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1. De novo variants in the RNU4-2 snRNA cause a frequent neurodevelopmental syndrome

Author

Chen, Yuyang, Dawes, Ruebena, Kim, Hyung Chul, Ljungdahl, Alicia, Stenton, Sarah L., Walker, Susan, Lord, Jenny, Lemire, Gabrielle, Martin-Geary, Alexandra C., Ganesh, Vijay S., Ma, Jialan, Ellingford, Jamie M., Delage, Erwan, D’Souza, Elston N., Dong, Shan, Adams, David R., Allan, Kirsten, Bakshi, Madhura, Baldwin, Erin E., Berger, Seth I., Bernstein, Jonathan A., Bhatnagar, Ishita, Blair, Ed, Brown, Natasha J., Burrage, Lindsay C., Chapman, Kimberly, Coman, David J., Compton, Alison G., Cunningham, Chloe A., D’Souza, Precilla, Danecek, Petr, Délot, Emmanuèle C., Dias, Kerith-Rae, Elias, Ellen R., Elmslie, Frances, Evans, Care-Anne, Ewans, Lisa, Ezell, Kimberly, Fraser, Jamie L., Gallacher, Lyndon, Genetti, Casie A., Goriely, Anne, Grant, Christina L., Haack, Tobias, Higgs, Jenny E., Hinch, Anjali G., Hurles, Matthew E., Kuechler, Alma, Lachlan, Katherine L., Lalani, Seema R., Lecoquierre, François, Leitão, Elsa, Fevre, Anna Le, Leventer, Richard J., Liebelt, Jan E., Lindsay, Sarah, Lockhart, Paul J., Ma, Alan S., Macnamara, Ellen F., Mansour, Sahar, Maurer, Taylor M., Mendez, Hector R., Metcalfe, Kay, Montgomery, Stephen B., Moosajee, Mariya, Nassogne, Marie-Cécile, Neumann, Serena, O’Donoghue, Michael, O’Leary, Melanie, Palmer, Elizabeth E., Pattani, Nikhil, Phillips, John, Pitsava, Georgia, Pysar, Ryan, Rehm, Heidi L., Reuter, Chloe M., Revencu, Nicole, Riess, Angelika, Rius, Rocio, Rodan, Lance, Roscioli, Tony, Rosenfeld, Jill A., Sachdev, Rani, Shaw-Smith, Charles J., Simons, Cas, Sisodiya, Sanjay M., Snell, Penny, St Clair, Laura, Stark, Zornitza, Stewart, Helen S., Tan, Tiong Yang, Tan, Natalie B., Temple, Suzanna E. L., Thorburn, David R., Tifft, Cynthia J., Uebergang, Eloise, VanNoy, Grace E., Vasudevan, Pradeep, Vilain, Eric, Viskochil, David H., Wedd, Laura, Wheeler, Matthew T., White, Susan M., Wojcik, Monica, Wolfe, Lynne A., Wolfenson, Zoe, Wright, Caroline F., Xiao, Changrui, Zocche, David, Rubenstein, John L., Markenscoff-Papadimitriou, Eirene, Fica, Sebastian M., Baralle, Diana, Depienne, Christel, MacArthur, Daniel G., Howson, Joanna M. M., Sanders, Stephan J., O’Donnell-Luria, Anne, and Whiffin, Nicola

Published
2024
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2. Multidisciplinary team directed analysis of whole genome sequencing reveals pathogenic non-coding variants in molecularly undiagnosed inherited retinal dystrophies

Author

Varela, Malena Daich, Bellingham, James, Motta, Fabiana, Jurkute, Neringa, Ellingford, Jamie M, Quinodoz, Mathieu, Oprych, Kathryn, Niblock, Michael, Janeschitz-Kriegl, Lucas, Kaminska, Karolina, Cancellieri, Francesca, Scholl, Hendrik PN, Lenassi, Eva, Schiff, Elena, Knight, Hannah, Black, Graeme, Rivolta, Carlo, Cheetham, Michael E, Michaelides, Michel, Mahroo, Omar A, Moore, Anthony T, Webster, Andrew R, and Arno, Gavin

Subjects
Biological Sciences, Genetics, Human Genome, Clinical Research, Aetiology, 2.1 Biological and endogenous factors, Humans, Mutation, Pedigree, Retinal Dystrophies, Whole Genome Sequencing, Patient Care Team, DNA Mutational Analysis, Eye Proteins, Membrane Proteins, Nerve Tissue Proteins, Medical and Health Sciences, Genetics & Heredity
Abstract

The purpose of this paper is to identify likely pathogenic non-coding variants in inherited retinal dystrophy (IRD) genes, using genome sequencing (GS). Patients with IRD were recruited to the study and underwent comprehensive ophthalmological evaluation and GS. The results of GS were investigated through virtual gene panel analysis, and plausible pathogenic variants and clinical phenotype evaluated by the multidisciplinary team (MDT) discussion. For unsolved patients in whom a specific gene was suspected to harbor a missed pathogenic variant, targeted re-analysis of non-coding regions was performed on GS data. Candidate variants were functionally tested by messenger RNA analysis, minigene or luciferase reporter assays. Previously unreported, likely pathogenic, non-coding variants in 7 genes (PRPF31, NDP, IFT140, CRB1, USH2A, BBS10 and GUCY2D), were identified in 11 patients. These were shown to lead to mis-splicing (PRPF31, IFT140, CRB1 and USH2A) or altered transcription levels (BBS10 and GUCY2D). MDT-led, phenotype-driven, non-coding variant re-analysis of GS is effective in identifying the missing causative alleles.

Published
2023

3. HNRNPC haploinsufficiency affects alternative splicing of intellectual disability-associated genes and causes a neurodevelopmental disorder

