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1. A multicenter, open-label, randomized, phase II study of cediranib with or without lenalidomide in iodine 131-refractory differentiated thyroid cancer.

Author

Rosenberg, A, Liao, C-Y, Karrison, T, de Souza, J, Worden, F, Libao, B, Krzyzanowska, M, Hayes, D, Winquist, E, Saloura, V, Prescott, K, Villaflor, V, Seiwert, T, Schechter, R, Stadler, W, Cohen, Ezra, and Vokes, E

Subjects
antiangiogenic, cediranib, immunomodulation, lenalidomide, thyroid cancer, tyrosine kinase inhibitor, Humans, Infant, Iodine Radioisotopes, Lenalidomide, Thyroid Neoplasms, Vascular Endothelial Growth Factor A, Receptors, Vascular Endothelial Growth Factor, Adenocarcinoma
Abstract

BACKGROUND: Multitargeted tyrosine kinase inhibitors (TKIs) of the vascular endothelial growth factor receptor (VEGFR) pathway have activity in differentiated thyroid cancer (DTC). Lenalidomide demonstrated preliminary efficacy in DTC, but its safety and efficacy in combination with VEGFR-targeted TKIs is unknown. We sought to determine the safety and efficacy of cediranib, a VEGFR-targeted TKI, with or without lenalidomide, in the treatment of iodine 131-refractory DTC. PATIENTS AND METHODS: In this multicenter, open-label, randomized, phase II clinical trial, 110 patients were enrolled and randomized to cediranib alone or cediranib with lenalidomide. The primary endpoint was progression-free survival (PFS). Secondary endpoints included response rate, duration of response, toxicity, and overall survival (OS). Patients (≥18 years of age) with DTC who were refractory to further surgical or radioactive iodine (RAI) therapy as reviewed at a multispecialty tumor board conference, and evidence of disease progression within the previous 12 months and no more than one prior line of systemic therapy were eligible. RESULTS: Of the 110 patients, 108 started therapy and were assessable for efficacy. The median PFS was 14.8 months [95% confidence interval (CI) 8.5-23.8 months] in the cediranib arm and 11.3 months (95% CI 8.7-18.9 months) in the cediranib with lenalidomide arm (P = 0.36). The 2-year OS was 64.8% (95% CI 43.3% to 86.4%) and 75.3% (95% CI 59.4% to 91.0%), respectively (P = 0.80). The serious adverse event rate was 41% in the cediranib arm and 46% in the cediranib with lenalidomide arm. CONCLUSIONS: Single-agent therapy with cediranib showed promising efficacy in RAI-refractory DTC similar to other VEGFR-targeted TKIs, while the addition of lenalidomide did not result in clinically meaningful improvements in outcomes.

Published
2023

3. Finding Diagnostically Useful Patterns in Quantitative Phenotypic Data

Author

Fitzgerald, T.W., Gerety, S.S., Jones, W.D., van Kogelenberg, M., King, D.A., McRae, J., Morley, K.I., Parthiban, V., Al-Turki, S., Ambridge, K., Barrett, D.M., Bayzetinova, T., Clayton, S., Coomber, E.L., Gribble, S., Jones, P., Krishnappa, N., Mason, L.E., Middleton, A., Miller, R., Prigmore, E., Rajan, D., Sifrim, A., Tivey, A.R., Ahmed, M., Akawi, N., Andrews, R., Anjum, U., Archer, H., Armstrong, R., Balasubramanian, M., Banerjee, R., Barelle, D., Batstone, P., Baty, D., Bennett, C., Berg, J., Bernhard, B., Bevan, A.P., Blair, E., Blyth, M., Bohanna, D., Bourdon, L., Bourn, D., Brady, A., Bragin, E., Brewer, C., Brueton, L., Brunstrom, K., Bumpstead, S.J., Bunyan, D.J., Burn, J., Burton, J., Canham, N., Castle, B., Chandler, K., Clasper, S., Clayton-Smith, J., Cole, T., Collins, A., Collinson, M.N., Connell, F., Cooper, N., Cox, H., Cresswell, L., Cross, G., Crow, Y., D’Alessandro, P.M., Dabir, T., Davidson, R., Davies, S., Dean, J., Deshpande, C., Devlin, G., Dixit, A., Dominiczak, A., Donnelly, C., Donnelly, D., Douglas, A., Duncan, A., Eason, J., Edkins, S., Ellard, S., Ellis, P., Elmslie, F., Evans, K., Everest, S., Fendick, T., Fisher, R., Flinter, F., Foulds, N., Fryer, A., Fu, B., Gardiner, C., Gaunt, L., Ghali, N., Gibbons, R., Pereira, S.L. Gomes, Goodship, J., Goudie, D., Gray, E., Greene, P., Greenhalgh, L., Harrison, L., Hawkins, R., Hellens, S., Henderson, A., Hobson, E., Holden, S., Holder, S., Hollingsworth, G., Homfray, T., Humphreys, M., Hurst, J., Ingram, S., Irving, M., Jarvis, J., Jenkins, L., Johnson, D., Jones, D., Jones, E., Josifova, D., Joss, S., Kaemba, B., Kazembe, S., Kerr, B., Kini, U., Kinning, E., Kirby, G., Kirk, C., Kivuva, E., Kraus, A., Kumar, D., Lachlan, K., Lam, W., Lampe, A., Langman, C., Lees, M., Lim, D., Lowther, G., Lynch, S.A., Magee, A., Maher, E., Mansour, S., Marks, K., Martin, K., Maye, U., McCann, E., McConnell, V., McEntagart, M., McGowan, R., McKay, K., McKee, S., McMullan, D.J., McNerlan, S., Mehta, S., Metcalfe, K., Miles, E., Mohammed, S., Montgomery, T., Moore, D., Morgan, S., Morris, A., Morton, J., Mugalaasi, H., Murday, V., Nevitt, L., Newbury-Ecob, R., Norman, A., O’Shea, R., Ogilvie, C., Park, S., Parker, M.J., Patel, C., Paterson, J., Payne, S., Phipps, J., Pilz, D.T., Porteous, D., Pratt, N., Prescott, K., Price, S., Pridham, A., Proctor, A., Purnell, H., Ragge, N., Rankin, J., Raymond, L., Rice, D., Robert, L., Roberts, E., Roberts, G., Roberts, J., Roberts, P., Ross, A., Rosser, E., Saggar, A., Samant, S., Sandford, R., Sarkar, A., Schweiger, S., Scott, C., Scott, R., Selby, A., Seller, A., Sequeira, C., Shannon, N., Sharif, S., Shaw-Smith, C., Shearing, E., Shears, D., Simonic, I., Simpkin, D., Singzon, R., Skitt, Z., Smith, A., Smith, B., Smith, K., Smithson, S., Sneddon, L., Splitt, M., Squires, M., Stewart, F., Stewart, H., Suri, M., Sutton, V., Swaminathan, G.J., Sweeney, E., Tatton-Brown, K., Taylor, C., Taylor, R., Tein, M., Temple, I.K., Thomson, J., Tolmie, J., Torokwa, A., Treacy, B., Turner, C., Turnpenny, P., Tysoe, C., Vandersteen, A., Vasudevan, P., Vogt, J., Wakeling, E., Walker, D., Waters, J., Weber, A., Wellesley, D., Whiteford, M., Widaa, S., Wilcox, S., Williams, D., Williams, N., Woods, G., Wragg, C., Wright, M., Yang, F., Yau, M., Carter, N.P., Parker, M., Firth, H.V., FitzPatrick, D.R., Wright, C.F., Barrett, J.C., Hurles, M.E., Aitken, Stuart, Firth, Helen V., McRae, Jeremy, Halachev, Mihail, Kini, Usha, Parker, Michael J., Lees, Melissa M., Lachlan, Katherine, Sarkar, Ajoy, Joss, Shelagh, Splitt, Miranda, McKee, Shane, Németh, Andrea H., Scott, Richard H., Wright, Caroline F., Marsh, Joseph A., Hurles, Matthew E., and FitzPatrick, David R.

Published
2019
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5. MA05.05 Patient Reported Experience as a Baseline for 4R Care Sequence Implementation at 8 Cancer Centers

Author

Prescott, K., primary, Weldon, C.B., additional, Mohindra, N., additional, Feldman, L.E., additional, Pasquinelli, M.M., additional, Nguyen, R.H., additional, Weinberg, F., additional, Chan, C., additional, Houseknecht, S., additional, Feliciano, J., additional, Sacks, R., additional, Carlisle, J.W., additional, Waugh, W., additional, Martin, J., additional, Woodyard, J., additional, Khosla, P., additional, Khan, S., additional, Ravelo, A., additional, Lycan, T., additional, Martin, N., additional, Boehmer, L., additional, and Trosman, J.R., additional

Published
2023
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8. Large-scale discovery of novel genetic causes of developmental disorders

