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1. Mutations in RYR1 are a common cause of exertional myalgia and rhabdomyolysis

Author

Dlamini, N., Voermans, N.C., Lillis, S., Stewart, K., Kamsteeg, E.-J., Drost, G., Quinlivan, R., Snoeck, M., Norwood, F., Radunovic, A., Straub, V., Roberts, M., Vrancken, A.F.J.E., van der Pol, W.L., de Coo, R.I.F.M., Manzur, A.Y., Yau, S., Abbs, S., King, A., Lammens, M., Hopkins, P.M., Mohammed, S., Treves, S., Muntoni, F., Wraige, E., Davis, M.R., van Engelen, B., and Jungbluth, H.

Published
2013
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5. 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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6. Whole genome sequencing for diagnosis of neurological repeat expansion disorders

Author

Greenhalgh L, Fowler T, Karen Temple, Kane Smith, Deshpande, Subramanian S. Ajay, Bourn D, Menzies L, James M. Polke, Pasko D, Polychronopoulos D, Augusto Rendon, Pietro Fratta, Madeleine Reilly, Daugherty L, Chitty Ls, Eggleton K, Raymond Fl, Thomas T. Warner, Paul Brennan, Sian Ellard, Denise L. Perry, Jill Davison, A. C. Need, Arianna Tucci, Prasad Korlipara Lv, Mark J. Caulfield, Meriel McEntagart, Huw R. Morris, Kikkeri N. Naresh, Jenny C. Taylor, Patrick F. Chinnery, Anette Schrag, Aditi Chawla, Deans Zc, Henry Houlden, Twiss P, Douglas A, Sheikh I, Jonathan M. Schott, Hill S, Moutsianas L, Nicholas W. Wood, Tanner Hagelstrom, Robinson R, D. Kasperaviciute, Faravelli F, Rajan, Kristina Ibáñez, Antonio Rueda Martin, Emma L. Baple, Robin Howard, Ellen M. McDonagh, Elisabeth Rosser, Oprych K, Richard Festenstein, John A. Sayer, Kailash P. Bhatia, Michael A. Eberle, Andrew D Mumford, Angus-Leppan H, Thomas E, Matilde Laura, McMullan D, Brittain H, Paola Giunti, Richard H. Scott, Wilson G, Taylor Tavares Al, Ryan J. Taft, Patch C, Hyder Z, Robyn Labrum, Almheiri G, Frances Flinter, Egor Dolzhenko, Santos L, Abbs S, William G. Newman, and Jana Vandrovcova

Subjects
Whole genome sequencing, Pediatrics, medicine.medical_specialty, medicine.diagnostic_test, business.industry, Genome, Medicine, Social care, False positive rate, Allele, Family history, business, Trinucleotide repeat expansion, Genetic testing
Abstract

BackgroundRepeat expansion (RE) disorders affect ~1 in 3000 individuals and are clinically heterogeneous diseases caused by expansions of short tandem DNA repeats. Genetic testing is often locus-specific, resulting in under diagnosis of atypical clinical presentations, especially in paediatric patients without a prior positive family history. Whole genome sequencing (WGS) is emerging as a first-line test for rare genetic disorders, but until recently REs were thought to be undetectable by this approach.MethodsWGS pipelines for RE disorder detection were deployed by the 100,000 Genomes Project and Illumina Clinical Services Laboratory. Performance was retrospectively assessed across the 13 most common neurological RE loci using 793 samples with prior orthogonal testing (182 with expanded alleles and 611 with alleles within normal size) and prospectively interrogated in 13,331 patients with suspected genetic neurological disorders.FindingsWGS RE detection showed minimum 97·3% sensitivity and 99·6% specificity across all 13 disease-associated loci. Applying the pipeline to patients from the 100,000 Genomes Project identified pathogenic repeat expansions which were confirmed in 69 patients, including seven paediatric patients with no reported family history of RE disorders, with a 0.09% false positive rate.InterpretationWe show here for the first time that WGS enables the detection of causative repeat expansions with high sensitivity and specificity, and that it can be used to resolve previously undiagnosed neurological disorders. This includes children with no prior suspicion of a RE disorder. These findings are leading to diagnostic implementation of this analytical pipeline in the NHS Genomic Medicine Centres in England.FundingMedical Research Council, Department of Health and Social Care, National Health Service England, National Institute for Health Research, Illumina Inc