Author

Ambrose, J.C., Arumugam, P., Bevers, R., Bleda, M., Boardman-Pretty, F., Boustred, C.R., Brittain, H., Brown, M.A., Caulfield, M.J., Chan, G.C., Giess, A., Griffin, J.N., Hamblin, A., Henderson, S., Hubbard, T.J.P., Jackson, R., Jones, L.J., Kasperaviciute, D., Kayikci, M., Kousathanas, A., Lahnstein, L., Lakey, A., Leigh, S.E.A., Leong, I.U.S., Lopez, F.J., Maleady-Crowe, F., McEntagart, M., Minneci, F., Mitchell, J., Moutsianas, L., Mueller, M., Murugaesu, N., Need, A.C., O‘Donovan, P., Odhams, C.A., Patch, C., Perez-Gil, D., Pereira, M.B., Pullinger, J., Rahim, T., Rendon, A., Rogers, T., Savage, K., Sawant, K., Scott, R.H., Siddiq, A., Sieghart, A., Smith, S.C., Sosinsky, A., Stuckey, A., Tanguy, M., Taylor Tavares, A.L., Thomas, E.R.A., Thompson, S.R., Tucci, A., Welland, M.J., Williams, E., Witkowska, K., Wood, S.M., Zarowiecki, M., Acosta, Maria T., Adams, David R., Alvarez, Raquel L., Alvey, Justin, Allworth, Aimee, Andrews, Ashley, Ashley, Euan A., Afzali, Ben, Bacino, Carlos A., Bademci, Guney, Balasubramanyam, Ashok, Baldridge, Dustin, Bale, Jim, Bamshad, Michael, Barbouth, Deborah, Bayrak-Toydemir, Pinar, Beck, Anita, Beggs, Alan H., Behrens, Edward, Bejerano, Gill, Bellen, Hugo J., Bennet, Jimmy, Bernstein, Jonathan A., Berry, Gerard T., Bican, Anna, Bivona, Stephanie, Blue, Elizabeth, Bohnsack, John, Bonner, Devon, Botto, Lorenzo, Briere, Lauren C., Brown, Gabrielle, Burke, Elizabeth A., Burrage, Lindsay C., Butte, Manish J., Byers, Peter, Byrd, William E., Carey, John, Carrasquillo, Olveen, Cassini, Thomas, Chang, Ta Chen, Chanprasert, Sirisak, Chao, Hsiao-Tuan, Chinn, Ivan, Clark, Gary D., Coakley, Terra R., Cobban, Laurel A., Cogan, Joy D., Coggins, Matthew, Cole, F. Sessions, Colley, Heather A., Cope, Heidi, Corona, Rosario, Craigen, William J., Crouse, Andrew B., Cunningham, Michael, D'Souza, Precilla, Dai, Hongzheng, Dasari, Surendra, Davis, Joie, Dayal, Jyoti G., Delgado, Margaret, Dell'Angelica, Esteban C., Dipple, Katrina, Doherty, Daniel, Dorrani, Naghmeh, Doss, Argenia L., Douine, Emilie D., Earl, Dawn, Eckstein, David J., Emrick, Lisa T., Eng, Christine M., Falk, Marni, Fieg, Elizabeth L., Fisher, Paul G., Fogel, Brent L., Forghani, Irman, Fu, Jiayu, Gahl, William A., Glass, Ian, Goddard, Page C., Godfrey, Rena A., Grajewski, Alana, Halley, Meghan C., Hamid, Rizwan, Hanchard, Neal, Hassey, Kelly, Hayes, Nichole, High, Frances, Hing, Anne, Hisama, Fuki M., Holm, Ingrid A., Hom, Jason, Horike-Pyne, Martha, Huang, Alden, Huang, Yan, Hutchison, Sarah, Introne, Wendy, Isasi, Rosario, Izumi, Kosuke, Jarvik, Gail P., Jarvik, Jeffrey, Jayadev, Suman, Jean-Marie, Orpa, Jobanputra, Vaidehi, Kaitryn, Emerald, Ketkar, Shamika, Kiley, Dana, Kilich, Gonench, Kobren, Shilpa N., Kohane, Isaac S., Kohler, Jennefer N., Korrick, Susan, Krakow, Deborah, Krasnewich, Donna M., Kravets, Elijah, Lalani, Seema R., Lam, Byron, Lam, Christina, Lanpher, Brendan C., Lanza, Ian R., LeBlanc, Kimberly, Lee, Brendan H., Levitt, Roy, Lewis, Richard A., Liu, Pengfei, Liu, Xue Zhong, Longo, Nicola, Loo, Sandra K., Loscalzo, Joseph, Maas, Richard L., Macnamara, Ellen F., MacRae, Calum A., Maduro, Valerie V., Maghiro, AudreyStephannie, Mahoney, Rachel, Malicdan, May Christine, Mamounas, Laura A., Manolio, Teri A., Mao, Rong, Marom, Ronit, Marth, Gabor, Martin, Beth A., Martin, Martin G., Martínez-Agosto, Julian A., Marwaha, Shruti, McCauley, Jacob, McConkie-Rosell, Allyn, McCray, Alexa T., McGee, Elisabeth, Might, Matthew, Miller, Danny, Mirzaa, Ghayda, Morava, Eva, Moretti, Paolo, Morimoto, Marie, Mulvihill, John J., Nakano-Okuno, Mariko, Nelson, Stanley F., Nieves-Rodriguez, Shirley, Novacic, Donna, Oglesbee, Devin, Orengo, James P., Pace, Laura, Pak, Stephen, Pallais, J. Carl, Papp, Jeanette C., Parker, Neil H., Petcharet, Leoyklang, Phillips, John A., III, Posey, Jennifer E., Potocki, Lorraine, Swerdzewski, Barbara N., Quinlan, Aaron, Rao, Deepak A., Raper, Anna, Raskind, Wendy, Renteria, Genecee, Reuter, Chloe, Rives, Lynette, Robertson, Amy K., Rodan, Lance H., Rosenfeld, Jill A., Rosenthal, Elizabeth, Rossignol, Francis, Ruzhnikov, Maura, Sabaii, Marla, Sacco, Ralph, Sampson, Jacinda B., Saporta, Mario, Schaechter, Judy, Schedl, Timothy, Schoch, Kelly, Scott, Daryl A., Seto, Elaine, Sharma, Prashant, Shashi, Vandana, Shelkowitz, Emily, Sheppeard, Sam, Shin, Jimann, Silverman, Edwin, Sinsheimer, Janet, Sisco, Kathy, Smith, Edward, Smith, Kevin, Solnica-Krezel, Lilianna, Solomon, Ben, Spillmann, Rebecca, Stergachis, Andrew, Stoler, Joan, Sullivan, Kathleen, Sullivan, Jennifer, Sutton, Shirley, Sweetser, David A., Sybert, Virginia, Tabor, Holly K., Tan, Queenie K.-G., Tan, Amelia L., Tarakad, Arjun, Tekin, Mustafa, Telischi, Fred, Thorson, Willa, Tifft, Cynthia, Toro, Camilo, Tran, Alyssa A., Ungar, Rachel A., Urv, Tiina K., Vanderver, Adeline, Velinder, Matt, Viskochil, Dave, Vogel, Tiphanie P., Wahl, Colleen E., Walker, Melissa, Walley, Nicole M., Wambach, Jennifer, Wan, Jijun, Wang, Lee-kai, Wangler, Michael F., Ward, Patricia A., Wegner, Daniel, Weisz, Monika, Wener, Mark, Wenger, Tara, Westerfield, Monte, Wheeler, Matthew T., Whitlock, Jordan, Wolfe, Lynne A., Yamamoto, Shinya, Zhang, Zhe, Zuchner, Stephan, Niggl, Eva, Bouman, Arjan, Hoogenboezem, Remco M., Wallaard, Ilse, Park, Joohyun, Admard, Jakob, Wilke, Martina, Harris-Mostert, Emilio D.R.O., Elgersma, Minetta, Bain, Jennifer, Balasubramanian, Meena, Banka, Siddharth, Benke, Paul J., Bertrand, Miriam, Blesson, Alyssa E., Clayton-Smith, Jill, Ellingford, Jamie M., Gillentine, Madelyn A., Goodloe, Dana H., Haack, Tobias B., Jain, Mahim, Krantz, Ian, Luu, Sharon M., McPheron, Molly, Muss, Candace L., Raible, Sarah E., Robin, Nathaniel H., Spiller, Michael, Starling, Susan, Thiffault, Isabelle, Vetrini, Francesco, Witt, Dennis, Woods, Emily, Zhou, Dihong, Elgersma, Ype, and van Esbroeck, Annelot C.M.

Published
2023
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4. Recommendations for clinical interpretation of variants found in non-coding regions of the genome

Author

Ellingford, Jamie M., Ahn, Joo Wook, Bagnall, Richard D., Baralle, Diana, Barton, Stephanie, Campbell, Chris, Downes, Kate, Ellard, Sian, Duff-Farrier, Celia, FitzPatrick, David R., Greally, John M., Ingles, Jodie, Krishnan, Neesha, Lord, Jenny, Martin, Hilary C., Newman, William G., O’Donnell-Luria, Anne, Ramsden, Simon C., Rehm, Heidi L., Richardson, Ebony, Singer-Berk, Moriel, Taylor, Jenny C., Williams, Maggie, Wood, Jordan C., Wright, Caroline F., Harrison, Steven M., and Whiffin, Nicola

Published
2022
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5. Extended gene panel testing in lobular breast cancer

Author

van Veen, Elke M., Evans, D. Gareth, Harkness, Elaine F., Byers, Helen J., Ellingford, Jamie M., Woodward, Emma R., Bowers, Naomi L., Wallace, Andrew J., Howell, Sacha J., Howell, Anthony, Lalloo, Fiona, Newman, William G., and Smith, Miriam J.

Published
2022
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6. Systematic reanalysis of copy number losses of uncertain clinical significance.