Author

Fitzgerald, T. W., Gerety, S. S., Jones, W. D., van Kogelenberg, M., King, D. A., McRae, J., Morley, K. I., Parthiban, V., Al-Turki, S., Ambridge, K., Barrett, D. M., Bayzetinova, T., Clayton, S., Coomber, E. L., Gribble, S., Jones, P., Krishnappa, N., Mason, L. E., Middleton, A., Miller, R., Prigmore, E., Rajan, D., Sifrim, A., Tivey, A. R., Ahmed, M., Akawi, N., Andrews, R., Anjum, U., Archer, H., Armstrong, R., Balasubramanian, M., Banerjee, R., Baralle, D., Batstone, P., Baty, D., Bennett, C., Berg, J., Bernhard, B., Bevan, A. P., Blair, E., Blyth, M., Bohanna, D., Bourdon, L., Bourn, D., Brady, A., Bragin, E., Brewer, C., Brueton, L., Brunstrom, K., Bumpstead, S. J., Bunyan, D. J., Burn, J., Burton, J., Canham, N., Castle, B., Chandler, K., Clasper, S., Clayton-Smith, J., Cole, T., Collins, A., Collinson, M. N., Connell, F., Cooper, N., Cox, H., Cresswell, L., Cross, G., Crow, Y., DʼAlessandro, M., Dabir, T., Davidson, R., Davies, S., Dean, J., Deshpande, C., Devlin, G., Dixit, A., Dominiczak, A., Donnelly, C., Donnelly, D., Douglas, A., Duncan, A., Eason, J., Edkins, S., Ellard, S., Ellis, P., Elmslie, F., Evans, K., Everest, S., Fendick, T., Fisher, R., Flinter, F., Foulds, N., Fryer, A., Fu, B., Gardiner, C., Gaunt, L., Ghali, N., Gibbons, R., Pereira, Gomes S. L., Goodship, J., Goudie, D., Gray, E., Greene, P., Greenhalgh, L., Harrison, L., Hawkins, R., Hellens, S., Henderson, A., Hobson, E., Holden, S., Holder, S., Hollingsworth, G., Homfray, T., Humphreys, M., Hurst, J., Ingram, S., Irving, M., Jarvis, J., Jenkins, L., Johnson, D., Jones, D., Jones, E., Josifova, D., Joss, S., Kaemba, B., Kazembe, S., Kerr, B., Kini, U., Kinning, E., Kirby, G., Kirk, C., Kivuva, E., Kraus, A., Kumar, D., Lachlan, K., Lam, W., Lampe, A., Langman, C., Lees, M., Lim, D., Lowther, G., Lynch, S. A., Magee, A., Maher, E., Mansour, S., Marks, K., Martin, K., Maye, U., McCann, E., McConnell, V., McEntagart, M., McGowan, R., McKay, K., McKee, S., McMullan, D. J., McNerlan, S., Mehta, S., Metcalfe, K., Miles, E., Mohammed, S., Montgomery, T., Moore, D., Morgan, S., Morris, A., Morton, J., Mugalaasi, H., Murday, V., Nevitt, L., Newbury-Ecob, R., Norman, A., OʼShea, R., Ogilvie, C., Park, S., Parker, M. J., Patel, C., Paterson, J., Payne, S., Phipps, J., Pilz, D. T., Porteous, D., Pratt, N., Prescott, K., Price, S., Pridham, A., Procter, A., Purnell, H., Ragge, N., Rankin, J., Raymond, L., Rice, D., Robert, L., Roberts, E., Roberts, G., Roberts, J., Roberts, P., Ross, A., Rosser, E., Saggar, A., Samant, S., Sandford, R., Sarkar, A., Schweiger, S., Scott, C., Scott, R., Selby, A., Seller, A., Sequeira, C., Shannon, N., Sharif, S., Shaw-Smith, C., Shearing, E., Shears, D., Simonic, I., Simpkin, D., Singzon, R., Skitt, Z., Smith, A., Smith, B., Smith, K., Smithson, S., Sneddon, L., Splitt, M., Squires, M., Stewart, F., Stewart, H., Suri, M., Sutton, V., Swaminathan, G. J., Sweeney, E., Tatton-Brown, K., Taylor, C., Taylor, R., Tein, M., Temple, I. K., Thomson, J., Tolmie, J., Torokwa, A., Treacy, B., Turner, C., Turnpenny, P., Tysoe, C., Vandersteen, A., Vasudevan, P., Vogt, J., Wakeling, E., Walker, D., Waters, J., Weber, A., Wellesley, D., Whiteford, M., Widaa, S., Wilcox, S., Williams, D., Williams, N., Woods, G., Wragg, C., Wright, M., Yang, F., Yau, M., Carter, N. P., Parker, M., Firth, H. V., FitzPatrick, D. R., Wright, C. F., Barrett, J. C., and Hurles, M. E.

Published
2015
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12. Development of clinical prediction models for outcomes of complicated intra-abdominal infection

Author

Ahmed, S, Bonnett, L, Melhuish, A, Adil, MT, Aggarwal, I, Ali, W, Bennett, J, Boldock, E, Burns, FA, Czarniak, E, Dennis, R, Flower, B, Fok, R, Goodman, A, Halai, S, Hanna, T, Hashem, M, Hodgson, SH, Hughes, G, Hurndalm, K-H, Hyland, R, Iqbal, MR, Jarchow-MacDonald, A, Kailavasan, M, Klimovskij, M, Laliotis, A, Lambourne, J, Lawday, S, Lee, F, Lindsey, B, Lund, JN, Mabayoje, DA, Malik, KI, Muir, A, Narula, HS, Ofor, U, Parsons, H, Pavelle, T, Prescott, K, Rajgopal, A, Roy, I, Sagar, J, Scarborough, C, Shaikh, S, Smart, CJ, Snape, S, Tabaqchali, M, Tennakoon, A, Tilley, R, Vink, E, White, L, Burke, D, and Kirby, A

Abstract

Methods A multicentre observational study was conducted from August 2016 to February 2017 in the UK. Adult patients diagnosed with cIAI were included. Multivariable logistic regression was performed to develop CPMs for mortality and cIAI relapse. The c-statistic was used to test model discrimination. Model calibration was tested using calibration slopes and calibration in the large (CITL). The CPMs were then presented as point scoring systems and validated further. Results Overall, 417 patients from 31 surgical centres were included in the analysis. At 90 days after diagnosis, 17.3 per cent had a cIAI relapse and the mortality rate was 11.3 per cent. Predictors in the mortality model were age, cIAI aetiology, presence of a perforated viscus and source control procedure. Predictors of cIAI relapse included the presence of collections, outcome of initial management, and duration of antibiotic treatment. The c-statistic adjusted for model optimism was 0.79 (95 per cent c.i. 0.75 to 0.87) and 0.74 (0.73 to 0.85) for mortality and cIAI relapse CPMs. Adjusted calibration slopes were 0.88 (95 per cent c.i. 0.76 to 0.90) for the mortality model and 0.91 (0.88 to 0.94) for the relapse model; CITL was −0.19 (95 per cent c.i. −0.39 to −0.12) and − 0.01 (− 0.17 to −0.03) respectively. Conclusion Relapse of infection and death after complicated intra-abdominal infections are common. Clinical prediction models were developed to identify patients at increased risk of relapse or death after treatment, although these require external validation.

Published
2021

15. Development and internal validation of clinical prediction models for outcomes of complicated intra-abdominal infection

Author

Ahmed, S, primary, Bonnett, L, additional, Melhuish, A, additional, Adil, M T, additional, Aggarwal, I, additional, Ali, W, additional, Bennett, J, additional, Boldock, E, additional, Burns, F A, additional, Czarniak, E, additional, Dennis, R, additional, Flower, B, additional, Fok, R, additional, Goodman, A L, additional, Halai, S, additional, Hanna, T, additional, Hashem, M, additional, Hodgson, S H, additional, Hughes, G, additional, Hurndall, K-H, additional, Hyland, R, additional, Iqbal, M R, additional, Jarchow-MacDonald, A, additional, Kailavasan, M, additional, Klimovskij, M, additional, Laliotis, A, additional, Lambourne, J, additional, Lawday, S, additional, Lee, F, additional, Lindsey, B, additional, Lund, J N, additional, Mabayoje, D A, additional, Malik, K I, additional, Muir, A, additional, Narula, H S, additional, Ofor, U, additional, Parsons, H, additional, Pavelle, T, additional, Prescott, K, additional, Rajgopal, A, additional, Roy, I, additional, Sagar, J, additional, Scarborough, C, additional, Shaikh, S, additional, Smart, C J, additional, Snape, S, additional, Tabaqchali, M A, additional, Tennakoon, A, additional, Tilley, R, additional, Vink, E, additional, White, L, additional, Burke, D, additional, and Kirby, A, additional

Published
2021
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17. Mutation Update for the CSB/ERCC6 and CSA/ERCC8 Genes Involved in Cockayne Syndrome

Author

Laugel, V., Dalloz, C., Durand, M., Sauvanaud, F., Kristensen, U., Vincent, M. C., Pasquier, L., Odent, S., Cormier-Daire, V., Gener, B., Tobias, E. S., Tolmie, J. L., Martin-Coignard, D., Drouin-Garraud, V., Heron, D., Journel, H., Raffo, E., Vigneron, J., Lyonnet, S., Murday, V., Gubser-Mercati, D., Funalot, B., Brueton, L., del Pozo, Sanchez J., Muñoz, E., Gennery, A. R., Salih, M., Noruzinia, M., Prescott, K., Ramos, L., Stark, Z., Fieggen, K., Chabrol, B., Sarda, P., Edery, P., Bloch-Zupan, A., Fawcett, H., Pham, D., Egly, J. M., Lehmann, A. R., Sarasin, A., and Dollfus, H.