Published
2020

10. Germline selection shapes human mitochondrial DNA diversity

Author

Wei, W, Tuna, S, Keogh, MJ, Smith, KR, Aitman, TJ, Beales, PL, Bennett, DL, Gale, DP, Bitner-Glindzicz, MAK, Black, GC, Brennan, P, Elliott, P, Flinter, FA, Floto, RA, Houlden, H, Irving, M, Koziell, A, Maher, ER, Markus, HS, Morrell, NW, Newman, WG, Roberts, I, Sayer, JA, Smith, KGC, Taylor, JC, Watkins, H, Webster, AR, Wilkie, AOM, Williamson, C, Attwood, A, Brown, M, Brod, NC, Crisp-Hihn, A, Davis, J, Deevi, SVV, Dewhurst, EF, Edwards, K, Erwood, M, Fox, J, Frary, AJ, Hu, F, Jolley, J, Kingston, N, Linger, R, Mapeta, R, Martin, J, Meacham, S, Papadia, S, Rayner-Matthews, PJ, Samarghitean, C, Shamardina, O, Simeoni, I, Staines, S, Staples, E, Stark, H, Stephens, J, Titterton, C, Von Ziegenweidt, J, Watt, C, Whitehorn, D, Wood, Y, Yates, K, Yu, P, James, R, Ashford, S, Penkett, CJ, Stirrups, KE, Bariana, T, Lentaigne, C, Sivapalaratnam, S, Westbury, SK, Allsup, DJ, Bakchoul, T, Biss, T, Boyce, S, Collins, J, Collins, PW, Curry, NS, Downes, K, Dutt, T, Erber, WN, Evans, G, Everington, T, Favier, R, Gomez, K, Greene, D, Gresele, P, Hart, D, Kazmi, R, Kelly, AM, Lambert, M, Madan, B, Mangles, S, Mathias, M, Millar, C, Obaji, S, Peerlinck, K, Roughley, C, Schulman, S, Scully, M, Shapiro, SE, Sibson, K, Sims, MC, Tait, RC, Talks, K, Thys, C, Toh, C-H, Van Geet, C, Westwood, J-P, Mumford, AD, Ouwehand, WH, Freson, K, Laffan, MA, Tan, RYY, Harkness, K, Mehta, S, Muir, KW, Hassan, A, Traylor, M, Drazyk, AM, Parry, D, Ahmed, M, Kazkaz, H, Vandersteen, AM, Ormondroyd, E, Thomson, K, Dent, T, Buchan, RJ, Bueser, T, Carr-White, G, Cook, S, Daniels, MJ, Harper, AR, Ware, JS, Dixon, PH, Chambers, J, Cheng, F, Estiu, MC, Hague, WM, Marschall, H-U, Vazquez-Lopez, M, Arno, G, French, CE, Michaelides, M, Moore, AT, Sanchis-Juan, A, Carss, K, Raymond, FL, Chinnery, PF, Griffiths, P, Horvath, R, Hudson, G, Jurkute, N, Pyle, A, Yu-Wai-Man, P, Whitworth, J, Adlard, J, Armstrong, R, Brewer, C, Casey, R, Cole, TRP, Evans, DG, Greenhalgh, L, Hanson, HL, Hoffman, J, Izatt, L, Kumar, A, Lalloo, F, Ong, KR, Park, S-M, Searle, C, Side, L, Snape, K, Woodward, E, Tischkowitz, M, Grozeva, D, Kurian, MA, Themistocleous, AC, Gosal, D, Marshall, A, Matthews, E, McCarthy, MI, Renton, T, Rice, ASC, Vale, T, Walker, SM, Woods, CG, Thaventhiran, JE, Allen, HL, Savic, S, Alachkar, H, Antrobus, R, Baxendale, HE, Browning, MJ, Buckland, MS, Cooper, N, Edgar, JDM, Egner, W, Gilmour, KC, Goddard, S, Gordins, P, Grigoriadou, S, Hackett, S, Hague, R, Hayman, G, Herwadkar, A, Huissoon, AP, Jolles, S, Kelleher, P, Kumararatne, D, Longhurst, H, Lorenzo, LE, Lyons, PA, Maimaris, J, Noorani, S, Richter, A, Sargur, RB, Sewell, WAC, Thomas, D, Thomas, MJ, Worth, A, Yong, PFK, Kuijpers, TW, Thrasher, AJ, Levine, AP, Sadeghi-Alavijeh, O, Wong, EKS, Cook, HT, Chan, MMY, Hall, M, Harris, C, McAlinden, P, Marchbank, KJ, Marks, S, Maxwell, H, Mozere, M, Wessels, J, Johnson, SA, Bleda, M, Hadinnapola, C, Haimel, M, Swietlik, E, Bogaard, H, Church, C, Coghlan, G, Condliffe, R, Corris, P, Danesino, C, Eyries, M, Gall, H, Ghofrani, H-A, Gibbs, JSR, Girerd, B, Holden, S, Houweling, A, Howard, LS, Humbert, M, Kiely, DG, Kovacs, G, Lawrie, A, Ross, RVM, Moledina, S, Montani, D, Newnham, M, Olschewski, A, Olschewski, H, Peacock, A, Pepke-Zaba, J, Scelsi, L, Seeger, W, Soubrier, F, Suntharalingam, J, Toshner, M, Treacy, C, Trembath, R, Noordegraaf, AV, Waisfisz, Q, Wharton, J, Wilkins, MR, Wort, SJ, Graf, S, Louka, E, Roy, NB, Rao, A, Ancliff, P, Babbs, C, Layton, DM, Mead, AJ, O'Sullivan, J, Okoli, S, Saleem, M, Bierzynska, A, Diz, CB, Colby, E, Ekani, MN, Satchell, S, Fowler, T, Rendon, A, Scott, R, Smedley, D, Thomas, E, Caulfield, M, Abbs, S, Burrows, N, Chitre, M, Gattens, M, Gurnell, M, Kelsall, W, Poole, KES, Ross-Russell, R, Spasic-Boskovic, O, Twiss, P, Wagner, A, Banka, S, Clayton-Smith, J, Douzgou, S, Abulhoul, L, Aurora, P, Bockenhauer, D, Cleary, M, Dattani, M, Ganesan, V, Pilkington, C, Rahman, S, Shah, N, Wedderburn, L, Compton, CJ, Deshpande, C, Fassihi, H, Haque, E, Josifova, D, Mohammed, SN, Robert, L, Rose, SJ, Ruddy, DM, Sarkany, RN, Sayer, G, Shaw, AC, Campbell, C, Gibson, K, Koelling, N, Lester, T, Nemeth, AH, Palles, C, Patel, S, Sen, A, Taylor, J, Tomlinson, IP, Malka, S, Browning, AC, Burn, J, De Soyza, A, Graham, J, Pearce, S, Quinton, R, Schaefer, AM, Wilson, BT, Wright, M, Simpson, M, Syrris, P, Bradley, JR, Turro, E, ARD - Amsterdam Reproduction and Development, AII - Inflammatory diseases, Paediatric Infectious Diseases / Rheumatology / Immunology, Medical Research Council (MRC), Wellcome Trust, Wei, Wei [0000-0002-2945-3543], Tuna, Salih [0000-0003-3606-4367], Smith, Katherine R [0000-0002-0329-5938], Beales, Phil L [0000-0002-9164-9782], Bennett, David L [0000-0002-7996-2696], Gale, Daniel P [0000-0002-9170-1579], Brennan, Paul [0000-0003-1128-6254], Elliott, Perry [0000-0003-3383-3984], Floto, R Andres [0000-0002-2188-5659], Houlden, Henry [0000-0002-2866-7777], Koziell, Ania [0000-0003-4882-0246], Maher, Eamonn R [0000-0002-6226-6918], Markus, Hugh S [0000-0002-9794-5996], Morrell, Nicholas W [0000-0001-5700-9792], Newman, William G [0000-0002-6382-4678], Sayer, John A [0000-0003-1881-3782], Smith, Kenneth GC [0000-0003-3829-4326], Taylor, Jenny C [0000-0003-3602-5704], Watkins, Hugh [0000-0002-5287-9016], Webster, Andrew R [0000-0001-6915-9560], Wilkie, Andrew OM [0000-0002-2972-5481], Penkett, Christopher J [0000-0003-4006-7261], Stirrups, Kathleen E [0000-0002-6823-3252], Rendon, Augusto [0000-0001-8994-0039], Bradley, John R [0000-0002-7774-8805], Turro, Ernest [0000-0002-1820-6563], Chinnery, Patrick F [0000-0002-7065-6617], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Non-Mendelian inheritance, Genome, Mitochondrial/genetics, DNA, Mitochondrial/genetics, 0302 clinical medicine, Ovum/growth & development, MTDNA, TRANSCRIPTION, Genetics, education.field_of_study, Multidisciplinary, NIHR BioResource–Rare Diseases, ASSOCIATION, Heteroplasmy, Mitochondrial, Multidisciplinary Sciences, GENOME, REPLACEMENT, Science & Technology - Other Topics, Female, Maternal Inheritance, Mitochondrial DNA, General Science & Technology, Genetic genealogy, Population, Biology, Human mitochondrial genetics, SEQUENCE, DNA, Mitochondrial, 03 medical and health sciences, Genetic, 100,000 Genomes Project–Rare Diseases Pilot, Genetic variation, MD Multidisciplinary, Humans, Selection, Genetic, education, Selection, Ovum, Science & Technology, MUTATIONS, Genetic Variation, DNA, LEIGH-DISEASE, 030104 developmental biology, REPLICATION, Genome, Mitochondrial, HETEROPLASMY, 030217 neurology & neurosurgery
Abstract