Author

Burghel, George J., Ellingford, Jamie M., Wright, Ronnie, Bradford, Lauren, Miller, Jake, Watt, Christopher, Edgerley, Jonathan, Naeem, Farah, and Banka, Siddharth

Abstract

Background Reanalysis of exome/genome data improves diagnostic yield. However, the value of reanalysis of clinical array comparative genomic hybridisation (aCGH) data has never been investigated. Case-by-case reanalysis can be challenging in busy diagnostic laboratories. Methods and results We harmonised historical postnatal clinical aCGH results from ~16 000 patients tested via our diagnostic laboratory over ~7 years with current clinical guidance. This led to identification of 37 009 copy number losses (CNLs) including 33 857 benign, 2173 of uncertain significance and 979 pathogenic. We found benign CNLs to be significantly less likely to encompass haploinsufficient genes compared with the pathogenic or CNLs of uncertain significance in our database. Based on this observation, we developed a reanalysis pipeline using up-to-date disease association data and haploinsufficiency scores and shortlisted 207 CNLs of uncertain significance encompassing at least one autosomal dominant diseasegene associated with haploinsufficiency or loss-of-function mechanism. Clinical scientist reviews led to reclassification of 15 CNLs of uncertain significance as pathogenic or likely pathogenic. This was ~0.7% of the starting cohort of 2173 CNLs of uncertain significance and 7.2% of 207 shortlisted CNLs. The reclassified CNLs included first cases of CNV-mediated disease for some genes where all previously described cases involved only point variants. Interestingly, some CNLs could not be reclassified because the phenotypes of patients with CNLs seemed distinct from the known clinical features resulting from point variants, thus raising questions about accepted underlying disease mechanisms. Conclusions Reanalysis of clinical aCGH data increases diagnostic yield. [ABSTRACT FROM AUTHOR]

Published
2024
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9. Loss-of-function variants in myocardin cause congenital megabladder in humans and mice

Author

Houweling, Arjan C., Beaman, Glenda M., Postma, Alex V., Gainous, T. Blair, Lichtenbelt, Klaske D., Brancati, Francesco, Lopes, Filipa M., van der Made, Ingeborg, Polstra, Abeltje M., Robinson, Michael L., Wright, Kevin D., Ellingford, Jamie M., Jackson, Ashley R., Overwater, Eline, Genesio, Rita, Romano, Silvio, Camerota, Letizia, DAngelo, Emanuela, Meijers-Heijboer, Elizabeth J., Christoffels, Vincent M., McHugh, Kirk M., Black, Brian L., Newman, William G., Woolf, Adrian S., and Creemers, Esther E.

Subjects
Transcription (Genetics), Medical research, Genetic disorders, Biochemistry, Genetic research, Developmental biology, Knowledge, Smooth muscle, Gene expression, Health care industry, Wellcome Trust
Abstract

Myocardin (MYOCD) is the founding member of a class of transcriptional coactivators that bind the serum-response factor to activate gene expression programs critical in smooth muscle (SM) and cardiac muscle development. Insights into the molecular functions of MYOCD have been obtained from cell culture studies, and to date, knowledge about in vivo roles of MYOCD comes exclusively from experimental animals. Here, we defined an often lethal congenital human disease associated with inheritance of pathogenic MYOCD variants. This disease manifested as a massively dilated urinary bladder, or megabladder, with disrupted SM in its wall. We provided evidence that monoallelic loss-of-function variants in MYOCD caused congenital megabladder in males only, whereas biallelic variants were associated with disease in both sexes, with a phenotype additionally involving the cardiovascular system. These results were supported by cosegregation of MYOCD variants with the phenotype in 4 unrelated families by in vitro transactivation studies in which pathogenic variants resulted in abrogated SM gene expression and by the finding of megabladder in 2 distinct mouse models with reduced Myocd activity. In conclusion, we have demonstrated that variants in MYOCD result in human disease, and the collective findings highlight a vital role for MYOCD in mammalian organogenesis., Introduction Urinary tract and kidney malformations often result in termination of pregnancy after being detected on ultrasound screening, and these anomalies are also a major cause of renal failure in [...]

Published
2019
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11. HNRNPC haploinsufficiency affects alternative splicing of intellectual disability-associated genes and causes a neurodevelopmental disorder