Published
2010
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19. CTCF variants in 39 individuals with a variable neurodevelopmental disorder broaden the mutational and clinical spectrum

Author

Konrad, E. D. (Enrico D. H.), Nardini, N. (Niels), Caliebe, A. (Almuth), Nagel, I. (Inga), Young, D. (Dana), Horvath, G. (Gabriella), Santoro, S. L. (Stephanie L.), Shuss, C. (Christine), Ziegler, A. (Alban), Bonneau, D. (Dominique), Kempers, M. (Marlies), Pfundt, R. (Rolph), Legius, E. (Eric), Bouman, A. (Arjan), Stuurman, K. E. (Kyra E.), Õunap, K. (Katrin), Pajusalu, S. (Sander), Wojcik, M. H. (Monica H.), Vasileiou, G. (Georgia), Le Guyader, G. (Gwenaël), Schnelle, H. M. (Hege M.), Berland, S. (Siren), Zonneveld-Huijssoon, E. (Evelien), Kersten, S. (Simone), Gupta, A. (Aditi), Blackburn, P. R. (Patrick R.), Ellingson, M. S. (Marissa S.), Ferber, M. J. (Matthew J.), Dhamija, R. (Radhika), Klee, E. W. (Eric W.), McEntagart, M. (Meriel), Lichtenbelt, K. D. (Klaske D.), Kenney, A. (Amy), Vergano, S. A. (Samantha A.), Jamra, R. A. (Rami Abou), Platzer, K. (Konrad), Pierpont, M. E. (Mary Ella), Khattar, D. (Divya), Hopkin, R. J. (Robert J.), Martin, R. J. (Richard J.), Jongmans, M. C. (Marjolijn C. J.), Chang, V. Y. (Vivian Y.), Martinez-Agosto, J. A. (Julian A.), Kuismin, O. (Outi), Kurki, M. I. (Mitja I.), Pietiläinen, O. (Olli), Palotie, A. (Aarno), Maarup, T. J. (Timothy J.), Johnson, D. S. (Diana S.), Venborg Pedersen, K. (Katja), Laulund, L. W. (Lone W.), Lynch, S. A. (Sally A.), Blyth, M. (Moira), Prescott, K. (Katrina), Canham, N. (Natalie), Ibitoye, R. (Rita), Brilstra, E. H. (Eva H.), Shinawi, M. (Marwan), Fassi, E. (Emily), Study, D. (DDD), Sticht, H. (Heinrich), Gregor, A. (Anne), Van Esch, H. (Hilde), and Zweier, C. (Christiane)

Subjects
Drosophila melanogaster, intellectual disability, neurodevelopmental disorders, CTCF, chromatin organization
Abstract

Purpose: Pathogenic variants in the chromatin organizer CTCF were previously reported in seven individuals with a neurodevelopmental disorder (NDD). Methods: Through international collaboration we collected data from 39 subjects with variants in CTCF. We performed transcriptome analysis on RNA from blood samples and utilized Drosophila melanogaster to investigate the impact of Ctcf dosage alteration on nervous system development and function. Results: The individuals in our cohort carried 2 deletions, 8 likely gene-disruptive, 2 splice-site, and 20 different missense variants, most of them de novo. Two cases were familial. The associated phenotype was of variable severity extending from mild developmental delay or normal IQ to severe intellectual disability. Feeding difficulties and behavioral abnormalities were common, and variable other findings including growth restriction and cardiac defects were observed. RNA-sequencing in five individuals identified 3828 deregulated genes enriched for known NDD genes and biological processes such as transcriptional regulation. Ctcf dosage alteration in Drosophila resulted in impaired gross neurological functioning and learning and memory deficits. Conclusion: We significantly broaden the mutational and clinical spectrum ofCTCF-associated NDDs. Our data shed light onto the functional role of CTCF by identifying deregulated genes and show that Ctcf alterations result in nervous system defects in Drosophila.

Published
2019

20. PORCN mutations in focal dermal hypoplasia: coping with lethality

Author

Bornholdt, D., Oeffner, F., Konig, A., Happle, R.H.G., Alanay, Y., Ascherman, J., Benke, P.J., Boente Mdel, C., Burgt, I. van der, Chassaing, N., Ellis, I., Francisco, C.R., Giovanna, P. Della, Hamel, B.C.J., Has, C., Heinelt, K., Janecke, A., Kastrup, W., Loeys, B.L., Lohrisch, I., Marcelis, C.L.M., Mehraein, Y., Nicolas, M.E., Pagliarini, D., Paradisi, M., Patrizi, A., Piccione, M., Piza-Katzer, H., Prager, B., Prescott, K., Strien, J., Utine, G.E., Zeller, M.S., Grzeschik, K.H., Bornholdt, D, Oeffner, F, König, A, Happle, R, Alanay, Y, Ascherman, J, Benke, PJ, Boente Mdel C, van der Burgt I, Chassaing, N, Ellis, I, Francisco, CR, Della Giovanna P, Hamel, B, Has, C, Heinelt, K, Janecke, A, Kastrup, W, Loeys, B, Lohrisch, I, Marcelis, C, Mehraein, Y, Nicolas, ME, Pagliarini, D, Paradisi, M, Patrizi, A, Piccione, M, Piza-Katzer, H, Prager, B, Prescott, K, Strien, J, Utine, GE, Zeller, MS, Grzeschik, KH, Bornholdt D, Oeffner F, König A, Happle R, Alanay Y, Ascherman J, Benke PJ, Chassaing N, Ellis I, Francisco CR, Hamel B, Has C, Heinelt K, Janecke A, Kastrup W, Loeys B, Lohrisch I, Marcelis C, Mehraein Y, Nicolas ME, Pagliarini D, Paradisi M, Patrizi A, Piccione M, Piza-Katzer H, Prager B, Prescott K, Strien J, Utine GE, Zeller MS, and Grzeschik KH

Subjects
Adult, Male, Adolescent, Base Sequence, DNA Mutational Analysis, Molecular Sequence Data, Infant, Newborn, Infant, Membrane Proteins, Genomic disorders and inherited multi-system disorders [IGMD 3], Focal Dermal Hypoplasia, Settore MED/38 - Pediatria Generale E Specialistica, Settore MED/03 - Genetica Medica, Child, Preschool, Mutation, Goltz syndrome, FDH, PORCN, WNT, skewed X-inactivation, postzygotic mosaic, Humans, Protein Isoforms, Female, Amino Acid Sequence, Child, Acyltransferases
Abstract

Contains fulltext : 81709.pdf (Publisher’s version ) (Closed access) The X-linked dominant trait focal dermal hypoplasia (FDH, Goltz syndrome) is a developmental defect with focal distribution of affected tissues due to a block of Wnt signal transmission from cells carrying a detrimental PORCN mutation on an active X-chromosome. Molecular characterization of 24 unrelated patients from different ethnic backgrounds revealed 23 different mutations of the PORCN gene in Xp11.23. Three were microdeletions eliminating PORCN and encompassing neighboring genes such as EBP, the gene associated with Conradi-Hunermann-Happle syndrome (CDPX2). 12/24 patients carried nonsense mutations resulting in loss of function. In one case a canonical splice acceptor site was mutated, and 8 missense mutations exchanged highly conserved amino acids. FDH patients overcome the consequences of potentially lethal X-chromosomal mutations by extreme skewing of X-chromosome inactivation in females, enabling transmission of the trait in families, or by postzygotic mosaicism both in male and female individuals. Molecular characterization of the PORCN mutations in cases diagnosed as Goltz syndrome is particularly relevant for genetic counseling of patients and their families since no functional diagnostic test is available and carriers of the mutation might otherwise be overlooked due to considerable phenotypic variability associated with the mosaic status.