INTRODUCTION Only 2.4% of the 16.5-kb mitochondrial DNA (mtDNA) genome shows homoplasmic variation at >1% frequency in humans. Migration patterns have contributed to geographic differences in the frequency of common genetic variants, but population genetic evidence indicates that selection shapes the evolving mtDNA phylogeny. The mechanism and timing of this process are not clear. Unlike the nuclear genome, mtDNA is maternally transmitted and there are many copies in each cell. Initially, a new genetic variant affects only a proportion of the mtDNA (heteroplasmy). During female germ cell development, a reduction in the amount of mtDNA per cell causes a “genetic bottleneck,” which leads to rapid segregation of mtDNA molecules and different levels of heteroplasmy between siblings. Although heteroplasmy is primarily governed by random genetic drift, there is evidence of selection occurring during this process in animals. Yet it has been difficult to demonstrate this convincingly in humans. RATIONALE To determine whether there is selection for or against heteroplasmic mtDNA variants during transmission, we studied 12,975 whole-genome sequences, including 1526 mother–offspring pairs of which 45.1% had heteroplasmy affecting >1% of mtDNA molecules. Harnessing both the mtDNA and nuclear genome sequences, we then determined whether the nuclear genetic background influenced mtDNA heteroplasmy, validating our findings in another 40,325 individuals. RESULTS Previously unknown mtDNA variants were less likely to be inherited than known variants, in which the level of heteroplasmy tended to increase on transmission. Variants in the ribosomal RNA genes were less likely to be transmitted, whereas variants in the noncoding displacement (D)–loop were more likely to be transmitted. MtDNA variants predicted to affect the protein sequence tended to have lower heteroplasmy levels than synonymous variants. In 12,975 individuals, we identified a correlation between the location of heteroplasmic sites and known D-loop polymorphisms, including the absence of variants in critical sites required for mtDNA transcription and replication. We defined 206 unrelated individuals for which the nuclear and mitochondrial genomes were from different human populations. In these individuals, new population-specific heteroplasmies were more likely to match the nuclear genetic ancestry than the mitochondrial genome on which the mutations occurred. These findings were independently replicated in 654 additional unrelated individuals. CONCLUSION The characteristics of mtDNA in the human population are shaped by selective forces acting on heteroplasmy within the female germ line and are influenced by the nuclear genetic background. The signature of selection can be seen over one generation, ensuring consistency between these two independent genetic systems.

Published
2019
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11. Whole genome sequencing reveals that genetic conditions are frequent in intensively ill children

Author

French, CE, Delon, I, Dolling, H, Sanchis-Juan, A, Shamardina, O, Mégy, K, Abbs, S, Austin, T, Bowdin, S, Branco, RG, Firth, H, Tuna, S, Aitman, TJ, Ashford, S, Astle, WJ, Bennet, DL, Bleda, M, Carss, KJ, Chinnery, PF, Deevi, SVV, Fletcher, D, Gale, DP, Gräf, SF, Hu, F, James, R, Kasanicki, MA, Kingston, N, Koziell, AB, Allen, HL, Maher, ER, Markus, HS, Meacham, S, Morrell, NW, Penkett, CJ, Roberts, I, Smith, KGC, Stark, H, Stirrups, KE, Turro, E, Watkins, H, Williamson, C, Young, T, Bradley, JR, Ouwehand, WH, Raymond, FL, Agrawal, S, Armstrong, R, Beardsall, K, Belteki, G, Bohatschek, M, Broster, S, Campbell, R, Chaudhary, R, Costa, C, D’Amore, A, Fitzsimmons, A, Hague, J, Harley, J, Hoodbhoy, S, Kayani, R, Kelsall, W, Mehta, SG, O’Donnell, R, O’Hare, S, Ogilvy-Stuart, A, Papakostas, S, Park, SM, Parker, A, Pathan, N, Prapa, M, Sammut, A, Sandford, R, Schon, K, Singh, Y, Spike, K, Tavares, ALT, Wari-Pepple, D, Wong, HS, Woods, CG, Rowitch, DH, Raymond, F Lucy [0000-0003-2652-3355], and Apollo - University of Cambridge Repository