Author

Niggl, Eva, primary, Bouman, Arjan, additional, Briere, Lauren C., additional, Hoogenboezem, Remco M., additional, Wallaard, Ilse, additional, Park, Joohyun, additional, Admard, Jakob, additional, Wilke, Martina, additional, Harris-Mostert, Emilio D.R.O., additional, Elgersma, Minetta, additional, Bain, Jennifer, additional, Balasubramanian, Meena, additional, Banka, Siddharth, additional, Benke, Paul J., additional, Bertrand, Miriam, additional, Blesson, Alyssa E., additional, Clayton-Smith, Jill, additional, Ellingford, Jamie M., additional, Gillentine, Madelyn A., additional, Goodloe, Dana H., additional, Haack, Tobias B., additional, Jain, Mahim, additional, Krantz, Ian, additional, Luu, Sharon M., additional, McPheron, Molly, additional, Muss, Candace L., additional, Raible, Sarah E., additional, Robin, Nathaniel H., additional, Spiller, Michael, additional, Starling, Susan, additional, Sweetser, David A., additional, Thiffault, Isabelle, additional, Vetrini, Francesco, additional, Witt, Dennis, additional, Woods, Emily, additional, Zhou, Dihong, additional, Elgersma, Ype, additional, van Esbroeck, Annelot C.M., additional, Ambrose, J.C., additional, Arumugam, P., additional, Bevers, R., additional, Bleda, M., additional, Boardman-Pretty, F., additional, Boustred, C.R., additional, Brittain, H., additional, Brown, M.A., additional, Caulfield, M.J., additional, Chan, G.C., additional, Giess, A., additional, Griffin, J.N., additional, Hamblin, A., additional, Henderson, S., additional, Hubbard, T.J.P., additional, Jackson, R., additional, Jones, L.J., additional, Kasperaviciute, D., additional, Kayikci, M., additional, Kousathanas, A., additional, Lahnstein, L., additional, Lakey, A., additional, Leigh, S.E.A., additional, Leong, I.U.S., additional, Lopez, F.J., additional, Maleady-Crowe, F., additional, McEntagart, M., additional, Minneci, F., additional, Mitchell, J., additional, Moutsianas, L., additional, Mueller, M., additional, Murugaesu, N., additional, Need, A.C., additional, O‘Donovan, P., additional, Odhams, C.A., additional, Patch, C., additional, Perez-Gil, D., additional, Pereira, M.B., additional, Pullinger, J., additional, Rahim, T., additional, Rendon, A., additional, Rogers, T., additional, Savage, K., additional, Sawant, K., additional, Scott, R.H., additional, Siddiq, A., additional, Sieghart, A., additional, Smith, S.C., additional, Sosinsky, A., additional, Stuckey, A., additional, Tanguy, M., additional, Taylor Tavares, A.L., additional, Thomas, E.R.A., additional, Thompson, S.R., additional, Tucci, A., additional, Welland, M.J., additional, Williams, E., additional, Witkowska, K., additional, Wood, S.M., additional, Zarowiecki, M., additional, Acosta, Maria T., additional, Adams, David R., additional, Alvarez, Raquel L., additional, Alvey, Justin, additional, Allworth, Aimee, additional, Andrews, Ashley, additional, Ashley, Euan A., additional, Afzali, Ben, additional, Bacino, Carlos A., additional, Bademci, Guney, additional, Balasubramanyam, Ashok, additional, Baldridge, Dustin, additional, Bale, Jim, additional, Bamshad, Michael, additional, Barbouth, Deborah, additional, Bayrak-Toydemir, Pinar, additional, Beck, Anita, additional, Beggs, Alan H., additional, Behrens, Edward, additional, Bejerano, Gill, additional, Bellen, Hugo J., additional, Bennet, Jimmy, additional, Bernstein, Jonathan A., additional, Berry, Gerard T., additional, Bican, Anna, additional, Bivona, Stephanie, additional, Blue, Elizabeth, additional, Bohnsack, John, additional, Bonner, Devon, additional, Botto, Lorenzo, additional, Brown, Gabrielle, additional, Burke, Elizabeth A., additional, Burrage, Lindsay C., additional, Butte, Manish J., additional, Byers, Peter, additional, Byrd, William E., additional, Carey, John, additional, Carrasquillo, Olveen, additional, Cassini, Thomas, additional, Chang, Ta Chen, additional, Chanprasert, Sirisak, additional, Chao, Hsiao-Tuan, additional, Chinn, Ivan, additional, Clark, Gary D., additional, Coakley, Terra R., additional, Cobban, Laurel A., additional, Cogan, Joy D., additional, Coggins, Matthew, additional, Cole, F. Sessions, additional, Colley, Heather A., additional, Cope, Heidi, additional, Corona, Rosario, additional, Craigen, William J., additional, Crouse, Andrew B., additional, Cunningham, Michael, additional, D'Souza, Precilla, additional, Dai, Hongzheng, additional, Dasari, Surendra, additional, Davis, Joie, additional, Dayal, Jyoti G., additional, Delgado, Margaret, additional, Dell'Angelica, Esteban C., additional, Dipple, Katrina, additional, Doherty, Daniel, additional, Dorrani, Naghmeh, additional, Doss, Argenia L., additional, Douine, Emilie D., additional, Earl, Dawn, additional, Eckstein, David J., additional, Emrick, Lisa T., additional, Eng, Christine M., additional, Falk, Marni, additional, Fieg, Elizabeth L., additional, Fisher, Paul G., additional, Fogel, Brent L., additional, Forghani, Irman, additional, Fu, Jiayu, additional, Gahl, William A., additional, Glass, Ian, additional, Goddard, Page C., additional, Godfrey, Rena A., additional, Grajewski, Alana, additional, Halley, Meghan C., additional, Hamid, Rizwan, additional, Hanchard, Neal, additional, Hassey, Kelly, additional, Hayes, Nichole, additional, High, Frances, additional, Hing, Anne, additional, Hisama, Fuki M., additional, Holm, Ingrid A., additional, Hom, Jason, additional, Horike-Pyne, Martha, additional, Huang, Alden, additional, Huang, Yan, additional, Hutchison, Sarah, additional, Introne, Wendy, additional, Isasi, Rosario, additional, Izumi, Kosuke, additional, Jarvik, Gail P., additional, Jarvik, Jeffrey, additional, Jayadev, Suman, additional, Jean-Marie, Orpa, additional, Jobanputra, Vaidehi, additional, Kaitryn, Emerald, additional, Ketkar, Shamika, additional, Kiley, Dana, additional, Kilich, Gonench, additional, Kobren, Shilpa N., additional, Kohane, Isaac S., additional, Kohler, Jennefer N., additional, Korrick, Susan, additional, Krakow, Deborah, additional, Krasnewich, Donna M., additional, Kravets, Elijah, additional, Lalani, Seema R., additional, Lam, Byron, additional, Lam, Christina, additional, Lanpher, Brendan C., additional, Lanza, Ian R., additional, LeBlanc, Kimberly, additional, Lee, Brendan H., additional, Levitt, Roy, additional, Lewis, Richard A., additional, Liu, Pengfei, additional, Liu, Xue Zhong, additional, Longo, Nicola, additional, Loo, Sandra K., additional, Loscalzo, Joseph, additional, Maas, Richard L., additional, Macnamara, Ellen F., additional, MacRae, Calum A., additional, Maduro, Valerie V., additional, Maghiro, AudreyStephannie, additional, Mahoney, Rachel, additional, Malicdan, May Christine, additional, Mamounas, Laura A., additional, Manolio, Teri A., additional, Mao, Rong, additional, Marom, Ronit, additional, Marth, Gabor, additional, Martin, Beth A., additional, Martin, Martin G., additional, Martínez-Agosto, Julian A., additional, Marwaha, Shruti, additional, McCauley, Jacob, additional, McConkie-Rosell, Allyn, additional, McCray, Alexa T., additional, McGee, Elisabeth, additional, Might, Matthew, additional, Miller, Danny, additional, Mirzaa, Ghayda, additional, Morava, Eva, additional, Moretti, Paolo, additional, Morimoto, Marie, additional, Mulvihill, John J., additional, Nakano-Okuno, Mariko, additional, Nelson, Stanley F., additional, Nieves-Rodriguez, Shirley, additional, Novacic, Donna, additional, Oglesbee, Devin, additional, Orengo, James P., additional, Pace, Laura, additional, Pak, Stephen, additional, Pallais, J. Carl, additional, Papp, Jeanette C., additional, Parker, Neil H., additional, Petcharet, Leoyklang, additional, Phillips, John A., additional, Posey, Jennifer E., additional, Potocki, Lorraine, additional, Swerdzewski, Barbara N., additional, Quinlan, Aaron, additional, Rao, Deepak A., additional, Raper, Anna, additional, Raskind, Wendy, additional, Renteria, Genecee, additional, Reuter, Chloe, additional, Rives, Lynette, additional, Robertson, Amy K., additional, Rodan, Lance H., additional, Rosenfeld, Jill A., additional, Rosenthal, Elizabeth, additional, Rossignol, Francis, additional, Ruzhnikov, Maura, additional, Sabaii, Marla, additional, Sacco, Ralph, additional, Sampson, Jacinda B., additional, Saporta, Mario, additional, Schaechter, Judy, additional, Schedl, Timothy, additional, Schoch, Kelly, additional, Scott, Daryl A., additional, Seto, Elaine, additional, Sharma, Prashant, additional, Shashi, Vandana, additional, Shelkowitz, Emily, additional, Sheppeard, Sam, additional, Shin, Jimann, additional, Silverman, Edwin, additional, Sinsheimer, Janet, additional, Sisco, Kathy, additional, Smith, Edward, additional, Smith, Kevin, additional, Solnica-Krezel, Lilianna, additional, Solomon, Ben, additional, Spillmann, Rebecca, additional, Stergachis, Andrew, additional, Stoler, Joan, additional, Sullivan, Kathleen, additional, Sullivan, Jennifer, additional, Sutton, Shirley, additional, Sybert, Virginia, additional, Tabor, Holly K., additional, Tan, Queenie K.-G., additional, Tan, Amelia L., additional, Tarakad, Arjun, additional, Tekin, Mustafa, additional, Telischi, Fred, additional, Thorson, Willa, additional, Tifft, Cynthia, additional, Toro, Camilo, additional, Tran, Alyssa A., additional, Ungar, Rachel A., additional, Urv, Tiina K., additional, Vanderver, Adeline, additional, Velinder, Matt, additional, Viskochil, Dave, additional, Vogel, Tiphanie P., additional, Wahl, Colleen E., additional, Walker, Melissa, additional, Walley, Nicole M., additional, Wambach, Jennifer, additional, Wan, Jijun, additional, Wang, Lee-kai, additional, Wangler, Michael F., additional, Ward, Patricia A., additional, Wegner, Daniel, additional, Weisz, Monika, additional, Wener, Mark, additional, Wenger, Tara, additional, Westerfield, Monte, additional, Wheeler, Matthew T., additional, Whitlock, Jordan, additional, Wolfe, Lynne A., additional, Yamamoto, Shinya, additional, Zhang, Zhe, additional, and Zuchner, Stephan, additional

Published
2023
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15. De novo variants in the RNU4-2snRNA cause a frequent neurodevelopmental syndrome

Author

Chen, Yuyang, Dawes, Ruebena, Kim, Hyung Chul, Ljungdahl, Alicia, Stenton, Sarah L., Walker, Susan, Lord, Jenny, Lemire, Gabrielle, Martin-Geary, Alexandra C., Ganesh, Vijay S., Ma, Jialan, Ellingford, Jamie M., Delage, Erwan, D’Souza, Elston N., Dong, Shan, Adams, David R., Allan, Kirsten, Bakshi, Madhura, Baldwin, Erin E., Berger, Seth I., Bernstein, Jonathan A., Bhatnagar, Ishita, Blair, Ed, Brown, Natasha J., Burrage, Lindsay C., Chapman, Kimberly, Coman, David J., Compton, Alison G., Cunningham, Chloe A., D’Souza, Precilla, Danecek, Petr, Délot, Emmanuèle C., Dias, Kerith-Rae, Elias, Ellen R., Elmslie, Frances, Evans, Care-Anne, Ewans, Lisa, Ezell, Kimberly, Fraser, Jamie L., Gallacher, Lyndon, Genetti, Casie A., Goriely, Anne, Grant, Christina L., Haack, Tobias, Higgs, Jenny E., Hinch, Anjali G., Hurles, Matthew E., Kuechler, Alma, Lachlan, Katherine L., Lalani, Seema R., Lecoquierre, François, Leitão, Elsa, Fevre, Anna Le, Leventer, Richard J., Liebelt, Jan E., Lindsay, Sarah, Lockhart, Paul J., Ma, Alan S., Macnamara, Ellen F., Mansour, Sahar, Maurer, Taylor M., Mendez, Hector R., Metcalfe, Kay, Montgomery, Stephen B., Moosajee, Mariya, Nassogne, Marie-Cécile, Neumann, Serena, O’Donoghue, Michael, O’Leary, Melanie, Palmer, Elizabeth E., Pattani, Nikhil, Phillips, John, Pitsava, Georgia, Pysar, Ryan, Rehm, Heidi L., Reuter, Chloe M., Revencu, Nicole, Riess, Angelika, Rius, Rocio, Rodan, Lance, Roscioli, Tony, Rosenfeld, Jill A., Sachdev, Rani, Shaw-Smith, Charles J., Simons, Cas, Sisodiya, Sanjay M., Snell, Penny, St Clair, Laura, Stark, Zornitza, Stewart, Helen S., Tan, Tiong Yang, Tan, Natalie B., Temple, Suzanna E. L., Thorburn, David R., Tifft, Cynthia J., Uebergang, Eloise, VanNoy, Grace E., Vasudevan, Pradeep, Vilain, Eric, Viskochil, David H., Wedd, Laura, Wheeler, Matthew T., White, Susan M., Wojcik, Monica, Wolfe, Lynne A., Wolfenson, Zoe, Wright, Caroline F., Xiao, Changrui, Zocche, David, Rubenstein, John L., Markenscoff-Papadimitriou, Eirene, Fica, Sebastian M., Baralle, Diana, Depienne, Christel, MacArthur, Daniel G., Howson, Joanna M. M., Sanders, Stephan J., O’Donnell-Luria, Anne, and Whiffin, Nicola