Published
2009

21. Finding Diagnostically Useful Patterns in Quantitative Phenotypic Data

Author

Aitken, Stuart, primary, Firth, Helen V., additional, McRae, Jeremy, additional, Halachev, Mihail, additional, Kini, Usha, additional, Parker, Michael J., additional, Lees, Melissa M., additional, Lachlan, Katherine, additional, Sarkar, Ajoy, additional, Joss, Shelagh, additional, Splitt, Miranda, additional, McKee, Shane, additional, Németh, Andrea H., additional, Scott, Richard H., additional, Wright, Caroline F., additional, Marsh, Joseph A., additional, Hurles, Matthew E., additional, FitzPatrick, David R., additional, Fitzgerald, T.W., additional, Gerety, S.S., additional, Jones, W.D., additional, van Kogelenberg, M., additional, King, D.A., additional, McRae, J., additional, Morley, K.I., additional, Parthiban, V., additional, Al-Turki, S., additional, Ambridge, K., additional, Barrett, D.M., additional, Bayzetinova, T., additional, Clayton, S., additional, Coomber, E.L., additional, Gribble, S., additional, Jones, P., additional, Krishnappa, N., additional, Mason, L.E., additional, Middleton, A., additional, Miller, R., additional, Prigmore, E., additional, Rajan, D., additional, Sifrim, A., additional, Tivey, A.R., additional, Ahmed, M., additional, Akawi, N., additional, Andrews, R., additional, Anjum, U., additional, Archer, H., additional, Armstrong, R., additional, Balasubramanian, M., additional, Banerjee, R., additional, Barelle, D., additional, Batstone, P., additional, Baty, D., additional, Bennett, C., additional, Berg, J., additional, Bernhard, B., additional, Bevan, A.P., additional, Blair, E., additional, Blyth, M., additional, Bohanna, D., additional, Bourdon, L., additional, Bourn, D., additional, Brady, A., additional, Bragin, E., additional, Brewer, C., additional, Brueton, L., additional, Brunstrom, K., additional, Bumpstead, S.J., additional, Bunyan, D.J., additional, Burn, J., additional, Burton, J., additional, Canham, N., additional, Castle, B., additional, Chandler, K., additional, Clasper, S., additional, Clayton-Smith, J., additional, Cole, T., additional, Collins, A., additional, Collinson, M.N., additional, Connell, F., additional, Cooper, N., additional, Cox, H., additional, Cresswell, L., additional, Cross, G., additional, Crow, Y., additional, D’Alessandro, P.M., additional, Dabir, T., additional, Davidson, R., additional, Davies, S., additional, Dean, J., additional, Deshpande, C., additional, Devlin, G., additional, Dixit, A., additional, Dominiczak, A., additional, Donnelly, C., additional, Donnelly, D., additional, Douglas, A., additional, Duncan, A., additional, Eason, J., additional, Edkins, S., additional, Ellard, S., additional, Ellis, P., additional, Elmslie, F., additional, Evans, K., additional, Everest, S., additional, Fendick, T., additional, Fisher, R., additional, Flinter, F., additional, Foulds, N., additional, Fryer, A., additional, Fu, B., additional, Gardiner, C., additional, Gaunt, L., additional, Ghali, N., additional, Gibbons, R., additional, Pereira, S.L. Gomes, additional, Goodship, J., additional, Goudie, D., additional, Gray, E., additional, Greene, P., additional, Greenhalgh, L., additional, Harrison, L., additional, Hawkins, R., additional, Hellens, S., additional, Henderson, A., additional, Hobson, E., additional, Holden, S., additional, Holder, S., additional, Hollingsworth, G., additional, Homfray, T., additional, Humphreys, M., additional, Hurst, J., additional, Ingram, S., additional, Irving, M., additional, Jarvis, J., additional, Jenkins, L., additional, Johnson, D., additional, Jones, D., additional, Jones, E., additional, Josifova, D., additional, Joss, S., additional, Kaemba, B., additional, Kazembe, S., additional, Kerr, B., additional, Kini, U., additional, Kinning, E., additional, Kirby, G., additional, Kirk, C., additional, Kivuva, E., additional, Kraus, A., additional, Kumar, D., additional, Lachlan, K., additional, Lam, W., additional, Lampe, A., additional, Langman, C., additional, Lees, M., additional, Lim, D., additional, Lowther, G., additional, Lynch, S.A., additional, Magee, A., additional, Maher, E., additional, Mansour, S., additional, Marks, K., additional, Martin, K., additional, Maye, U., additional, McCann, E., additional, McConnell, V., additional, McEntagart, M., additional, McGowan, R., additional, McKay, K., additional, McKee, S., additional, McMullan, D.J., additional, McNerlan, S., additional, Mehta, S., additional, Metcalfe, K., additional, Miles, E., additional, Mohammed, S., additional, Montgomery, T., additional, Moore, D., additional, Morgan, S., additional, Morris, A., additional, Morton, J., additional, Mugalaasi, H., additional, Murday, V., additional, Nevitt, L., additional, Newbury-Ecob, R., additional, Norman, A., additional, O’Shea, R., additional, Ogilvie, C., additional, Park, S., additional, Parker, M.J., additional, Patel, C., additional, Paterson, J., additional, Payne, S., additional, Phipps, J., additional, Pilz, D.T., additional, Porteous, D., additional, Pratt, N., additional, Prescott, K., additional, Price, S., additional, Pridham, A., additional, Proctor, A., additional, Purnell, H., additional, Ragge, N., additional, Rankin, J., additional, Raymond, L., additional, Rice, D., additional, Robert, L., additional, Roberts, E., additional, Roberts, G., additional, Roberts, J., additional, Roberts, P., additional, Ross, A., additional, Rosser, E., additional, Saggar, A., additional, Samant, S., additional, Sandford, R., additional, Sarkar, A., additional, Schweiger, S., additional, Scott, C., additional, Scott, R., additional, Selby, A., additional, Seller, A., additional, Sequeira, C., additional, Shannon, N., additional, Sharif, S., additional, Shaw-Smith, C., additional, Shearing, E., additional, Shears, D., additional, Simonic, I., additional, Simpkin, D., additional, Singzon, R., additional, Skitt, Z., additional, Smith, A., additional, Smith, B., additional, Smith, K., additional, Smithson, S., additional, Sneddon, L., additional, Splitt, M., additional, Squires, M., additional, Stewart, F., additional, Stewart, H., additional, Suri, M., additional, Sutton, V., additional, Swaminathan, G.J., additional, Sweeney, E., additional, Tatton-Brown, K., additional, Taylor, C., additional, Taylor, R., additional, Tein, M., additional, Temple, I.K., additional, Thomson, J., additional, Tolmie, J., additional, Torokwa, A., additional, Treacy, B., additional, Turner, C., additional, Turnpenny, P., additional, Tysoe, C., additional, Vandersteen, A., additional, Vasudevan, P., additional, Vogt, J., additional, Wakeling, E., additional, Walker, D., additional, Waters, J., additional, Weber, A., additional, Wellesley, D., additional, Whiteford, M., additional, Widaa, S., additional, Wilcox, S., additional, Williams, D., additional, Williams, N., additional, Woods, G., additional, Wragg, C., additional, Wright, M., additional, Yang, F., additional, Yau, M., additional, Carter, N.P., additional, Parker, M., additional, Firth, H.V., additional, FitzPatrick, D.R., additional, Wright, C.F., additional, Barrett, J.C., additional, and Hurles, M.E., additional

Published
2019
Full Text
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23. CTCF variants in 39 individuals with a variable neurodevelopmental disorder broaden the mutational and clinical spectrum

Author

Konrad, E.D.H., Nardini, N., Caliebe, A., Nagel, I., Young, D., Horvath, G., Santoro, S.L., Shuss, C., Ziegler, A., Bonneau, D., Kempers, M.J.E., Pfundt, R.P., Legius, E., Bouman, A., Stuurman, K.E., Ounap, K., Pajusalu, S., Wojcik, M.H., Vasileiou, G., Guyader, G. Le, Schnelle, H.M., Berland, S., Zonneveld-Huijssoon, E., Kersten, S., Gupta, A., Blackburn, P.R., Ellingson, M.S., Ferber, M.J., Dhamija, R., Klee, E.W., McEntagart, M., Lichtenbelt, K.D., Kenney, A., Vergano, Samantha A., Jamra, R. Abou, Platzer, K., Pierpont, M. Ella, Khattar, D., Hopkin, R.J., Martin, R.J., Jongmans, M.C.J., Chang, V.Y., Martinez-Agosto, J.A., Kuismin, O., Kurki, M.I., Pietilainen, O., Palotie, A., Maarup, T.J., Johnson, D.S., Pedersen, K., Laulund, L.W., Lynch, S.A., Blyth, M., Prescott, K., Canham, N., Ibitoye, R., Brilstra, E.H., Shinawi, M., Fassi, E., Sticht, H., Gregor, A., Esch, H. Van, Zweier, C., Konrad, E.D.H., Nardini, N., Caliebe, A., Nagel, I., Young, D., Horvath, G., Santoro, S.L., Shuss, C., Ziegler, A., Bonneau, D., Kempers, M.J.E., Pfundt, R.P., Legius, E., Bouman, A., Stuurman, K.E., Ounap, K., Pajusalu, S., Wojcik, M.H., Vasileiou, G., Guyader, G. Le, Schnelle, H.M., Berland, S., Zonneveld-Huijssoon, E., Kersten, S., Gupta, A., Blackburn, P.R., Ellingson, M.S., Ferber, M.J., Dhamija, R., Klee, E.W., McEntagart, M., Lichtenbelt, K.D., Kenney, A., Vergano, Samantha A., Jamra, R. Abou, Platzer, K., Pierpont, M. Ella, Khattar, D., Hopkin, R.J., Martin, R.J., Jongmans, M.C.J., Chang, V.Y., Martinez-Agosto, J.A., Kuismin, O., Kurki, M.I., Pietilainen, O., Palotie, A., Maarup, T.J., Johnson, D.S., Pedersen, K., Laulund, L.W., Lynch, S.A., Blyth, M., Prescott, K., Canham, N., Ibitoye, R., Brilstra, E.H., Shinawi, M., Fassi, E., Sticht, H., Gregor, A., Esch, H. Van, and Zweier, C.

Abstract

Contains fulltext : 215582.pdf (publisher's version ) (Open Access), PURPOSE: Pathogenic variants in the chromatin organizer CTCF were previously reported in seven individuals with a neurodevelopmental disorder (NDD). METHODS: Through international collaboration we collected data from 39 subjects with variants in CTCF. We performed transcriptome analysis on RNA from blood samples and utilized Drosophila melanogaster to investigate the impact of Ctcf dosage alteration on nervous system development and function. RESULTS: The individuals in our cohort carried 2 deletions, 8 likely gene-disruptive, 2 splice-site, and 20 different missense variants, most of them de novo. Two cases were familial. The associated phenotype was of variable severity extending from mild developmental delay or normal IQ to severe intellectual disability. Feeding difficulties and behavioral abnormalities were common, and variable other findings including growth restriction and cardiac defects were observed. RNA-sequencing in five individuals identified 3828 deregulated genes enriched for known NDD genes and biological processes such as transcriptional regulation. Ctcf dosage alteration in Drosophila resulted in impaired gross neurological functioning and learning and memory deficits. CONCLUSION: We significantly broaden the mutational and clinical spectrum ofCTCF-associated NDDs. Our data shed light onto the functional role of CTCF by identifying deregulated genes and show that Ctcf alterations result in nervous system defects in Drosophila.