Subjects
Male, NICU, medicine.medical_specialty, Palliative care, Adolescent, PICU, Original, Critical Illness, Critically ill children, Genomics, Critical Care and Intensive Care Medicine, Intensive Care Units, Pediatric, State Medicine, Cohort Studies, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Anesthesiology, Intensive care, Intensive Care Units, Neonatal, Genetics, Medicine, Humans, Prospective Studies, Medical diagnosis, Intensive care medicine, Prospective cohort study, Child, Whole genome sequencing, Whole Genome Sequencing, business.industry, Genetic Diseases, Inborn, Infant, Newborn, Infant, 030208 emergency & critical care medicine, 030228 respiratory system, England, FOS: Biological sciences, Child, Preschool, Female, business, Genetic Background, Cohort study
Abstract

Purpose With growing evidence that rare single gene disorders present in the neonatal period, there is a need for rapid, systematic, and comprehensive genomic diagnoses in ICUs to assist acute and long-term clinical decisions. This study aimed to identify genetic conditions in neonatal (NICU) and paediatric (PICU) intensive care populations. Methods We performed trio whole genome sequence (WGS) analysis on a prospective cohort of families recruited in NICU and PICU at a single site in the UK. We developed a research pipeline in collaboration with the National Health Service to deliver validated pertinent pathogenic findings within 2–3 weeks of recruitment. Results A total of 195 families had whole genome analysis performed (567 samples) and 21% received a molecular diagnosis for the underlying genetic condition in the child. The phenotypic description of the child was a poor predictor of the gene identified in 90% of cases, arguing for gene agnostic testing in NICU/PICU. The diagnosis affected clinical management in more than 65% of cases (83% in neonates) including modification of treatments and care pathways and/or informing palliative care decisions. A 2–3 week turnaround was sufficient to impact most clinical decision-making. Conclusions The use of WGS in intensively ill children is acceptable and trio analysis facilitates diagnoses. A gene agnostic approach was effective in identifying an underlying genetic condition, with phenotypes and symptomatology being primarily used for data interpretation rather than gene selection. WGS analysis has the potential to be a first-line diagnostic tool for a subset of intensively ill children. Electronic supplementary material The online version of this article (10.1007/s00134-019-05552-x) contains supplementary material, which is available to authorized users.

Published
2019

12. Re-annotation of 191 developmental and epileptic encephalopathy-associated genes unmasks de novo variants in SCN1A

Author

Steward, CA, Roovers, J, Suner, M-M, Gonzalez, JM, Uszczynska-Ratajczak, B, Pervouchine, D, Fitzgerald, S, Viola, M, Stamberger, H, Hamdan, FF, Ceulemans, B, Leroy, P, Nava, C, Lepine, A, Tapanari, E, Keiller, D, Abbs, S, Sanchis-Juan, A, Grozeva, D, Rogers, AS, Diekhans, M, Guigo, R, Petryszak, R, Minassian, BA, Cavalleri, G, Vitsios, D, Petrovski, S, Harrow, J, Flicek, P, Raymond, FL, Lench, NJ, De Jonghe, P, Mudge, JM, Weckhuysen, S, Sisodiya, SM, Frankish, A, Steward, CA, Roovers, J, Suner, M-M, Gonzalez, JM, Uszczynska-Ratajczak, B, Pervouchine, D, Fitzgerald, S, Viola, M, Stamberger, H, Hamdan, FF, Ceulemans, B, Leroy, P, Nava, C, Lepine, A, Tapanari, E, Keiller, D, Abbs, S, Sanchis-Juan, A, Grozeva, D, Rogers, AS, Diekhans, M, Guigo, R, Petryszak, R, Minassian, BA, Cavalleri, G, Vitsios, D, Petrovski, S, Harrow, J, Flicek, P, Raymond, FL, Lench, NJ, De Jonghe, P, Mudge, JM, Weckhuysen, S, Sisodiya, SM, and Frankish, A

Abstract

The developmental and epileptic encephalopathies (DEE) are a group of rare, severe neurodevelopmental disorders, where even the most thorough sequencing studies leave 60-65% of patients without a molecular diagnosis. Here, we explore the incompleteness of transcript models used for exome and genome analysis as one potential explanation for a lack of current diagnoses. Therefore, we have updated the GENCODE gene annotation for 191 epilepsy-associated genes, using human brain-derived transcriptomic libraries and other data to build 3,550 putative transcript models. Our annotations increase the transcriptional 'footprint' of these genes by over 674 kb. Using SCN1A as a case study, due to its close phenotype/genotype correlation with Dravet syndrome, we screened 122 people with Dravet syndrome or a similar phenotype with a panel of exon sequences representing eight established genes and identified two de novo SCN1A variants that now - through improved gene annotation - are ascribed to residing among our exons. These two (from 122 screened people, 1.6%) molecular diagnoses carry significant clinical implications. Furthermore, we identified a previously classified SCN1A intronic Dravet syndrome-associated variant that now lies within a deeply conserved exon. Our findings illustrate the potential gains of thorough gene annotation in improving diagnostic yields for genetic disorders.