Abstract

Around 60% of individuals with neurodevelopmental disorders (NDD) remain undiagnosed after comprehensive genetic testing, primarily of protein-coding genes1. Large genome-sequenced cohorts are improving our ability to discover new diagnoses in the non-coding genome. Here we identify the non-coding RNA RNU4-2as a syndromic NDD gene. RNU4-2encodes the U4 small nuclear RNA (snRNA), which is a critical component of the U4/U6.U5 tri-snRNP complex of the major spliceosome2. We identify an 18 base pair region of RNU4-2mapping to two structural elements in the U4/U6 snRNA duplex (the T-loop and stem III) that is severely depleted of variation in the general population, but in which we identify heterozygous variants in 115 individuals with NDD. Most individuals (77.4%) have the same highly recurrent single base insertion (n.64_65insT). In 54 individuals in whom it could be determined, the de novo variants were all on the maternal allele. We demonstrate that RNU4-2is highly expressed in the developing human brain, in contrast to RNU4-1and other U4 homologues. Using RNA sequencing, we show how 5′ splice-site use is systematically disrupted in individuals with RNU4-2variants, consistent with the known role of this region during spliceosome activation. Finally, we estimate that variants in this 18 base pair region explain 0.4% of individuals with NDD. This work underscores the importance of non-coding genes in rare disorders and will provide a diagnosis to thousands of individuals with NDD worldwide.

Published
2024
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16. Clinical and genetic variability in children with partial albinism

Author

Campbell, Patrick, Ellingford, Jamie M., Parry, Neil R. A., Fletcher, Tracy, Ramsden, Simon C., Gale, Theodora, Hall, Georgina, Smith, Katherine, Kasperaviciute, Dalia, Thomas, Ellen, Lloyd, I. Chris, Douzgou, Sofia, Clayton-Smith, Jill, Biswas, Susmito, Ashworth, Jane L., Black, Graeme C. M., and Sergouniotis, Panagiotis I.

Published
2019
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17. Germline intergenic duplications at Xq26.1 underlie Bazex–Dupré–Christol basal cell carcinoma susceptibility syndrome

Author

Liu, Yanshan, primary, Banka, Siddharth, additional, Huang, Yingzhi, additional, Hardman-Smart, Jonathan, additional, Pye, Derek, additional, Torrelo, Antonio, additional, Beaman, Glenda M., additional, Kazanietz, Marcelo G., additional, Baker, Martin J., additional, Ferrazzano, Carlo, additional, Shi, Chenfu, additional, Orozco, Gisela, additional, Eyre, Stephen, additional, van Geel, Michel, additional, Bygum, Anette, additional, Fischer, Judith, additional, Miedzybrodzka, Zosia, additional, Abuzahra, Faris, additional, Rübben, Albert, additional, Cuvertino, Sara, additional, Ellingford, Jamie M., additional, Smith, Miriam J., additional, Evans, D. Gareth, additional, Weppner-Parren, Lizelotte J.M.T., additional, van Steensel, Maurice A.M., additional, Chaudhary, Iskander H., additional, Mangham, D. Chas, additional, Lear, John T., additional, Paus, Ralf, additional, Frank, Jorge, additional, Newman, William G., additional, and Zhang, Xue, additional

Published
2022
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18. EyeG2P: an automated variant filtering approach improves efficiency of diagnostic genomic testing for inherited ophthalmic disorders.

Author

Lenassi, Eva, Carvalho, Ana, Thormann, Anja, Abrahams, Liam, Arno, Gavin, Fletcher, Tracy, Hardcastle, Claire, Lopez, Javier, Hunt, Sarah E., Short, Patrick, Sergouniotis, Panagiotis I., Michaelides, Michel, Webster, Andrew, Cunningham, Fiona, Ramsden, Simon C., Kasperaviciute, Dalia, Fitzpatrick, David R., Black, Graeme C., and Ellingford, Jamie M.

Abstract

Background Genomic variant prioritisation is one of the most significant bottlenecks to mainstream genomic testing in healthcare. Tools to improve precision while ensuring high recall are critical to successful mainstream clinical genomic testing, in particular for whole genome sequencing where millions of variants must be considered for each patient. Methods We developed EyeG2P, a publicly available database and web application using the Ensembl Variant Effect Predictor. EyeG2P is tailored for efficient variant prioritisation for individuals with inherited ophthalmic conditions. We assessed the sensitivity of EyeG2P in 1234 individuals with a broad range of eye conditions who had previously received a confirmed molecular diagnosis through routine genomic diagnostic approaches. For a prospective cohort of 83 individuals, we assessed the precision of EyeG2P in comparison with routine diagnostic approaches. For 10 additional individuals, we assessed the utility of EyeG2P for whole genome analysis. Results EyeG2P had 99.5% sensitivity for genomic variants previously identified as clinically relevant through routine diagnostic analysis (n=1234 individuals). Prospectively, EyeG2P enabled a significant increase in precision (35% on average) in comparison with routine testing strategies (p<0.001). We demonstrate that incorporation of EyeG2P into whole genome sequencing analysis strategies can reduce the number of variants for analysis to six variants, on average, while maintaining high diagnostic yield. Conclusion Automated filtering of genomic variants through EyeG2P can increase the efficiency of diagnostic testing for individuals with a broad range of inherited ophthalmic disorders. [ABSTRACT FROM AUTHOR]

Published
2023
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19. Differential involvement of germline pathogenic variants in breast cancer genes between DCIS and low-grade invasive cancers.

Author

Evans, D. Gareth, Sithambaram, Siva, van Veen, Elke Maria, Burghel, George J., Schlecht, Helene, Harkness, Elaine F., Byers, Helen, Ellingford, Jamie M., Gandhi, Ashu, Howel, Sacha J., Howel, Anthony, Forde, Claire, Lalloo, Fiona, Newman, William G., Smith, Miriam Jane, and Woodward, Emma Roisin

Abstract

Purpose To investigate frequency of germline pathogenic variants (PVs) in women with ductal carcinoma in situ (DCIS) and grade 1 invasive breast cancer (G1BC). Methods We undertook BRCA1/2 analysis in 311 women with DCIS and 392 with G1BC and extended panel testing (non-BRCA1/2) in 176/311 with DCIS and 156/392 with G1BC. We investigated PV detection by age at diagnosis, Manchester Score (MS), DCIS grade and receptor status. Results 30/311 (9.6%) with DCIS and 16/392 with G1BC (4.1%) had a BRCA1/2 PV (p=0.003), and 24/176-(13.6%) and 7/156-(4.5%), respectively, a non-BRCA1/2 PV (p=0.004). Increasing MS was associated with increased likelihood of BRCA1/2 PV in both DCIS and G1BC, although the 10% threshold was not predictive for G1GB. 13/32 (40.6%) DCIS and 0/17 with G1BC <40 years had a non-BRCA1/2 PV (p<0.001). 0/16 DCIS G1 had a PV. For G2 and G3 DCIS, PV rates were 10/98 (BRCA1/2) and 9/90 (non-BRCA1/2), and 8/47 (BRCA1/2) and 8/45 (non-BRCA1/2), respectively. 6/9 BRCA1 and 3/26 BRCA2-associated DCIS were oestrogen receptor negative-(p=0.003). G1BC population testing showed no increased PV rate (OR=1.16, 95% CI 0.28 to 4.80). Conclusion DCIS is more likely to be associated with both BRCA1/2 and non-BRCA1/2 PVs than G1BC. Extended panel testing ought to be offered in young-onset DCIS where PV detection rates are highest. [ABSTRACT FROM AUTHOR]

