H, Jackson A, Johansson L, Johari M, Kamsteeg EJ, Kellner M, Kleefstra T, Lacombe D, Lochmüller H, López-Martín E, Macaya A, Marcé-Grau A, Maver A, Morsy H, Muntoni F, Musacchia F, Nelson I, Nigro V, Olimpio C, Oliveira C, Paulasová Schwabová J, Pauly MG, Peterlin B, Peters S, Pfundt R, Piluso G, Piscia D, Posada M, Reich S, Renieri A, Ryba L, Šablauskas K, Savarese M, Schöls L, Schütz L, Steinke-Lange V, Stevanin G, Straub V, Sturm M, Swertz MA, Tartaglia M, Te Paske IBAW, Thompson R, Torella A, Trainor C, Udd B, Van de Vondel L, van de Warrenburg B, van Reeuwijk J, Vandrovcova J, Vitobello A, Vos J, Vyhnálková E, Wijngaard R, Wilke C, William D, Xu J, Yaldiz B, Zalatnai L, Zurek B, Brookes AJ, Evangelista T, Gilissen C, Graessner H, Hoogerbrugge N, Ossowski S, Riess O, Schüle R, Synofzik M, Verloes A, Matalonga L, Brunner HG, Lohmann K, de Voer RM, Töpf A, Vissers LELM, Beltran S, and Hoischen A

Subjects
Humans, Europe, Male, Female, Pedigree, Databases, Genetic, Computational Biology methods, Genome, Human genetics, Exome genetics, Rare Diseases genetics, Rare Diseases diagnosis, Genomics methods
Abstract

Genetic diagnosis of rare diseases requires accurate identification and interpretation of genomic variants. Clinical and molecular scientists from 37 expert centers across Europe created the Solve-Rare Diseases Consortium (Solve-RD) resource, encompassing clinical, pedigree and genomic rare-disease data (94.5% exomes, 5.5% genomes), and performed systematic reanalysis for 6,447 individuals (3,592 male, 2,855 female) with previously undiagnosed rare diseases from 6,004 families. We established a collaborative, two-level expert review infrastructure that allowed a genetic diagnosis in 506 (8.4%) families. Of 552 disease-causing variants identified, 464 (84.1%) were single-nucleotide variants or short insertions/deletions. These variants were either located in recently published novel disease genes (n = 67), recently reclassified in ClinVar (n = 187) or reclassified by consensus expert decision within Solve-RD (n = 210). Bespoke bioinformatics analyses identified the remaining 15.9% of causative variants (n = 88). Ad hoc expert review, parallel to the systematic reanalysis, diagnosed 249 (4.1%) additional families for an overall diagnostic yield of 12.6%. The infrastructure and collaborative networks set up by Solve-RD can serve as a blueprint for future further scalable international efforts. The resource is open to the global rare-disease community, allowing phenotype, variant and gene queries, as well as genome-wide discoveries., Competing Interests: Competing interests: M. Synofzik has received consultancy honoraria from Janssen, Ionis, Orphazyme, Servier, Reata, GenOrph and AviadoBio, all unrelated to the present manuscript. B.v.d.W. has received consultancy honoraria from, and/or has served on advisory boards for, Servier, Biohaven Pharmaceuticals, Vico Therapeutics and Biogen, all unrelated to the present manuscript. The other authors declare no competing interests., (© 2025. The Author(s).)

Published
2025
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15. Variants in mitochondrial disease genes are common causes of inherited peripheral neuropathies.

Author

Ferreira T, Polavarapu K, Olimpio C, Paramonov I, Lochmüller H, and Horvath R

Subjects
Humans, Male, Female, Adult, Middle Aged, Aged, Young Adult, Mutation, Mitochondrial Proteins genetics, Cohort Studies, Adolescent, Charcot-Marie-Tooth Disease genetics, Peripheral Nervous System Diseases genetics, Mitochondrial Diseases genetics
Abstract