Published
2019

13. 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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14. Evaluation of universal immunohistochemical screening of sebaceous neoplasms in a service setting

Author

Schon, K, Rytina, E, Drummond, J, Simmonds, J, Abbs, S, Sandford, R, Tischkowitz, M, Schon, K [0000-0001-8054-8954], and Apollo - University of Cambridge Repository

Subjects
Adenoma, Adult, Aged, 80 and over, Male, Carcinoma, Middle Aged, DNA Mismatch Repair, Immunohistochemistry, Young Adult, Muir-Torre Syndrome, Humans, Mass Screening, Female, Sebaceous Gland Neoplasms, Germ-Line Mutation, Aged, Mismatch Repair Endonuclease PMS2
Abstract

BACKGROUND: Muir-Torre syndrome (MTS) is a subtype of Lynch syndrome, which encompasses the combination of sebaceous skin tumours or keratoacanthomas and internal malignancy, due to mutations in DNA mismatch repair genes. Sebaceous neoplasms (SNs) may occur before other malignancies, and may lead to the diagnosis, which allows testing of other family members, cancer surveillance, risk-reducing surgery or prevention therapies. AIM: To evaluate the efficacy of universal immunohistochemistry (IHC) screening of SNs in a service setting. METHODS: Patients with SNs were ascertained by a regional clinical pathology service over a 3-year period. Results of tumour IHC, clinical genetics notes and germline genetic testing were retrospectively reviewed. RESULTS: In total, 62 patients presented with 71 SNs; 9 (15%) of these patients had previously diagnosed MTS. Tumour IHC was performed for 50 of the 53 remaining patients (94%); 26 (52%) had loss of staining of one or more mismatch repair proteins. Fifteen patients were referred to the Clinical Genetics department, and 10 patients underwent germline genetic testing. Two had a new diagnosis of MTS confirmed, with heterozygous pathogenic mutations detected in the MSH2 and PMS2 genes (diagnostic yield 20%). The PMS2 mutation was identified in a 57-year-old woman with a sebaceous adenoma and history of endometrial cancer; to our knowledge, this is the first time a PMS2 mutation has been reported in MTS. CONCLUSIONS: Universal IHC screening of SNs is an effective method to identify cases for further genetic evaluation. Rates of referral to clinical genetics were only moderate (58%). Increased awareness of MTS could help improve the rate of onward referral.

Published
2018

15. Mosaicism for a pathogenic $\textit{MFN2}$ mutation causes minimal clinical features of CMT2A in the parent of a severely affected child

Author

Schon, K, Spasic-Boskovic, O, Brugger, K, Graves, TD, Abbs, S, Park, S-M, Ambegaonkar, G, Armstrong, R, Schon, Katherine [0000-0001-8054-8954], and Apollo - University of Cambridge Repository

Subjects
MFN2, CMT2A, mosaicism, Charcot-Marie-tooth disease
Abstract

Charcot-Marie-Tooth disease (CMT) refers to a genetically heterogeneous group of disorders which cause a peripheral motor and sensory neuropathy. The overall prevalence is 1 in 2500 individuals. Mutations in the $\textit{MFN2}$ gene are the commonest cause for the axonal (CMT2) type. We describe a Caucasian 5-year old girl affected by CMT2A since the age of 2 years. She presented with unsteady gait, inturning of the feet and progressive foot deformities. Nerve conduction studies suggested an axonal neuropathy and molecular testing identified a previously reported pathogenic variant c.1090C > T, p.(Arg364Trp) in the $\textit{MFN2}$ gene. This variant was also detected in a mosaic state in blood and saliva by Sanger sequencing in her subjectively healthy father. Next generation sequencing showed that the level of mosaicism was 21% in blood and 24% in saliva. A high recurrence risk was given because the father had proven somatic mosaicism and an affected child implying gonadal mosaicism. The parents were referred for pre-implantation genetic diagnosis. To the best of our knowledge, this is the first reported case of somatic mosaicism for $\textit{MFN2}$. This study has important implications for genetic counselling in families with CMT2A.

Published
2017

17. 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., C.O’Dubhshlaine, 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 (CSG) as though having equivalent penetrance, despite increasing evidence of inter-variant variability in risk associations. Using existing variant interpretation approaches, largely based on full-penetrance models, variants where reduced penetrance is suspected may be classified inconsistently and/or as variants of uncertain significance (VUS). We aimed to develop a national consensus approach for such variants within the Cancer Variant Interpretation Group UK (CanVIG-UK) multidisciplinary network.

Published
2024
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18. Molecular analysis and prenatal screening in spinal muscular atrophy in Singapore

Author

Lai, P.S., Liew, M.H., Abbs, S., Tay, S., Yee, W.C., Biswas, A., Ng, S.C., and Low, P.S.

Subjects
Genetic disorders -- Research, Human chromosome abnormalities -- Research, Human genetics -- Research, Spinal muscular atrophy -- Genetic aspects, Prenatal diagnosis -- Genetic aspects, Biological sciences
Published
2001

20. Congenital myopathies--clinical features and frequency of individual subtypes diagnosed over a 5-year period in the United Kingdom

Author

Maggi, L, Scoto, M, Cirak, S, Robb, S A, Klein, A, Lillis, S, Cullup, T, Feng, L, Manzur, A Y, Sewry, C A, Abbs, S, Jungbluth, H, Muntoni, F, University of Zurich, and Maggi, L

Subjects
2716 Genetics (clinical), 2728 Neurology (clinical), 10036 Medical Clinic, 2808 Neurology, 610 Medicine & health, 2735 Pediatrics, Perinatology and Child Health
Published
2013

23. Local restoration of dystrophin expression with the morpholino oligomer AVI-4658 in Duchenne muscular dystrophy: a single-blind, placebo-controlled, dose-esclation, proof-of-concept study