Published
2023
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20. Differential involvement of germline pathogenic variants in breast cancer genes between DCIS and low-grade invasive cancers

Author

Evans, D Gareth, primary, Sithambaram, Siva, additional, van Veen, Elke Maria, additional, Burghel, George J, additional, Schlecht, Helene, additional, Harkness, Elaine F, additional, Byers, Helen, additional, Ellingford, Jamie M, additional, Gandhi, Ashu, additional, Howell, Sacha J, additional, Howell, Anthony, additional, Forde, Claire, additional, Lalloo, Fiona, additional, Newman, William G, additional, Smith, Miriam Jane, additional, and Woodward, Emma Roisin, additional

Published
2022
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21. Multidisciplinary team directed analysis of whole genome sequencing reveals pathogenic non-coding variants in molecularly undiagnosed inherited retinal dystrophies

Author

Daich Varela, Malena, primary, Bellingham, James, additional, Motta, Fabiana, additional, Jurkute, Neringa, additional, Ellingford, Jamie M, additional, Quinodoz, Mathieu, additional, Oprych, Kathryn, additional, Niblock, Michael, additional, Janeschitz-Kriegl, Lucas, additional, Kaminska, Karolina, additional, Cancellieri, Francesca, additional, Scholl, Hendrik P N, additional, Lenassi, Eva, additional, Schiff, Elena, additional, Knight, Hannah, additional, Black, Graeme, additional, Rivolta, Carlo, additional, Cheetham, Michael E, additional, Michaelides, Michel, additional, Mahroo, Omar A, additional, Moore, Anthony T, additional, Webster, Andrew R, additional, and Arno, Gavin, additional

Published
2022
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24. MRSD: a quantitative approach for assessing suitability of RNA-seq in the investigation of mis-splicing in Mendelian disease

Author

Rowlands, Charlie F., Taylor, Algy, Rice, Gillian I, Whiffin, Nicola, Hall, Hildegard Nikki, Newman, William G., Black, Graeme C.M., Investigators, kConFab, O'Keefe, Raymond T., Hubbard, Simon, Douglas, Andrew, Baralle, Diana, Briggs, Tracy A., and Ellingford, Jamie M.

Abstract

Background: RNA-sequencing of patient biosamples is a promising approach to delineate the impact of genomic variants on splicing, but variable gene expression between tissues complicates selection of appropriate tissues. Relative expression level is often used as a metric to predict RNA-sequencing utility. Here, we describe a gene- and tissue-specific metric to inform the feasibility of RNA-sequencing, overcoming some issues with using expression values alone.Results: We derive a novel metric, Minimum Required Sequencing Depth (MRSD), for all genes across three human biosamples (whole blood, lymphoblastoid cell lines (LCLs) and skeletal muscle). MRSD estimates the depth of sequencing required from RNA-sequencing to achieve user-specified sequencing coverage of a gene, transcript or group of genes of interest. MRSD predicts levels of splice junction coverage with high precision (90.1-98.2%) and overcomes transcript region-specific sequencing biases. Applying MRSD scoring to established disease gene panels shows that LCLs are the optimum source of RNA, of the three investigated biosamples, for 69.3% of gene panels. Our approach demonstrates that up to 59.4% of variants of uncertain significance in ClinVar predicted to impact splicing could be functionally assayed by RNA-sequencing in at least one of the investigated biosamples.Conclusions: We demonstrate the power of MRSD as a metric to inform choice of appropriate biosamples for the functional assessment of splicing aberrations. We apply MRSD in the context of Mendelian genetic disorders and illustrate its benefits over expression-based approaches. We anticipate that the integration of MRSD into clinical pipelines will improve variant interpretation and, ultimately, diagnostic yield.

Published
2022

25. Additional file 2 of Recommendations for clinical interpretation of variants found in non-coding regions of the genome

Author

Ellingford, Jamie M., Ahn, Joo Wook, Bagnall, Richard D., Baralle, Diana, Barton, Stephanie, Campbell, Chris, Downes, Kate, Ellard, Sian, Duff-Farrier, Celia, FitzPatrick, David R., Greally, John M., Ingles, Jodie, Krishnan, Neesha, Lord, Jenny, Martin, Hilary C., Newman, William G., O’Donnell-Luria, Anne, Ramsden, Simon C., Rehm, Heidi L., Richardson, Ebony, Singer-Berk, Moriel, Taylor, Jenny C., Williams, Maggie, Wood, Jordan C., Wright, Caroline F., Harrison, Steven M., and Whiffin, Nicola

Abstract

Additional file 2: Fig S1. Identifying regulatory variants in trans with pLoF variants in GEL.

Published
2022
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26. Germline intergenic duplications at Xq26.1 underlie Bazex-Dupre-Christol syndrome, an inherited basal cell carcinoma susceptibility condition

Author

Liu, Yanshan, primary, Banka, Siddharth, additional, Huang, Yingzhi, additional, Hardman-Smart, Jonathan, additional, Pye, Derek, additional, Torrelo, Antonio, additional, Beaman, Glenda M., additional, Kazanietz, Marcelo G., additional, Bake, Martin J., additional, Ferrazzano, Carlo, additional, Shi, Chenfu, additional, Orozco, Gisela, additional, Eyre, Stephen, additional, van Geel, Michel, additional, Bygum, Anette, additional, Fischer, Judith, additional, Miedzybrodzka, Zosia, additional, Abuzahra, Faris, additional, Ruebben, Albert, additional, Cuvertino, Sara, additional, Ellingford, Jamie M., additional, Smith, Miriam J., additional, Evans, Gareth, additional, Weppner-Parren, Lizelotte J.M.T, additional, van Steensel, Maurice A.M., additional, Chaudhary, Iskander H., additional, Mangham, Chas, additional, Lear, John T., additional, Paus, Ralf, additional, Frank, Jorge, additional, Newman, William G., additional, and Zhang, Xue, additional

Published
2022
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27. MRSD: A quantitative approach for assessing suitability of RNA-seq in the investigation of mis-splicing in Mendelian disease

Author

Rowlands, Charlie F., primary, Taylor, Algy, additional, Rice, Gillian, additional, Whiffin, Nicola, additional, Hall, Hildegard Nikki, additional, Newman, William G., additional, Black, Graeme C.M., additional, O’Keefe, Raymond T., additional, Hubbard, Simon, additional, Douglas, Andrew G.L., additional, Baralle, Diana, additional, Briggs, Tracy A., additional, and Ellingford, Jamie M., additional

Published
2022
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28. Recommendations for clinical interpretation of variants found in non-coding regions of the genome

Author

Ellingford, Jamie M, primary, Ahn, Joo Wook, additional, Bagnall, Richard D, additional, Baralle, Diana, additional, Barton, Stephanie, additional, Campbell, Chris, additional, Downes, Kate, additional, Ellard, Sian, additional, Duff-Farrier, Celia, additional, FitzPatrick, David R, additional, Ingles, Jodie, additional, Krishnan, Neesha, additional, Lord, Jenny, additional, Martin, Hilary C, additional, Newman, William G, additional, O’Donnell-Luria, Anne, additional, Ramsden, Simon C, additional, Rehm, Heidi L, additional, Richardson, Ebony, additional, Singer-Berk, Moriel, additional, Taylor, Jenny C, additional, Williams, Maggie, additional, Wood, Jordan C, additional, Wright, Caroline F, additional, Harrison, Steven M, additional, and Whiffin, Nicola, additional

Published
2021
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29. Molecular diagnoses in the congenital malformations caused by ciliopathies cohort of the 100,000 Genomes Project