Published
2019

24. CTCF variants in 39 individuals with a variable neurodevelopmental disorder broaden the mutational and clinical spectrum

Author

Konrad, E.D.H. (Enrico D. H.), Nardini, N. (Niels), Caliebe, A. (Almuth), Nagel, I. (Inga), Young, D. (Dana), Horvath, G. (Gabriella), Santoro, S.L. (Stephanie L.), Shuss, C. (Christine), Ziegler, A. (Alban), Bonneau, D. (Dominique), Kempers, M.J.E. (Marlies), Pfundt, R. (Rolph), Legius, E. (Eric), Bouman, A. (Arjan), Stuurman, K.E. (Kyra E.), Õunap, K. (Katrin), Pajusalu, S. (Sander), Wojcik, M.H. (Monica H.), Vasileiou, G. (Georgia), Le Guyader, G. (Gwenaël), Schnelle, H.M. (Hege M.), Berland, S. (Siren), Zonneveld-Huijssoon, E. (Evelien), Kersten, S. (Simone), Gupta, A. (Aditi), Blackburn, P.R. (Patrick R.), Ellingson, M.S. (Marissa S.), Ferber, M.J. (Matthew J.), Dhamija, R. (Radhika), Klee, E.W. (Eric W.), McEntagart, M. (Meriel), Lichtenbelt, K.D. (Klaske), Kenney, A. (Amy), Vergano, S.A. (Samantha A.), Abou Jamra, R. (Rami), Platzer, K. (Konrad), Ella Pierpont, M. (Mary), Khattar, D. (Divya), Hopkin, R., Martin, R.J. (Richard J.), Jongmans, M.C.J. (Marjolijn), Chang, V.Y. (Vivian Y.), Martinez-Agosto, J.A. (Julian A.), Kuismin, O. (Outi), Kurki, M.I. (Mitja I.), Pietiläinen, O.P.H. (Olli), Palotie, A. (Aarno), Maarup, T.J. (Timothy J.), Johnson, D. (David), Venborg Pedersen, K. (Katja), Laulund, L.W. (Lone W.), Lynch, S.A. (Sally A.), Blyth, M. (Moira), Prescott, K. (Katrina), Canham, N. (Natalie), Ibitoye, R. (Rita), Brilstra, E.H. (Eva H.), Shinawi, M. (Marwan), Fassi, E. (Emily), Sticht, H. (Heinrich), Gregor, A. (Anne), Esch, H. (Hilde) van, Zweier, C. (Christiane), Konrad, E.D.H. (Enrico D. H.), Nardini, N. (Niels), Caliebe, A. (Almuth), Nagel, I. (Inga), Young, D. (Dana), Horvath, G. (Gabriella), Santoro, S.L. (Stephanie L.), Shuss, C. (Christine), Ziegler, A. (Alban), Bonneau, D. (Dominique), Kempers, M.J.E. (Marlies), Pfundt, R. (Rolph), Legius, E. (Eric), Bouman, A. (Arjan), Stuurman, K.E. (Kyra E.), Õunap, K. (Katrin), Pajusalu, S. (Sander), Wojcik, M.H. (Monica H.), Vasileiou, G. (Georgia), Le Guyader, G. (Gwenaël), Schnelle, H.M. (Hege M.), Berland, S. (Siren), Zonneveld-Huijssoon, E. (Evelien), Kersten, S. (Simone), Gupta, A. (Aditi), Blackburn, P.R. (Patrick R.), Ellingson, M.S. (Marissa S.), Ferber, M.J. (Matthew J.), Dhamija, R. (Radhika), Klee, E.W. (Eric W.), McEntagart, M. (Meriel), Lichtenbelt, K.D. (Klaske), Kenney, A. (Amy), Vergano, S.A. (Samantha A.), Abou Jamra, R. (Rami), Platzer, K. (Konrad), Ella Pierpont, M. (Mary), Khattar, D. (Divya), Hopkin, R., Martin, R.J. (Richard J.), Jongmans, M.C.J. (Marjolijn), Chang, V.Y. (Vivian Y.), Martinez-Agosto, J.A. (Julian A.), Kuismin, O. (Outi), Kurki, M.I. (Mitja I.), Pietiläinen, O.P.H. (Olli), Palotie, A. (Aarno), Maarup, T.J. (Timothy J.), Johnson, D. (David), Venborg Pedersen, K. (Katja), Laulund, L.W. (Lone W.), Lynch, S.A. (Sally A.), Blyth, M. (Moira), Prescott, K. (Katrina), Canham, N. (Natalie), Ibitoye, R. (Rita), Brilstra, E.H. (Eva H.), Shinawi, M. (Marwan), Fassi, E. (Emily), Sticht, H. (Heinrich), Gregor, A. (Anne), Esch, H. (Hilde) van, and Zweier, C. (Christiane)

Abstract

Purpose: Pathogenic variants in the chromatin organizer CTCF were previously reported in seven individuals with a neurodevelopmental disorder (NDD). Methods: Through international collaboration we collected data from 39 subjects with variants in CTCF. We performed transcriptome analysis on RNA from blood samples and utilized Drosophila melanogaster to investigate the impact of Ctcf dosage alteration on nervous system development and function. Results: The individuals in our cohort carried 2 deletions, 8 likely gene-disruptive, 2 splice-site, and 20 different missense variants, most of them de novo. Two cases were familial. The associated phenotype was of variable severity extending from mild developmental delay or normal IQ to severe intellectual disability. Feeding difficulties and behavioral abnormalities were common, and variable other findings including growth restriction and cardiac defects were observed. RNA-sequencing in five individuals identified 3828 deregulated genes enriched for known NDD genes and biological processes such as transcriptional regulation. Ctcf dosage alteration in Drosophila resulted in impaired gross neurological functioning and learning and memory deficits. Conclusion: We significantly broaden the mutational and clinical spectrum of CTCF-associated NDDs. Our data shed light onto the functional role of CTCF by identifying deregulated genes and show that Ctcf alterations result in nervous system defects in Drosophila.

Published
2019
Full Text
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25. Prevalence and architecture of de novo mutations in developmental disorders

Author

McRae, JF, Clayton, S, Fitzgerald, TW, Kaplanis, J, Prigmore, E, Rajan, D, Sifrim, A, Aitken, S, Akawi, N, Alvi, M, Ambridge, K, Barrett, DM, Bayzetinova, T, Jones, P, Jones, WD, King, D, Krishnappa, N, Mason, LE, Singh, T, Tivey, AR, Ahmed, M, Anjum, U, Archer, H, Armstrong, R, Awada, J, Balasubramanian, M, Banka, S, Baralle, D, Barnicoat, A, Batstone, P, Baty, D, Bennett, C, Berg, J, Bernhard, B, Bevan, AP, Bitner-Glindzicz, M, Blair, E, Blyth, M, Bohanna, D, Bourdon, L, Bourn, D, Bradley, L, Brady, A, Brent, S, Brewer, C, Brunstrom, K, Bunyan, DJ, Burn, J, Canham, N, Castle, B, Chandler, K, Chatzimichali, E, Cilliers, D, Clarke, A, Clasper, S, Clayton-Smith, J, Clowes, V, Coates, A, Cole, T, Colgiu, I, Collins, A, Collinson, MN, Connell, F, Cooper, N, Cox, H, Cresswell, L, Cross, G, Crow, Y, D’Alessandro, M, Dabir, T, Davidson, R, Davies, S, de Vries, D, Dean, J, Deshpande, C, Devlin, G, Dixit, A, Dobbie, A, Donaldson, A, Donnai, D, Donnelly, D, Donnelly, C, Douglas, A, Douzgou, S, Duncan, A, Eason, J, Ellard, S, Ellis, I, Elmslie, F, Evans, K, Everest, S, Fendick, T, Fisher, R, Flinter, F, Foulds, N, Fry, A, Fryer, A, Gardiner, C, Gaunt, L, Ghali, N, Gibbons, R, Gill, H, Goodship, J, Goudie, D, Gray, E, Green, A, Greene, P, Greenhalgh, L, Gribble, S, Harrison, R, Harrison, L, Harrison, V, Hawkins, R, He, L, Hellens, S, Henderson, A, Hewitt, S, Hildyard, L, Hobson, E, Holden, S, Holder, M, Holder, S, Hollingsworth, G, Homfray, T, Humphreys, M, Hurst, J, Hutton, B, Ingram, S, Irving, M, Islam, L, Jackson, A, Jarvis, J, Jenkins, L, Johnson, D, Jones, E, Josifova, D, Joss, S, Kaemba, B, Kazembe, S, Kelsell, R, Kerr, B, Kingston, H, Kini, U, Kinning, E, Kirby, G, Kirk, C, Kivuva, E, Kraus, A, Kumar, D, Kumar, VKA, Lachlan, K, Lam, W, Lampe, A, Langman, C, Lees, M, Lim, D, Longman, C, Lowther, G, Lynch, SA, Magee, A, Maher, E, Male, A, Mansour, S, Marks, K, Martin, K, Maye, U, McCann, E, McConnell, V, McEntagart, M, McGowan, R, McKay, K, McKee, S, McMullan, DJ, McNerlan, S, McWilliam, C, Mehta, S, Metcalfe, K, Middleton, A, Miedzybrodzka, Z, Miles, E, Mohammed, S, Montgomery, T, Moore, D, Morgan, S, Morton, J, Mugalaasi, H, Murday, V, Murphy, H, Naik, S, Nemeth, A, Nevitt, L, Newbury-Ecob, R, Norman, A, O’Shea, R, Ogilvie, C, Ong, K-R, Park, S-M, Parker, MJ, Patel, C, Paterson, J, Payne, S, Perrett, D, Phipps, J, Pilz, DT, Pollard, M, Pottinger, C, Poulton, J, Pratt, N, Prescott, K, Price, S, Pridham, A, Procter, A, Purnell, H, Quarrell, O, Ragge, N, Rahbari, R, Randall, J, Rankin, J, Raymond, L, Rice, D, Robert, L, Roberts, E, Roberts, J, Roberts, P, Roberts, G, Ross, A, Rosser, E, Saggar, A, Samant, S, Sampson, J, Sandford, R, Sarkar, A, Schweiger, S, Scott, R, Scurr, I, Selby, A, Seller, A, Sequeira, C, Shannon, N, Sharif, S, Shaw-Smith, C, Shearing, E, Shears, D, Sheridan, E, Simonic, I, Singzon, R, Skitt, Z, Smith, A, Smith, K, Smithson, S, Sneddon, L, Splitt, M, Squires, M, Stewart, F, Stewart, H, Straub, V, Suri, M, Sutton, V, Swaminathan, GJ, Sweeney, E, Tatton-Brown, K, Taylor, C, Taylor, R, Tein, M, Temple, IK, Thomson, J, Tischkowitz, M, Tomkins, S, Torokwa, A, Treacy, B, Turner, C, Turnpenny, P, Tysoe, C, Vandersteen, A, Varghese, V, Vasudevan, P, Vijayarangakannan, P, Vogt, J, Wakeling, E, Wallwark, S, Waters, J, Weber, A, Wellesley, D, Whiteford, M, Widaa, S, Wilcox, S, Wilkinson, E, Williams, D, Williams, N, Wilson, L, Woods, G, Wragg, C, Wright, M, Yates, L, Yau, M, Nellåker, C, Parker, M, Firth, HV, Wright, CF, FitzPatrick, DR, Barrett, JC, and Hurles, ME