Author

Kinali, M, Arechavala-Gomeza, V, Feng, L, Cirak, S, Hunt, D, Adkin, C, Guglieri, M, Ashton, E, Abbs, S, Nihoyannopoulos, P, Garralda, M E, Rutherford, M, McCulley, C, Popplewell, L, Graham, I R, Dickson, G, Wood, M J, Wells, D J, Wilton, S D, Kole, R, Staub, V, Bushby, K, Sewry, C, Morgan, J E, Muntoni, F, Guy's Hospital, London, Hammersmith Hospital, Imperial College London, Institute of Child Health, London, Newcastle, and St Mary's Hospital, London

Published
2009

27. Exon skipping and dystrophin restoration in patients with Duchenne muscular dystrophy after systemic phosphorodiamidate morpholino oligomer treatment: An open-label, phase 2, dose-escalation study

Author

Cirak, S., Arechavala-Gomeza, V., Guglieri, M., Feng, L., Torelli, S., Anthony, K., Abbs, S., Garralda, M.E., Bourke, J., Wells, D.J., Dickson, G., Wood, M.J.A., Wilton, S.D., Straub, V., Kole, R., Shrewsbury, S.B., Sewry, C., Morgan, J.E., Bushby, K., Muntoni, F., Cirak, S., Arechavala-Gomeza, V., Guglieri, M., Feng, L., Torelli, S., Anthony, K., Abbs, S., Garralda, M.E., Bourke, J., Wells, D.J., Dickson, G., Wood, M.J.A., Wilton, S.D., Straub, V., Kole, R., Shrewsbury, S.B., Sewry, C., Morgan, J.E., Bushby, K., and Muntoni, F.

Abstract

Background We report clinical safety and biochemical efficacy from a dose-ranging study of intravenously administered AVI-4658 phosphorodiamidate morpholino oligomer (PMO) in patients with Duchenne muscular dystrophy. Method We undertook an open-label, phase 2, dose-escalation study (0·5, 1·0, 2·0, 4·0, 10·0, and 20·0 mg/kg bodyweight) in ambulant patients with Duchenne muscular dystrophy aged 5—15 years with amenable deletions in DMD. Participants had a muscle biopsy before starting treatment and after 12 weekly intravenous infusions of AVI-4658. The primary study objective was to assess safety and tolerability of AVI-4658. The secondary objectives were pharmacokinetic properties and the ability of AVI-4658 to induce exon 51 skipping and dystrophin restoration by RT-PCR, immunohistochemistry, and immunoblotting. The study is registered, number NCT00844597. Findings 19 patients took part in the study. AVI-4658 was well tolerated with no drug-related serious adverse events. AVI-4658 induced exon 51 skipping in all cohorts and new dystrophin protein expression in a significant dose-dependent (p=0·0203), but variable, manner in boys from cohort 3 (dose 2 mg/kg) onwards. Seven patients responded to treatment, in whom mean dystrophin fluorescence intensity increased from 8·9% (95% CI 7·1—10·6) to 16·4% (10·8—22·0) of normal control after treatment (p=0·0287). The three patients with the greatest responses to treatment had 21%, 15%, and 55% dystrophin-positive fibres after treatment and these findings were confirmed with western blot, which showed an increase after treatment of protein levels from 2% to 18%, from 0·9% to 17%, and from 0% to 7·7% of normal muscle, respectively. The dystrophin-associated proteins α-sarcoglycan and neuronal nitric oxide synthase were also restored at the sarcolemma. Analysis of the inflammatory infiltrate indicated a reduction of cytotoxic T cells in the post-treatment muscle biopsies in the two high-dose cohorts. Interpretation The safety a

Published
2011

28. SEPN1-related myopathies: clinical course in a large cohort of patients

Author

Scoto, M, Cirak, S, Mein, R, Feng, L, Manzur, Ay, Robb, S, Childs, A, Quinlivan, Rm, Roper, H, Jones, Dh, Longman, C, Chow, G, Pane, Marika, Main, M, Hanna, Mg, Bushby, K, Sewry, C, Abbs, S, Mercuri, Eugenio Maria, Muntoni, F., Pane, Marika (ORCID:0000-0002-4851-6124), Mercuri, Eugenio Maria (ORCID:0000-0002-9851-5365), Scoto, M, Cirak, S, Mein, R, Feng, L, Manzur, Ay, Robb, S, Childs, A, Quinlivan, Rm, Roper, H, Jones, Dh, Longman, C, Chow, G, Pane, Marika, Main, M, Hanna, Mg, Bushby, K, Sewry, C, Abbs, S, Mercuri, Eugenio Maria, Muntoni, F., Pane, Marika (ORCID:0000-0002-4851-6124), and Mercuri, Eugenio Maria (ORCID:0000-0002-9851-5365)

Abstract

To assess the clinical course and genotype-phenotype correlations in patients with selenoprotein-related myopathy (SEPN1-RM) due to selenoprotein N1 gene (SEPN1) mutations for a retrospective cross-sectional study.

Published
2011

29. Muscle magnetic resonance imaging in congenital myopathies due to ryanodine receptor type 1 gene mutations

Author

Klein, A, Jungbluth, H, Clement, E, Lillis, S, Abbs, S, Munot, P, Pane, Marika, Wraige, E, Schara, U, Straub, V, Mercuri, Eugenio Maria, Muntoni, F., Pane, Marika (ORCID:0000-0002-4851-6124), Mercuri, Eugenio Maria (ORCID:0000-0002-9851-5365), Klein, A, Jungbluth, H, Clement, E, Lillis, S, Abbs, S, Munot, P, Pane, Marika, Wraige, E, Schara, U, Straub, V, Mercuri, Eugenio Maria, Muntoni, F., Pane, Marika (ORCID:0000-0002-4851-6124), and Mercuri, Eugenio Maria (ORCID:0000-0002-9851-5365)

Abstract

To establish the consistency of the previously reported pattern of muscle involvement in a large cohort of patients with molecularly defined ryanodine receptor type 1 (RYR1)-related myopathies, to identify possible additional patterns, and to compare magnetic resonance imaging (MRI) findings with clinical and genetic findings.