Author

Best, Sunayna, primary, Lord, Jenny, additional, Roche, Matthew, additional, Watson, Christopher M, additional, Poulter, James A, additional, Bevers, Roel P J, additional, Stuckey, Alex, additional, Szymanska, Katarzyna, additional, Ellingford, Jamie M, additional, Carmichael, Jenny, additional, Brittain, Helen, additional, Toomes, Carmel, additional, Inglehearn, Chris, additional, Johnson, Colin A, additional, and Wheway, Gabrielle, additional

Published
2021
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30. Gene Panel Testing for Breast Cancer Reveals Differential Effect of Prior BRCA1/2 Probability

Author

Evans, D. Gareth, primary, van Veen, Elke M., additional, Woodward, Emma R., additional, Harkness, Elaine F., additional, Ellingford, Jamie M., additional, Bowers, Naomi L., additional, Wallace, Andrew J., additional, Howell, Sacha J., additional, Howell, Anthony, additional, Lalloo, Fiona, additional, Newman, William G., additional, and Smith, Miriam J., additional

Published
2021
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32. EyeG2P: an automated variant filtering approach improves efficiency of diagnostic genomic testing for inherited ophthalmic disorders

Author

Lenassi, Eva, primary, Carvalho, Ana, additional, Thormann, Anja, additional, Fletcher, Tracy, additional, Hardcastle, Claire, additional, Hunt, Sarah E, additional, Sergouniotis, Panagiotis I, additional, Michaelides, Michel, additional, Webster, Andrew R, additional, Cunningham, F, additional, Ramsden, Simon, additional, FitzPatrick, David R, additional, Black, Graeme CM, additional, and Ellingford, Jamie M, additional

Published
2021
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35. Molecular diagnoses in the congenital malformations caused by ciliopathies cohort of the 100,000 Genomes Project.

Author

Best, Sunayna, Lord, Jenny, Roche, Matthew, Watson, Christopher M., Poulter, James A., Bevers, Roel P. J., Stuckey, Alex, Szymanska, Katarzyna, Ellingford, Jamie M., Carmichael, Jenny, Brittain, Helen, Toomes, Carmel, Inglehearn, Chris, Johnson, Colin A., and Wheway, Gabrielle

Abstract

Background Primary ciliopathies represent a group of inherited disorders due to defects in the primary cilium, the 'cell's antenna'. The 100,000 Genomes Project was launched in 2012 by Genomics England (GEL), recruiting National Health Service (NHS) patients with eligible rare diseases and cancer. Sequence data were linked to Human Phenotype Ontology (HPO) terms entered by recruiting clinicians. Methods Eighty-three prescreened probands were recruited to the 100,000 Genomes Project suspected to have congenital malformations caused by ciliopathies in the following disease categories: Bardet-Biedl syndrome (n=45), Joubert syndrome (n=14) and 'Rare Multisystem Ciliopathy Disorders' (n=24). We implemented a bespoke variant filtering and analysis strategy to improve molecular diagnostic rates for these participants. Results We determined a research molecular diagnosis for n=43/83 (51.8%) probands. This is 19.3% higher than previously reported by GEL (n=27/83 (32.5%)). A high proportion of diagnoses are due to variants in non-ciliopathy disease genes (n=19/43, 44.2%) which may reflect difficulties in clinical recognition of ciliopathies. n=11/83 probands (13.3%) had at least one causative variant outside the tiers 1 and 2 variant prioritisation categories (GEL's automated triaging procedure), which would not be reviewed in standard 100,000 Genomes Project diagnostic strategies. These include four structural variants and three predicted to cause non-canonical splicing defects. Two unrelated participants have biallelic likely pathogenic variants in LRRC45, a putative novel ciliopathy disease gene. Conclusion These data illustrate the power of linking large-scale genome sequence to phenotype information. They demonstrate the value of research collaborations in order to maximise interpretation of genomic data. [ABSTRACT FROM AUTHOR]

Published
2022
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37. BBS1 branchpoint variant is associated with non-syndromic retinitis pigmentosa

Author

Fadaie, Zeinab, primary, Whelan, Laura, additional, Dockery, Adrian, additional, Li, Catherina H Z, additional, van den Born, L Ingeborgh, additional, Hoyng, Carel B, additional, Gilissen, Christian, additional, Corominas, Jordi, additional, Rowlands, Charlie, additional, Megaw, Roly, additional, Lampe, Anne K, additional, Cremers, Frans P M, additional, Farrar, Gwyneth Jane, additional, Ellingford, Jamie M, additional, Kenna, Paul F., additional, and Roosing, Susanne, additional

Published
2021
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38. Personalised virtual gene panels reduce interpretation workload and maintain diagnostic rates of proband-only clinical exome sequencing for rare disorders

Author

Molina-Ramírez, Leslie Patricia, primary, Kyle, Claire, additional, Ellingford, Jamie M, additional, Wright, Ronnie, additional, Taylor, Algy, additional, Bhaskar, Sanjeev S, additional, Campbell, Christopher, additional, Jackson, Harriet, additional, Fairclough, Adele, additional, Rousseau, Abigail, additional, Burghel, George J, additional, Dutton, Laura, additional, Banka, Siddharth, additional, Briggs, Tracy A, additional, Clayton-Smith, Jill, additional, Douzgou, Sofia, additional, Jones, Elizabeth A, additional, Kingston, Helen M, additional, Kerr, Bronwyn, additional, Ealing, John, additional, Somarathi, Suresh, additional, Chandler, Kate E, additional, Stuart, Helen M, additional, Burkitt-Wright, Emma MM, additional, Newman, William G, additional, Bruce, Iain A, additional, Black, Graeme C, additional, and Gokhale, David, additional

Published
2021
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39. Extended gene panel testing in lobular breast cancer

Author

van Veen, Elke M., primary, Evans, D. Gareth, additional, Harkness, Elaine F., additional, Byers, Helen J., additional, Ellingford, Jamie M., additional, Woodward, Emma R., additional, Bowers, Naomi L., additional, Wallace, Andrew J., additional, Howell, Sacha J., additional, Howell, Anthony, additional, Lalloo, Fiona, additional, Newman, William G., additional, and Smith, Miriam J., additional

Published
2021
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41. High likelihood of actionable pathogenic variant detection in breast cancer genes in women with very early onset breast cancer

Author

Evans, D Gareth, primary, van Veen, Elke Maria, additional, Byers, Helen J, additional, Evans, Sarah J, additional, Burghel, George J, additional, Woodward, Emma Roisin, additional, Harkness, Elaine F, additional, Eccles, Diana M, additional, Greville-Haygate, Stephanie L, additional, Ellingford, Jamie M, additional, Bowers, Naomi L, additional, Pereira, Marta, additional, Wallace, Andrew J, additional, Howell, Sasha J, additional, Howell, Anthony, additional, Lalloo, Fiona, additional, Newman, William G, additional, and Smith, Miriam Jane, additional

Published
2021
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42. Comparison of in Silico Strategies to Prioritize Rare Genomic Variants Impacting RNA Splicing for the Diagnosis of Genomic Disorders

Author

Rowlands, Charlie, primary, Thomas, Huw B, additional, Lord, Jenny, additional, Wai, Htoo A, additional, Arno, Gavin, additional, Beaman, Glenda, additional, Sergouniotis, Panagiotis, additional, Gomes-Silva, Beatriz, additional, Campbell, Christopher, additional, Gossan, Nicole, additional, Hardcastle, Claire, additional, Webb, Kevin, additional, O’Callaghan, Christopher, additional, Hirst, Robert A, additional, Ramsden, Simon, additional, Jones, Elizabeth, additional, -Smith, Jill Clayton, additional, Webster, Andrew R, additional, Douglas, Andrew GL, additional, O’Keefe, Raymond T, additional, Newman, William G, additional, Baralle, Diana, additional, Black, Graeme CM, additional, and Ellingford, Jamie M, additional

Published
2021
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46. BBS1 branchpoint variant is associated with non-syndromic retinitis pigmentosa.