Subjects
Male, Parents, Heredity, Developmental Disabilities, GRIN2B, POGZ, Autoantigens, SMAD4, CASK, GATAD2B, 0302 clinical medicine, TRIO, SMARCA2, KCNH1, Average Faces, CTNNB1, SCN1A, Young adult, Casein Kinase II, Child, AUTS2, MEF2C, Exome, ADNP, Exome sequencing, EP300, KCNQ2, KCNQ3, EHMT1, CNKSR2, CREBBP, MYT1L, MED13L, CSNK2A1, Protein Phosphatase 2C, PPP2R1A, ZBTB18, CDKL5, WAC, HNRNPU, Cohort, STXBP1, Medical genetics, SYNGAP1, Mi-2 Nucleosome Remodeling and Deacetylase Complex, Sex characteristics, AHDC1, SCN8A, medicine.medical_specialty, SLC6A1, FOXP1, USP9X, Article, ANKRD11, PUF60, BRAF, 03 medical and health sciences, SATB2, SMC1A, Intellectual Disability, BCL11A, GABRB3, IQSEC2, Humans, TBL1XR1, TCF4, MSL3, TCF20, DNM1, EEF1A2, SUV420H1, DYRK1A, SETD5, COL4A3BP, CTCF, CHD2, R1, CHD4, 030104 developmental biology, NAA10, HDAC8, Mutation, KDM5B, CHAMP1, PhenIcons, 030217 neurology & neurosurgery, Transcription Factors, 0301 basic medicine, ZMYND11, PTEN, De novo mutation, Chromosomal Proteins, Non-Histone, PTPN11, ASXL1, Bioinformatics, medicine.disease_cause, ASXL3, Cohort Studies, DEAD-box RNA Helicases, CHD8, Prevalence, QRICH1, KIF1A, Genetics, Sex Characteristics, GNAI1, Multidisciplinary, WDR45, Middle Aged, KMT2A, PPM1D, MECP2, DNA-Binding Proteins, PPP2R5D, Phenotype, PACS1, ras GTPase-Activating Proteins, DDX3X, Female, FOXG1, SET, Myeloid-Lymphoid Leukemia Protein, Developmental Disease, Adult, KANSL1, Adolescent, NFIX, Nerve Tissue Proteins, PURA, Biology, KAT6B, KAT6A, NSD1, PDHA1, ALG13, Young Adult, Seizures, CDC2 Protein Kinase, medicine, Journal Article, QH426, Homeodomain Proteins, ITPR1, DYNC1H1, GNAO1, Histone-Lysine N-Methyltransferase, Sequence Analysis, DNA, ZC4H2, ARID1B, Repressor Proteins, CNOT3, SCN2A, SLC35A2, CDK13
Abstract

Children with severe, undiagnosed developmental disorders (DDs) are enriched for damaging de novo mutations (DNMs) in developmentally important genes. We exome sequenced 4,294 families with children with DDs, and meta-analysed these data with published data on 3,287 children with similar disorders. We show that the most significant factors influencing the diagnostic yield of de novo mutations are the sex of the child, the relatedness of their parents and the age of both father and mother. We identified 95 genes enriched for damaging de novo mutation at genome-wide significance (P < 5 x 10-7), including fourteen genes for which compelling data for causation was previously lacking. The large number of genome-wide significant findings allow us to demonstrate that, at current cost differentials, exome sequencing has much greater power than genome sequencing for novel gene discovery in genetically heterogeneous disorders. We estimate that 42.5% of our cohort likely carry pathogenic de novo single nucleotide variants (SNVs) and indels in coding sequences, with approximately half operating by a loss-of-function mechanism, and the remainder being gain-of-function. We established that most haploinsufficient developmental disorders have already been identified, but that many gain-of-function disorders remain to be discovered. Extrapolating from the DDD cohort to the general population, we estimate that de novo dominant developmental disorders have an average birth prevalence of 1 in 168 to 1 in 377, depending on parental age.

Published
2017
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26. The Koolen-de Vries syndrome: a phenotypic comparison of patients with a 17q21.31 microdeletion versus a KANSL1 sequence variant

Author

Koolen, D.A., Pfundt, R., Linda, K., Beunders, G., Veenstra-Knol, H.E., Conta, J.H., Fortuna, A.M., Gillessen-Kaesbach, G., Dugan, S., Halbach, S., Abdul-Rahman, O.A., Winesett, H.M., Chung, W.K., Dalton, M., Dimova, P.S., Mattina, T., Prescott, K., Zhang, H.Z., Saal, H.M., Hehir-Kwa, J.Y., Willemsen, M.H., Ockeloen, C.W., Jongmans, M.C., Aa, N. van der, Failla, P., Barone, C., Avola, E., Brooks, A.S., Kant, S.G., Gerkes, E.H., Firth, H.V., Ounap, K., Bird, L.M., Masser-Frye, D., Friedman, J.R., Sokunbi, M.A., Dixit, A., Splitt, M., Kukolich, M.K., McGaughran, J., Coe, B.P., Florez, J., Kasri, N.N., Brunner, H.G., Thompson, E.M., Gecz, J., Romano, C., Eichler, E.E., Vries, B.B.A. de, DDD Study, Clinical Genetics, Klinische Genetica, MUMC+: DA Klinische Genetica (5), Genetica & Celbiologie, RS: FHML non-thematic output, RS: GROW - School for Oncology and Reproduction, RS: GROW - R4 - Reproductive and Perinatal Medicine, and DDD Study

Subjects
0301 basic medicine, Male, Congenital, Epilepsy, Intellectual disability, MAPT, 2.1 Biological and endogenous factors, Koolen-de Vries syndrome, KANSL1, phenotype, Genetics(clinical), Copy-number variation, Aetiology, Non-U.S. Gov't, Child, Genetics (clinical), Pediatric, Genetics & Heredity, Genetics, COMMON INVERSION, DEVELOPMENTAL DELAY, Research Support, Non-U.S. Gov't, Nuclear Proteins, Single Nucleotide, Microdeletion syndrome, Middle Aged, Hypotonia, Chemistry, DROSOPHILA, Phenotype, Female, Abnormalities, medicine.symptom, Chromosome Deletion, Haploinsufficiency, Multiple, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9], Human, Adult, Adolescent, Koolen De Vries syndrome, INVERSION POLYMORPHISM, Intellectual and Developmental Disabilities (IDD), Clinical Sciences, Copy number analysis, COPY-NUMBER VARIATION, Biology, Research Support, Polymorphism, Single Nucleotide, Chromosomes, Article, 03 medical and health sciences, Rare Diseases, Clinical Research, Intellectual Disability, Journal Article, medicine, Humans, Abnormalities, Multiple, Polymorphism, DDD Study, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], COMPLEX, MUTATIONS, Pair 17, DISABILITY, Neurosciences, medicine.disease, Brain Disorders, DELINEATION, 030104 developmental biology, Congenital Structural Anomalies, Human medicine, Chromosomes, Human, Pair 17
Abstract

Contains fulltext : 168191.pdf (Publisher’s version ) (Open Access) The Koolen-de Vries syndrome (KdVS; OMIM #610443), also known as the 17q21.31 microdeletion syndrome, is a clinically heterogeneous disorder characterised by (neonatal) hypotonia, developmental delay, moderate intellectual disability, and characteristic facial dysmorphism. Expressive language development is particularly impaired compared with receptive language or motor skills. Other frequently reported features include social and friendly behaviour, epilepsy, musculoskeletal anomalies, congenital heart defects, urogenital malformations, and ectodermal anomalies. The syndrome is caused by a truncating variant in the KAT8 regulatory NSL complex unit 1 (KANSL1) gene or by a 17q21.31 microdeletion encompassing KANSL1. Herein we describe a novel cohort of 45 individuals with KdVS of whom 33 have a 17q21.31 microdeletion and 12 a single-nucleotide variant (SNV) in KANSL1 (19 males, 26 females; age range 7 months to 50 years). We provide guidance about the potential pitfalls in the laboratory testing and emphasise the challenges of KANSL1 variant calling and DNA copy number analysis in the complex 17q21.31 region. Moreover, we present detailed phenotypic information, including neuropsychological features, that contribute to the broad phenotypic spectrum of the syndrome. Comparison of the phenotype of both the microdeletion and SNV patients does not show differences of clinical importance, stressing that haploinsufficiency of KANSL1 is sufficient to cause the full KdVS phenotype.