Published
2011

30. Early developmental regression in autism spectrum disorder: Evidence from an international multiplex sample

Author

Parr, J., Le Couteur, A., Baird, G., Rutter, M., Pickles, A., Fombonne, E., Bailey, A., Wallace, S., Wittemeyer, K., Monaco, A., Barnby, G., Bolton, P., Moore, J., Murin, M., McConachie, H., Berney, T., Docherty, Z., Abbs, S., Ogilvie, C., Warburton, P., Lamb, J., Green, J., Bolton, B., Packer, R., Haracopos, D., Pedersen, L., Isager, T., Brondum-Nielsen, K., Roge, B., Tauber, M., Mantoulan, C., Poustka, F., Bölte, Sven, Feineis-Matthews, S., Rühl, D., Schmötzer, G., Poustka, A., Klauck, S., Tsiantis, J., Papanikolaou, K., Maestrini, E., Van Engeland, H., De Jonge, M., Lord, C., Corsello, C., Cook, E., Salt, J., Guter, S., Leventhal, B., Volkmar, F., Koenig, K., Parr, J., Le Couteur, A., Baird, G., Rutter, M., Pickles, A., Fombonne, E., Bailey, A., Wallace, S., Wittemeyer, K., Monaco, A., Barnby, G., Bolton, P., Moore, J., Murin, M., McConachie, H., Berney, T., Docherty, Z., Abbs, S., Ogilvie, C., Warburton, P., Lamb, J., Green, J., Bolton, B., Packer, R., Haracopos, D., Pedersen, L., Isager, T., Brondum-Nielsen, K., Roge, B., Tauber, M., Mantoulan, C., Poustka, F., Bölte, Sven, Feineis-Matthews, S., Rühl, D., Schmötzer, G., Poustka, A., Klauck, S., Tsiantis, J., Papanikolaou, K., Maestrini, E., Van Engeland, H., De Jonge, M., Lord, C., Corsello, C., Cook, E., Salt, J., Guter, S., Leventhal, B., Volkmar, F., and Koenig, K.

Abstract

The characteristics of early developmental regression (EDR) were investigated in individuals with ASD from affected relative pairs recruited to the International Molecular Genetic Study of Autism Consortium (IMGSAC). Four hundred and fifty-eight individuals with ASD were recruited from 226 IMGSAC families. Regression before age 36 months occurred in 23.9% of individuals. The observed concordance rate for EDR within sibling pairs (18.9%) was not significantly above the rate expected under independence (13.5%, p = 0.10). The rate of regression in individuals with ASD from multiplex families was similar to that reported in singleton and epidemiological samples. Regression concordance data were not supportive of a separate familial influence on EDR, other than as a part of autism itself. © Springer Science+Business Media, LLC 2010.

Published
2011

31. Identification and quantification of somatic mosaicism for a point mutation in a Duchenne muscular dystrophy family

Author

Smith, T., Yau, S., Bobrow, M., and Abbs, S.

Subjects
Male, Mosaicism, Humans, Point Mutation, Original Articles, Polymerase Chain Reaction, Muscular Dystrophies
Abstract

Relatively few point mutations have been found in the dystrophin gene and of these only two have been associated with mosaicism. A single base insertion has been identified and quantified in a mother of two sons affected with Duchenne muscular dystrophy. It has been determined that she is a somatic mosaic with the mutation present in 25% of lymphocyte DNA. Further tissue lineages have been tested and the time at which the mutation arose was determined to be before the cellular differentiation into the bilaminar disc at approximately eight days after fertilisation. We suggest that the incidence of mosaicism for dystrophin point mutations may be higher than current data suggest. Keywords: Duchenne muscular dystrophy; point mutation; mosaic

Published
1999

32. Local restoration of dystrophin expression with the morpholino oligomer AVI-4658 in Duchenne muscular dystrophy: a single-blind, placebo-controlled, dose-escalation, proof-of-concept study

Author

Kinali, M., Arechavala-Gomeza, V., Feng, L., Cirak, S., Hunt, D., Adkin, C., Guglieri, M., Ashton, E., Abbs, S., Nihoyannopoulos, P., Garralda, M.E., Rutherford, M., Mcculley, C., Popplewell, L., Graham, I.R., Dickson, G., Wood, M.J.A., Wells, D.J., Wilton, S.D., Kole, R., Straub, V., Bushby, K., Sewry, C., Morgan, J.E., Muntoni, F., Kinali, M., Arechavala-Gomeza, V., Feng, L., Cirak, S., Hunt, D., Adkin, C., Guglieri, M., Ashton, E., Abbs, S., Nihoyannopoulos, P., Garralda, M.E., Rutherford, M., Mcculley, C., Popplewell, L., Graham, I.R., Dickson, G., Wood, M.J.A., Wells, D.J., Wilton, S.D., Kole, R., Straub, V., Bushby, K., Sewry, C., Morgan, J.E., and Muntoni, F.