Author

Fadaie, Zeinab, Whelan, Laura, Dockery, Adrian, Li, Catherina H. Z., Ingeborgh van den Born, L., Hoyng, Carel B., Gilissen, Christian, Corominas, Jordi, Rowlands, Charlie, Megaw, Roly, Lampe, Anne K., Cremers, Frans P. M., Farrar, Gwyneth Jane, Ellingford, Jamie M., Kenna, Paul F., and Roosing, Susanne

Abstract

Background Inherited retinal diseases (IRDs) can be caused by variants in >270 genes. The Bardet-Biedl syndrome 1 (BBS1) gene is one of these genes and may be associated with syndromic and non-syndromic autosomal recessive retinitis pigmentosa (RP). Here, we identified a branchpoint variant in BBS1 and assessed its pathogenicity by in vitro functional analysis. Methods Whole genome sequencing was performed for three unrelated monoallelic BBS1 cases with nonsyndromic RP. A fourth case received MGCM 105 gene panel analysis. Functional analysis using a midigene splice assay was performed for the putative pathogenic branchpoint variant in BBS1. After confirmation of its pathogenicity, patients were clinically re-evaluated, including assessment of non-ocular features of BardetBiedl syndrome. Results Clinical assessments of probands showed that all individuals displayed non-syndromic RP with macular involvement. Through detailed variant analysis and prioritisation, two pathogenic variants in BBS1, the most common missense variant, c.1169T>G (p.(Met390Arg)), and a branchpoint variant, c.592-21A>T, were identified. Segregation analysis confirmed that in all families, probands were compound heterozygous for c.1169T>Gand c.592-21A>T. Functional analysis of the branchpoint variant revealed a complex splicing defect including exon 8 and exon 7/8 skipping, and partial inframe deletion of exon 8. Conclusion A putative severe branchpoint variant in BBS1, together with a mild missense variant, underlies non-syndromic RP in four unrelated individuals. To our knowledge, this is the first report of a pathogenic branchpoint variant in IRDs that results in a complex splice defect. In addition, this research highlights the importance of the analysis of non-coding regions in order to provide a conclusive molecular diagnosis. [ABSTRACT FROM AUTHOR]

Published
2022
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47. Improving the clinical interpretation of missense variants in X linked genes using structural analysis.

Author

Sallah, Shalaw Rassul, Ellingford, Jamie M., Sergouniotis, Panagiotis I., Ramsden, Simon C., Lench, Nicholas, Lovell, Simon C., and Black, Graeme C.

Abstract

Background Improving the clinical interpretation of missense variants can increase the diagnostic yield of genomic testing and lead to personalised management strategies. Currently, due to the imprecision of bioinformatic tools that aim to predict variant pathogenicity, their role in clinical guidelines remains limited. There is a clear need for more accurate prediction algorithms and this study aims to improve performance by harnessing structural biology insights. The focus of this work is missense variants in a subset of genes associated with X linked disorders. Methods We have developed a protein-specific variant interpreter (ProSper) that combines genetic and protein structural data. This algorithm predicts missense variant pathogenicity by applying machine learning approaches to the sequence and structural characteristics of variants. Results ProSper outperformed seven previously described tools, including meta-predictors, in correctly evaluating whether or not variants are pathogenic; this was the case for 11 of the 21 genes associated with X linked disorders that met the inclusion criteria for this study. We also determined gene-specific pathogenicity thresholds that improved the performance of VEST4, REVEL and ClinPred, the three best-performing tools out of the seven that were evaluated; this was the case in 11, 11 and 12 different genes, respectively. Conclusion ProSper can form the basis of a molecule-specific prediction tool that can be implemented into diagnostic strategies. It can allow the accurate prioritisation of missense variants associated with X linked disorders, aiding precise and timely diagnosis. In addition, we demonstrate that gene-specific pathogenicity thresholds for a range of missense prioritisation tools can lead to an increase in prediction accuracy. [ABSTRACT FROM AUTHOR]

Published
2022
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48. A Dominantly Inherited 5′ UTR Variant Causing Methylation-Associated Silencing of BRCA1 as a Cause of Breast and Ovarian Cancer

Author

Evans, D Gareth R, van Veen, Elke M, Byers, Helen J, Wallace, Andrew J, Ellingford, Jamie M, Beaman, Glenda, Santoyo-Lopez, Javier, Aitman, Timothy J., Eccles, Diana M, Lalloo, Fiona I, Smith, Miriam J, and Newman, William G

Subjects
Adult, Aged, 80 and over, BRCA2 Protein, Ovarian Neoplasms, endocrine system diseases, familial breast and ovarian cancer, BRCA1 Protein, promoter hypermethylation, Breast Neoplasms, DNA Methylation, Middle Aged, BRCA1, Article, Epigenesis, Genetic, secondary epimutation, Humans, Female, Genetic Predisposition to Disease, skin and connective tissue diseases, 5' Untranslated Regions, Promoter Regions, Genetic, epigenetic, Germ-Line Mutation, Aged
Abstract

Pathogenic variants in BRCA1 or BRCA2 are identified in ∼20% of families with multiple individuals affected by early-onset breast and/or ovarian cancer. Extensive searches for additional highly penetrant genes or alternative mutational mechanisms altering BRCA1 or BRCA2 have not explained the missing heritability. Here, we report a dominantly inherited 5' UTR variant associated with epigenetic BRCA1 silencing due to promoter hypermethylation in two families affected by breast and ovarian cancer. BRCA1 promoter methylation of ten CpG dinucleotides in families who are affected by breast and/or ovarian cancer but do not have germline BRCA1 or BRCA2 pathogenic variants was assessed by pyrosequencing and clonal bisulfite sequencing. RNA and DNA sequencing of BRCA1 from lymphocytes was undertaken to establish allelic expression and the presence of germline variants. BRCA1 promoter hypermethylation was identified in 2 of 49 families in which multiple women are affected by grade 3 breast cancer or high-grade serous ovarian cancer. Soma-wide BRCA1 promoter hypermethylation was confirmed in blood, buccal mucosa, and hair follicles. Pyrosequencing showed that DNA was ∼50% methylated, consistent with the silencing of one allele, which was confirmed by clonal bisulfite sequencing. RNA sequencing revealed the allelic loss of BRCA1 expression in both families and that this loss of expression segregated with the heterozygous variant c.-107A>T in the BRCA1 5' UTR. Our results establish a mechanism whereby familial breast and ovarian cancer is caused by an in cis 5' UTR variant associated with epigenetic silencing of the BRCA1 promoter in two independent families. We propose that methylation analyses be undertaken to establish the frequency of this mechanism in families affected by early-onset breast and/or ovarian cancer without a BRCA1 or BRCA2 pathogenic variant.

Published
2018

50. Expanding the genotypic spectrum of TXNL4A variants in Burn‐McKeown syndrome.

Author

Wood, Katherine A., Ellingford, Jamie M., Thomas, Huw B., Douzgou, Sofia, Beaman, Glenda M., Hobson, Emma, Prescott, Katrina, O'Keefe, Raymond T., and Newman, William G.

Subjects
*RNA splicing, *GENOTYPES, *BINDING sites, *TRANSCRIPTION factors, *TELEOLOGY
Abstract

The developmental disorder Burn‐McKeown Syndrome (BMKS) is characterised by choanal atresia and specific craniofacial features. BMKS is caused by biallelic variants in the pre‐messenger RNA splicing factor TXNL4A. Most patients have a loss‐of‐function variant in trans with a 34‐base pair (bp) deletion (type 1 Δ34) in the promoter region. Here, we identified two patients with BMKS. One individual has a TXNL4A c.93_94delCC, p.His32Argfs *21 variant combined with a type 1 Δ34 promoter deletion. The other has an intronic TXNL4A splice site variant (c.258‐3C>G) and a type 1 Δ34 promoter deletion. We show the c.258‐3C>G variant and a previously reported c.258‐2A>G variant, cause skipping of the final exon of TXNL4A in a minigene splicing assay. Furthermore, we identify putative transcription factor binding sites within the 56 bp of the TXNL4A promoter affected by the type 1 and type 2 Δ34 and use dual luciferase assays to identify a 22 bp repeated motif essential for TXNL4A expression within this promoter region. We propose that additional variants affecting critical transcription factor binding nucleotides within the 22 bp repeated motif could be relevant to BMKS aetiology. Finally, our data emphasises the need to analyse the non‐coding sequence in individuals where a single likely pathogenic coding variant is identified in an autosomal recessive disorder consistent with the clinical presentation. [ABSTRACT FROM AUTHOR]

Published
2022
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