Published
2016

29. Genetic heterogeneity in Cornelia de Lange syndrome (CdLS) and CdLS-like phenotypes with observed and predicted levels of mosaicism

Author

Ansari, M, Poke, G, Ferry, Q, Williamson, K, Aldridge, R, Meynert, AM, Bengani, H, Chan, CY, Kayserili, H, Avci, S, Hennekam, RC, Lampe, AK, Redeker, E, Homfray, T, Ross, A, Falkenberg Smeland, M, Mansour, S, Parker, MJ, Cook, JA, Splitt, M, Fisher, RB, Fryer, A, Magee, AC, Wilkie, A, Barnicoat, A, Brady, AF, Cooper, NS, Mercer, C, Deshpande, C, Bennett, CP, Pilz, DT, Ruddy, D, Cilliers, D, Johnson, DS, Josifova, D, Rosser, E, Thompson, EM, Wakeling, E, Kinning, E, Stewart, F, Flinter, F, Girisha, KM, Cox, H, Firth, HV, Kingston, H, Wee, JS, Hurst, JA, Clayton-Smith, J, Tolmie, J, Vogt, J, Tatton-Brown, K, Chandler, K, Prescott, K, Wilson, L, Behnam, M, McEntagart, M, Davidson, R, Lynch, SA, Sisodiya, S, Mehta, SG, McKee, SA, Mohammed, S, Holden, S, Park, SM, Holder, SE, Harrison, V, McConnell, V, Lam, WK, Green, AJ, Donnai, D, Bitner-Glindzicz, M, Donnelly, DE, Nellåker, C, Taylor, MS, FitzPatrick, DR, ANS - Amsterdam Neuroscience, APH - Amsterdam Public Health, Human Genetics, ACS - Amsterdam Cardiovascular Sciences, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, and Other Research

Subjects
Genetic Heterogeneity, Copy-number, Phenotype, Mosaicism, De Lange Syndrome, Face, Mutation, Genotype-Phenotype Correlations, Humans, Molecular genetics, Clinical genetics, Genetic Association Studies
Abstract

BACKGROUND: Cornelia de Lange syndrome (CdLS) is a multisystem disorder with distinctive facial appearance, intellectual disability and growth failure as prominent features. Most individuals with typical CdLS have de novo heterozygous loss-of-function mutations in NIPBL with mosaic individuals representing a significant proportion. Mutations in other cohesin components, SMC1A, SMC3, HDAC8 and RAD21 cause less typical CdLS.METHODS: We screened 163 affected individuals for coding region mutations in the known genes, 90 for genomic rearrangements, 19 for deep intronic variants in NIPBL and 5 had whole-exome sequencing.RESULTS: Pathogenic mutations [including mosaic changes] were identified in: NIPBL 46 [3] (28.2%); SMC1A 5 [1] (3.1%); SMC3 5 [1] (3.1%); HDAC8 6 [0] (3.6%) and RAD21 1 [0] (0.6%). One individual had a de novo 1.3 Mb deletion of 1p36.3. Another had a 520 kb duplication of 12q13.13 encompassing ESPL1, encoding separase, an enzyme that cleaves the cohesin ring. Three de novo mutations were identified in ANKRD11 demonstrating a phenotypic overlap with KBG syndrome. To estimate the number of undetected mosaic cases we used recursive partitioning to identify discriminating features in the NIPBL-positive subgroup. Filtering of the mutation-negative group on these features classified at least 18% as ‘NIPBL-like’. A computer composition of the average face of this NIPBL-like subgroup was also more typical in appearance than that of all others in the mutation-negative group supporting the existence of undetected mosaic cases.CONCLUSIONS: Future diagnostic testing in ‘mutation-negative’ CdLS thus merits deeper sequencing of multiple DNA samples derived from different tissues.

Published
2014
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30. Heterozygous Loss-of-Function Mutations in DLL4 Cause Adams-Oliver Syndrome

Author

Meester, J.A., Southgate, L., Stittrich, A.B., Venselaar, H., Beekmans, S.J., Hollander, N. den, Bijlsma, E.K., Helderman-van den Enden, A.T., Verheij, J.B., Glusman, G., Roach, J.C., Lehman, A., Patel, M.S., Vries, B. de, Ruivenkamp, C., Itin, P., Prescott, K., Clarke, S., Trembath, R., Zenker, M., Sukalo, M., Laer, L. Van, Loeys, B.L., Wuyts, W., Meester, J.A., Southgate, L., Stittrich, A.B., Venselaar, H., Beekmans, S.J., Hollander, N. den, Bijlsma, E.K., Helderman-van den Enden, A.T., Verheij, J.B., Glusman, G., Roach, J.C., Lehman, A., Patel, M.S., Vries, B. de, Ruivenkamp, C., Itin, P., Prescott, K., Clarke, S., Trembath, R., Zenker, M., Sukalo, M., Laer, L. Van, Loeys, B.L., and Wuyts, W.

Abstract

Contains fulltext : 152973.pdf (publisher's version ) (Closed access), Adams-Oliver syndrome (AOS) is a rare developmental disorder characterized by the presence of aplasia cutis congenita (ACC) of the scalp vertex and terminal limb-reduction defects. Cardiovascular anomalies are also frequently observed. Mutations in five genes have been identified as a cause for AOS prior to this report. Mutations in EOGT and DOCK6 cause autosomal-recessive AOS, whereas mutations in ARHGAP31, RBPJ, and NOTCH1 lead to autosomal-dominant AOS. Because RBPJ, NOTCH1, and EOGT are involved in NOTCH signaling, we hypothesized that mutations in other genes involved in this pathway might also be implicated in AOS pathogenesis. Using a candidate-gene-based approach, we prioritized DLL4, a critical NOTCH ligand, due to its essential role in vascular development in the context of cardiovascular features in AOS-affected individuals. Targeted resequencing of the DLL4 gene with a custom enrichment panel in 89 independent families resulted in the identification of seven mutations. A defect in DLL4 was also detected in two families via whole-exome or genome sequencing. In total, nine heterozygous mutations in DLL4 were identified, including two nonsense and seven missense variants, the latter encompassing four mutations that replace or create cysteine residues, which are most likely critical for maintaining structural integrity of the protein. Affected individuals with DLL4 mutations present with variable clinical expression with no emerging genotype-phenotype correlations. Our findings demonstrate that DLL4 mutations are an additional cause of autosomal-dominant AOS or isolated ACC and provide further evidence for a key role of NOTCH signaling in the etiology of this disorder.