Background: Peripheral neuropathies in mitochondrial disease are caused by mutations in nuclear genes encoding mitochondrial proteins, or in the mitochondrial genome. Whole exome or genome sequencing enable parallel testing of nuclear and mtDNA genes, and it has significantly advanced the genetic diagnosis of inherited diseases. Despite this, approximately 40% of all Charcot-Marie-Tooth (CMT) cases remain undiagnosed., Methods: The genome-phenome analysis platform (GPAP) in RD-Connect was utilised to create a cohort of 2087 patients with at least one Human Phenotype Ontology (HPO) term suggestive of a peripheral neuropathy, from a total of 10,935 patients. These patients' genetic data were then analysed and searched for variants in known mitochondrial disease genes., Results: A total of 1,379 rare variants were identified, 44 of which were included in this study as either reported pathogenic or likely causative in 42 patients from 36 families. The most common genes found to be likely causative for an autosomal dominant neuropathy were GDAP1 and GARS1. We also detected heterozygous likely pathogenic variants in DNA2, MFN2, DNM2, PDHA1, SDHA, and UCHL1. Biallelic variants in SACS, SPG7, GDAP1, C12orf65, UCHL1, NDUFS6, ETFDH and DARS2 and variants in the mitochondrial DNA (mtDNA)-encoded MT-ATP6 and MT-TK were also causative for mitochondrial CMT. Only 50% of these variants were already reported as solved in GPAP., Conclusion: Variants in mitochondrial disease genes are frequent in patients with inherited peripheral neuropathies. Due to the clinical overlap between mitochondrial disease and CMT, agnostic exome or genome sequencing have better diagnostic yields than targeted gene panels., (© 2024. The Author(s).)

Published
2024
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16. Increased Diagnostic Yield by Reanalysis of Whole Exome Sequencing Data in Mitochondrial Disease.

Author

Olimpio C, Paramonov I, Matalonga L, Laurie S, Schon K, Polavarapu K, Kirschner J, Schara-Schmidt U, Lochmüller H, Chinnery PF, and Horvath R

Subjects
Humans, Child, Male, Female, Cohort Studies, DNA, Mitochondrial genetics, Mitochondrial Diseases genetics, Mitochondrial Diseases diagnosis, Exome Sequencing methods
Abstract

Background: The genetic diagnosis of mitochondrial disorders is complicated by its genetic and phenotypic complexity. Next generation sequencing techniques have much improved the diagnostic yield for these conditions. A cohort of individuals with multiple respiratory chain deficiencies, reported in the literature 10 years ago, had a diagnostic rate of 60% by whole exome sequencing (WES) but 40% remained undiagnosed., Objective: We aimed to identify a genetic diagnosis by reanalysis of the WES data for the undiagnosed arm of this 10-year-old cohort of patients with suspected mitochondrial disorders., Methods: The WES data was transferred and processed by the RD-Connect Genome-Phenome Analysis Platform (GPAP) using their standardized pipeline. Variant prioritisation was carried out on the RD-Connect GPAP., Results: Singleton WES data from 14 individuals was reanalysed. We identified a possible or likely genetic diagnosis in 8 patients (8/14, 57%). The variants identified were in a combination of mitochondrial DNA (n = 1, MT-TN), nuclear encoded mitochondrial genes (n = 2, PDHA1, and SUCLA2) and nuclear genes associated with nonmitochondrial disorders (n = 5, PNPLA2, CDC40, NBAS and SLC7A7). Variants in both the NBAS and CDC40 genes were established as disease causing after the original cohort was published. We increased the diagnostic yield for the original cohort by 15% without generating any further genomic data., Conclusions: In the era of multiomics we highlight that reanalysis of existing WES data is a valid tool for generating additional diagnosis in patients with suspected mitochondrial disease, particularly when more time has passed to allow for new bioinformatic pipelines to emerge, for the development of new tools in variant interpretation aiding in reclassification of variants and the expansion of scientific knowledge on additional genes.

Published
2024
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17. Case report: Mutations in DNAJC30 causing autosomal recessive Leber hereditary optic neuropathy are common amongst Eastern European individuals.

Author

Major TC, Arany ES, Schon K, Simo M, Karcagi V, van den Ameele J, Yu Wai Man P, Chinnery PF, Olimpio C, and Horvath R

Abstract

Background: Leber Hereditary Optic Neuropathy (LHON) is the most common inherited mitochondrial disease characterized by bilateral, painless, subacute visual loss with a peak age of onset in the second to third decade. Historically, LHON was thought to be exclusively maternally inherited due to mutations in mitochondrial DNA (mtDNA); however, recent studies have identified an autosomal recessive form of LHON (arLHON) caused by point mutations in the nuclear gene, DNAJC30 ., Case Presentations: In this study, we report the cases of three Eastern European individuals presenting with bilateral painless visual loss, one of whom was also exhibiting motor symptoms. After a several-year-long diagnostic journey, all three patients were found to carry the homozygous c.152A>G (p.Tyr51Cys) mutation in DNAJC30 . This has been identified as the most common arLHON pathogenic variant and has been shown to exhibit a significant founder effect amongst Eastern European individuals., Conclusion: This finding adds to the growing cohort of patients with arLHON and demonstrates the importance of DNAJC30 screening in patients with molecularly undiagnosed LHON, particularly in Eastern European individuals. It is of heightened translational significance as patients diagnosed with arLHON exhibit a better prognosis and response to therapeutic treatment with the co-enzyme Q10 analog idebenone., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Major, Arany, Schon, Simo, Karcagi, van den Ameele, Yu Wai Man, Chinnery, Olimpio and Horvath.)