Abstract

BACKGROUND: Mutations that disrupt the open reading frame and prevent full translation of DMD, the gene that encodes dystrophin, underlie the fatal X-linked disease Duchenne muscular dystrophy. Oligonucleotides targeted to splicing elements (splice switching oligonucleotides) in DMD pre-mRNA can lead to exon skipping, restoration of the open reading frame, and the production of functional dystrophin in vitro and in vivo, which could benefit patients with this disorder. METHODS: We did a single-blind, placebo-controlled, dose-escalation study in patients with DMD recruited nationally, to assess the safety and biochemical efficacy of an intramuscular morpholino splice-switching oligonucleotide (AVI-4658) that skips exon 51 in dystrophin mRNA. Seven patients with Duchenne muscular dystrophy with deletions in the open reading frame of DMD that are responsive to exon 51 skipping were selected on the basis of the preservation of their extensor digitorum brevis (EDB) muscle seen on MRI and the response of cultured fibroblasts from a skin biopsy to AVI-4658. AVI-4658 was injected into the EDB muscle; the contralateral muscle received saline. Muscles were biopsied between 3 and 4 weeks after injection. The primary endpoint was the safety of AVI-4658 and the secondary endpoint was its biochemical efficacy. This trial is registered, number NCT00159250. FINDINGS: Two patients received 0.09 mg AVI-4658 in 900 microL (0.9%) saline and five patients received 0.9 mg AVI-4658 in 900 microL saline. No adverse events related to AVI-4658 administration were reported. Intramuscular injection of the higher-dose of AVI-4658 resulted in increased dystrophin expression in all treated EDB muscles, although the results of the immunostaining of EDB-treated muscle for dystrophin were not uniform. In the areas of the immunostained sections that were adjacent to the needle track through which AVI-4658 was given, 44-79% of myofibres had increased expression of dystrophin. In randomly chosen sectio

Published
2009

37. SEPN1-related myopathies: Clinical course in a large cohort of patients

Author

Scoto, M., primary, Cirak, S., additional, Mein, R., additional, Feng, L., additional, Manzur, A. Y., additional, Robb, S., additional, Childs, A.- M., additional, Quinlivan, R. M., additional, Roper, H., additional, Jones, D. H., additional, Longman, C., additional, Chow, G., additional, Pane, M., additional, Main, M., additional, Hanna, M. G., additional, Bushby, K., additional, Sewry, C., additional, Abbs, S., additional, Mercuri, E., additional, and Muntoni, F., additional

Published
2011
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38. 1FC2.5 Recessive mutations in the skeletal muscle ryanodine receptor (RYR1) gene may mimick X-linked centronuclear (myotubular) myopathy (XLMTM)

Author

Gika, A.D., primary, Lillis, S., additional, Cullup, T., additional, Bodi, I., additional, Manta, P., additional, Pons, R., additional, Yatrakou, E., additional, Karachristou, K., additional, Tzeti, M., additional, Youroukos, S., additional, Muntoni, F., additional, Abbs, S., additional, and Jungbluth, H., additional

Published
2011
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40. P67 SEPN1 related myopathies: Clinical course in a large cohort of patients

Author

Scoto, M., primary, Cirak, S., additional, Mein, R., additional, Feng, L., additional, Manzur, A.Y., additional, Robb, S., additional, Childs, A.-M., additional, Quinlivan, R.M., additional, Roper, H., additional, Hilton-Jones, D., additional, Longman, C., additional, Chow, G., additional, Pane, M., additional, Main, M., additional, Hanna, M.G., additional, Bushby, K., additional, Sewry, C., additional, Abbs, S., additional, Mercuri, E., additional, and Muntoni, F., additional

Published
2011
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43. RYR1 mutations are a common cause of congenital myopathies with central nuclei

Author

Wilmshurst, J.M., primary, Lillis, S., additional, Zhou, H., additional, Pillay, K., additional, Henderson, H., additional, Kress, W., additional, Müller, C.R., additional, Ndondo, A., additional, Cloke, V., additional, Cullup, T., additional, Bertini, E., additional, Boennemann, C., additional, Straub, V., additional, Quinlivan, R., additional, Dowling, J.J., additional, Al‐ Sarraj, S., additional, Treves, S., additional, Abbs, S., additional, Manzur, A.Y., additional, Sewry, C.A., additional, Muntoni, F., additional, and Jungbluth, H., additional

Published
2010
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45. T.O.3 Restoration of dystrophin expression in Duchenne muscular dystrophy: A single blind, placebo-controlled dose escalation study using morpholino oligomer AVI-4658

Author

Kinali, M., primary, Arechavala-Gomeza, V., additional, Feng, L., additional, Cirak, S., additional, Hunt, D., additional, Adkin, C., additional, Guglieri, M., additional, Abbs, S., additional, Nihoyannopoulos, P., additional, Garralda, M.E., additional, Rutherford, M., additional, McCulley, C., additional, Popplewell, L., additional, Graham, I.R., additional, Dickson, G., additional, Wood, M.J.A., additional, Wells, D.J., additional, Wilton, S.D., additional, Holt, T., additional, Kole, R., additional, Straub, V., additional, Bushby, K., additional, Sewry, C., additional, Morgan, J.E., additional, and Muntoni, F., additional

Published
2009
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47. G.P.1.04 An autosomal-recessive form of centronuclear myopathy is caused by mutations in the skeletal muscle ryanodine receptor (RYR1) gene

Author

Wilmshurst, J., primary, Lillis, S., additional, Zhou, H., additional, Kress, W., additional, Solomon, R., additional, Ndondo, A., additional, Greenberg, J., additional, Sinclair-Smith, C.C., additional, Bertini, E., additional, Boennemann, C., additional, Straub, V., additional, Quinlivan, R., additional, Sewry, C.A., additional, Wraige, E., additional, Abbs, S., additional, Muntoni, F., additional, and Jungbluth, H., additional

Published
2009
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48. O7-6 Restoration of dystrophin in DMD: a single blind, placebo-controlled dose escalation study using Morpholino oligomer AVI-4658

Author

Kinali, M., primary, Arechavala-Gomeza, V., additional, Feng, L., additional, Cirak, S., additional, Hunt, D., additional, Adkin, C., additional, Guglieri, M., additional, Ashton, E., additional, Rutherford, M., additional, Mcculley, C., additional, Popplewell, L., additional, Graham, I.R., additional, Wells, D.J., additional, Wilton, S., additional, Holt, T., additional, Kole, R., additional, Straub, V., additional, Bushby, K., additional, Sewry, C., additional, Muntoni, F., additional, Morgan, J.E., additional, Nihoyannopoulos, P., additional, Garralda, M.E., additional, Abbs, S., additional, Dickson, G., additional, and Wood, M.J.A., additional

Published
2009
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