Published
2023
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18. TEFM variants impair mitochondrial transcription causing childhood-onset neurological disease.

Author

Van Haute L, O'Connor E, Díaz-Maldonado H, Munro B, Polavarapu K, Hock DH, Arunachal G, Athanasiou-Fragkouli A, Bardhan M, Barth M, Bonneau D, Brunetti-Pierri N, Cappuccio G, Caruana NJ, Dominik N, Goel H, Helman G, Houlden H, Lenaers G, Mention K, Murphy D, Nandeesh B, Olimpio C, Powell CA, Preethish-Kumar V, Procaccio V, Rius R, Rebelo-Guiomar P, Simons C, Vengalil S, Zaki MS, Ziegler A, Thorburn DR, Stroud DA, Maroofian R, Christodoulou J, Gustafsson C, Nalini A, Lochmüller H, Minczuk M, and Horvath R

Subjects
Child, Animals, Humans, RNA, Mitochondrial, DNA, Mitochondrial genetics, Transcription, Genetic, Mutation, Mitochondrial Proteins genetics, Mitochondrial Proteins metabolism, Transcription Factors genetics, Zebrafish genetics, Zebrafish metabolism
Abstract

Mutations in the mitochondrial or nuclear genomes are associated with a diverse group of human disorders characterized by impaired mitochondrial respiration. Within this group, an increasing number of mutations have been identified in nuclear genes involved in mitochondrial RNA biology. The TEFM gene encodes the mitochondrial transcription elongation factor responsible for enhancing the processivity of mitochondrial RNA polymerase, POLRMT. We report for the first time that TEFM variants are associated with mitochondrial respiratory chain deficiency and a wide range of clinical presentations including mitochondrial myopathy with a treatable neuromuscular transmission defect. Mechanistically, we show muscle and primary fibroblasts from the affected individuals have reduced levels of promoter distal mitochondrial RNA transcripts. Finally, tefm knockdown in zebrafish embryos resulted in neuromuscular junction abnormalities and abnormal mitochondrial function, strengthening the genotype-phenotype correlation. Our study highlights that TEFM regulates mitochondrial transcription elongation and its defect results in variable, tissue-specific neurological and neuromuscular symptoms., (© 2023. The Author(s).)

Published
2023
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19. Primary mitochondrial myopathies in childhood.

Author

Olimpio C, Tiet MY, and Horvath R

Subjects
Child, DNA, Mitochondrial genetics, Humans, Metabolism, Inborn Errors genetics, Mitochondria pathology, Muscle Weakness genetics, Muscle, Skeletal pathology, Mitochondrial Myopathies genetics
Abstract

Primary mitochondrial myopathies are genetic metabolic disorders of mitochondrial dysfunction affecting mainly, but not exclusively, skeletal muscle. Although individually rare, they are the most common inherited metabolic disorders in childhood. They can be similar to other childhood muscle diseases such as congenital myopathies, dystrophies, myasthenic syndromes or metabolic myopathies and a muscle biopsy and genetic testing are important in the differential diagnosis. Mitochondrial myopathies can present at any age but typically childhood onset myopathies have more significant muscle involvement and are caused by genes encoded in the nuclear DNA. Mitochondrial myopathy in infants presents with hypotonia, muscle weakness and difficulty feeding. In toddlers and older children delayed motor development, exercise intolerance and premature fatigue are common. A number of nuclear DNA and mitochondrial DNA encoded genes are known to cause isolated myopathy in childhood and they are important in a range of mitochondrial functions such as oxidative phosphorylation, mitochondrial transcription/translation and mitochondrial fusion/fission. A rare cause of isolated myopathy in children, reversible infantile respiratory chain deficiency myopathy, is non-progressive and typically associated with spontaneous full recovery. Promising targeted treatments have been reported for a number or mitochondrial myopathies including riboflavin in ACAD9 and ETFDH-myopathies and deoxynucleoside for TK2-related disease., Competing Interests: Declaration of Competing Interest I confirm that none of the co-authors of the paper “Primary mitochondrial myopathies in childhood” have a conflict of interest or anything to disclose., (Copyright © 2021. Published by Elsevier B.V.)

Published
2021
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