Published
2015

31. Large-scale discovery of novel genetic causes of developmental disorders

Author

Fitzgerald, TW, Gerety, SS, Jones, WD, van Kogelenberg, M, King, DA, McRae, J, Morley, KI, Parthiban, V, Al-Turki, S, Ambridge, K, Barrett, DM, Bayzetinova, T, Clayton, S, Coomber, EL, Gribble, S, Jones, P, Krishnappa, N, Mason, LE, Middleton, A, Miller, R, Prigmore, E, Rajan, D, Sifrim, A, Tivey, AR, Ahmed, M, Akawi, N, Andrews, R, Anjum, U, Archer, H, Armstrong, R, Balasubramanian, M, Banerjee, R, Baralle, D, Batstone, P, Baty, D, Bennett, C, Berg, J, Bernhard, B, Bevan, AP, Blair, E, Blyth, M, Bohanna, D, Bourdon, L, Bourn, D, Brady, A, Bragin, E, Brewer, C, Brueton, L, Brunstrom, K, Bumpstead, SJ, Bunyan, DJ, Burn, J, Burton, J, Canham, N, Castle, B, Chandler, K, Clasper, S, Clayton-Smith, J, Cole, T, Collins, A, Collinson, MN, Connell, F, Cooper, N, Cox, H, Cresswell, L, Cross, G, Crow, Y, D'Alessandro, M, Dabir, T, Davidson, R, Davies, S, Dean, J, Deshpande, C, Devlin, G, Dixit, A, Dominiczak, A, Donnelly, C, Donnelly, D, Douglas, A, Duncan, A, Eason, J, Edkins, S, Ellard, S, Ellis, P, Elmslie, F, Evans, K, Everest, S, Fendick, T, Fisher, R, Flinter, F, Foulds, N, Fryer, A, Fu, B, Gardiner, C, Gaunt, L, Ghali, N, Gibbons, R, Pereira, SLG, Goodship, J, Goudie, D, Gray, E, Greene, P, Greenhalgh, L, Harrison, L, Hawkins, R, Hellens, S, Henderson, A, Hobson, E, Holden, S, Holder, S, Hollingsworth, G, Homfray, T, Humphreys, M, Hurst, J, Ingram, S, Irving, M, Jarvis, J, Jenkins, L, Johnson, D, Jones, D, Jones, E, Josifova, D, Joss, S, Kaemba, B, Kazembe, S, Kerr, B, Kini, U, Kinning, E, Kirby, G, Kirk, C, Kivuva, E, Kraus, A, Kumar, D, Lachlan, K, Lam, W, Lampe, A, Langman, C, Lees, M, Lim, D, Lowther, G, Lynch, SA, Magee, A, Maher, E, Mansour, S, Marks, K, Martin, K, Maye, U, McCann, E, McConnell, V, McEntagart, M, McGowan, R, McKay, K, McKee, S, McMullan, DJ, McNerlan, S, Mehta, S, Metcalfe, K, Miles, E, Mohammed, S, Montgomery, T, Moore, D, Morgan, S, Morris, A, Morton, J, Mugalaasi, H, Murday, V, Nevitt, L, Newbury-Ecob, R, Norman, A, O'Shea, R, Ogilvie, C, Park, S, Parker, MJ, Patel, C, Paterson, J, Payne, S, Phipps, J, Pilz, DT, Porteous, D, Pratt, N, Prescott, K, Price, S, Pridham, A, Procter, A, Purnell, H, Ragge, N, Rankin, J, Raymond, L, Rice, D, Robert, L, Roberts, E, Roberts, G, Roberts, J, Roberts, P, Ross, A, Rosser, E, Saggar, A, Samant, S, Sandford, R, Sarkar, A, Schweier, S, Scott, C, Scott, R, Selby, A, Seller, A, Sequeira, C, Shannon, N, Shanrif, S, Shaw-Smith, C, Shearing, E, Shears, D, Simonic, I, Simpkin, D, Singzon, R, Skitt, Z, Smith, A, Smith, B, Smith, K, Smithson, S, Sneddon, L, Splitt, M, Squires, M, Stewart, F, Stewart, H, Suri, M, Sutton, V, Swaminathan, GJ, Sweeney, E, Tatton-Brown, K, Taylor, C, Taylor, R, Tein, M, Temple, IK, Thomson, J, Tolmie, J, Torokwa, A, Treacy, B, Turner, C, Turnpenny, P, Tysoe, C, Vandersteen, A, Vasudevan, P, Vogt, J, Wakeling, E, Walker, D, Waters, J, Weber, A, Wellesley, D, Whiteford, M, Widaa, S, Wilcox, S, Williams, D, Williams, N, Woods, G, Wragg, C, Wright, M, Yang, F, Yau, M, Carter, NP, Parker, M, Firth, HV, FitzPatrick, DR, Wright, CF, Barrett, JC, Hurles, ME, Fitzgerald, TW, Gerety, SS, Jones, WD, van Kogelenberg, M, King, DA, McRae, J, Morley, KI, Parthiban, V, Al-Turki, S, Ambridge, K, Barrett, DM, Bayzetinova, T, Clayton, S, Coomber, EL, Gribble, S, Jones, P, Krishnappa, N, Mason, LE, Middleton, A, Miller, R, Prigmore, E, Rajan, D, Sifrim, A, Tivey, AR, Ahmed, M, Akawi, N, Andrews, R, Anjum, U, Archer, H, Armstrong, R, Balasubramanian, M, Banerjee, R, Baralle, D, Batstone, P, Baty, D, Bennett, C, Berg, J, Bernhard, B, Bevan, AP, Blair, E, Blyth, M, Bohanna, D, Bourdon, L, Bourn, D, Brady, A, Bragin, E, Brewer, C, Brueton, L, Brunstrom, K, Bumpstead, SJ, Bunyan, DJ, Burn, J, Burton, J, Canham, N, Castle, B, Chandler, K, Clasper, S, Clayton-Smith, J, Cole, T, Collins, A, Collinson, MN, Connell, F, Cooper, N, Cox, H, Cresswell, L, Cross, G, Crow, Y, D'Alessandro, M, Dabir, T, Davidson, R, Davies, S, Dean, J, Deshpande, C, Devlin, G, Dixit, A, Dominiczak, A, Donnelly, C, Donnelly, D, Douglas, A, Duncan, A, Eason, J, Edkins, S, Ellard, S, Ellis, P, Elmslie, F, Evans, K, Everest, S, Fendick, T, Fisher, R, Flinter, F, Foulds, N, Fryer, A, Fu, B, Gardiner, C, Gaunt, L, Ghali, N, Gibbons, R, Pereira, SLG, Goodship, J, Goudie, D, Gray, E, Greene, P, Greenhalgh, L, Harrison, L, Hawkins, R, Hellens, S, Henderson, A, Hobson, E, Holden, S, Holder, S, Hollingsworth, G, Homfray, T, Humphreys, M, Hurst, J, Ingram, S, Irving, M, Jarvis, J, Jenkins, L, Johnson, D, Jones, D, Jones, E, Josifova, D, Joss, S, Kaemba, B, Kazembe, S, Kerr, B, Kini, U, Kinning, E, Kirby, G, Kirk, C, Kivuva, E, Kraus, A, Kumar, D, Lachlan, K, Lam, W, Lampe, A, Langman, C, Lees, M, Lim, D, Lowther, G, Lynch, SA, Magee, A, Maher, E, Mansour, S, Marks, K, Martin, K, Maye, U, McCann, E, McConnell, V, McEntagart, M, McGowan, R, McKay, K, McKee, S, McMullan, DJ, McNerlan, S, Mehta, S, Metcalfe, K, Miles, E, Mohammed, S, Montgomery, T, Moore, D, Morgan, S, Morris, A, Morton, J, Mugalaasi, H, Murday, V, Nevitt, L, Newbury-Ecob, R, Norman, A, O'Shea, R, Ogilvie, C, Park, S, Parker, MJ, Patel, C, Paterson, J, Payne, S, Phipps, J, Pilz, DT, Porteous, D, Pratt, N, Prescott, K, Price, S, Pridham, A, Procter, A, Purnell, H, Ragge, N, Rankin, J, Raymond, L, Rice, D, Robert, L, Roberts, E, Roberts, G, Roberts, J, Roberts, P, Ross, A, Rosser, E, Saggar, A, Samant, S, Sandford, R, Sarkar, A, Schweier, S, Scott, C, Scott, R, Selby, A, Seller, A, Sequeira, C, Shannon, N, Shanrif, S, Shaw-Smith, C, Shearing, E, Shears, D, Simonic, I, Simpkin, D, Singzon, R, Skitt, Z, Smith, A, Smith, B, Smith, K, Smithson, S, Sneddon, L, Splitt, M, Squires, M, Stewart, F, Stewart, H, Suri, M, Sutton, V, Swaminathan, GJ, Sweeney, E, Tatton-Brown, K, Taylor, C, Taylor, R, Tein, M, Temple, IK, Thomson, J, Tolmie, J, Torokwa, A, Treacy, B, Turner, C, Turnpenny, P, Tysoe, C, Vandersteen, A, Vasudevan, P, Vogt, J, Wakeling, E, Walker, D, Waters, J, Weber, A, Wellesley, D, Whiteford, M, Widaa, S, Wilcox, S, Williams, D, Williams, N, Woods, G, Wragg, C, Wright, M, Yang, F, Yau, M, Carter, NP, Parker, M, Firth, HV, FitzPatrick, DR, Wright, CF, Barrett, JC, and Hurles, ME

Abstract

Despite three decades of successful, predominantly phenotype-driven discovery of the genetic causes of monogenic disorders, up to half of children with severe developmental disorders of probable genetic origin remain without a genetic diagnosis. Particularly challenging are those disorders rare enough to have eluded recognition as a discrete clinical entity, those with highly variable clinical manifestations, and those that are difficult to distinguish from other, very similar, disorders. Here we demonstrate the power of using an unbiased genotype-driven approach to identify subsets of patients with similar disorders. By studying 1,133 children with severe, undiagnosed developmental disorders, and their parents, using a combination of exome sequencing and array-based detection of chromosomal rearrangements, we discovered 12 novel genes associated with developmental disorders. These newly implicated genes increase by 10% (from 28% to 31%) the proportion of children that could be diagnosed. Clustering of missense mutations in six of these newly implicated genes suggests that normal development is being perturbed by an activating or dominant-negative mechanism. Our findings demonstrate the value of adopting a comprehensive strategy, both genome-wide and nationwide, to elucidate the underlying causes of rare genetic disorders.

Published
2015

34. Mutation update for the CSB/ERCC6 and CSA/ERCC8 genes involved in the Cockayne syndrome

Author

Laugel V, Dalloz C, Durand M, Sauvanaud F, Kristensen U, Vincent MC, Pasquier L, Odent S, Cormier-Daire V, Gener B, Tobias ES, Tolmie JL, Martin-Coignard D, Drouin-Garraud V, Heron D, Journel H, Raffo E, Vigneron J, Lyonnet S, Murday V, Gubser-Mercati D, Funalot B, Brueton L, Sanchez Del Pozo J, Muxf1oz E, Gennery AR, Salih M, Noruzinia M, Prescott K, Ramos L, Stark Z, Fieggen K, Chabrol B, Sarda P, Edery P, Bloch-Zupan A, Fawcett H, Pham D, Egly JM, Lehmann AR, Sarasin A, and Dollfus H.

Published
2010

35. A homozygous STIM1 mutation impairs store-operated calcium entry and natural killer cell effector function without clinical immunodeficiency

Author

Parry, DA, Holmes, TD, Gamper, N, El-Sayed, W, Hettiarachchi, NT, Ahmed, M, Cook, GP, Logan, CV, Johnson, CA, Joss, S, Peers, C, Prescott, K, Savic, S, Inglehearn, CF, and Mighell, AJ

Subjects
Immunology, Homozygote, Membrane Proteins, Genes, Recessive, Neoplasm Proteins, Killer Cells, Natural, Consanguinity, Phenotype, Mutation, Immunology and Allergy, Humans, Calcium, Family, Stromal Interaction Molecule 1, Letter to the Editor, Genetic Association Studies
Published
2016

38. DICER1 syndrome: clarifying the diagnosis, clinical features and management implications of a pleiotropic tumour predisposition syndrome

Author

Slade, I., primary, Bacchelli, C., additional, Davies, H., additional, Murray, A., additional, Abbaszadeh, F., additional, Hanks, S., additional, Barfoot, R., additional, Burke, A., additional, Chisholm, J., additional, Hewitt, M., additional, Jenkinson, H., additional, King, D., additional, Morland, B., additional, Pizer, B., additional, Prescott, K., additional, Saggar, A., additional, Side, L., additional, Traunecker, H., additional, Vaidya, S., additional, Ward, P., additional, Futreal, P. A., additional, Vujanic, G., additional, Nicholson, A. G., additional, Sebire, N., additional, Turnbull, C., additional, Priest, J. R., additional, Pritchard-Jones, K., additional, Houlston, R., additional, Stiller, C., additional, Stratton, M. R., additional, Douglas, J., additional, and Rahman, N., additional

Published
2011
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40. Mutation update for theCSB/ERCC6andCSA/ERCC8genes involved in Cockayne syndrome

Author

Laugel, V., primary, Dalloz, C., additional, Durand, M., additional, Sauvanaud, F., additional, Kristensen, U., additional, Vincent, M.C., additional, Pasquier, L., additional, Odent, S., additional, Cormier-Daire, V., additional, Gener, B., additional, Tobias, E.S., additional, Tolmie, J.L., additional, Martin-Coignard, D., additional, Drouin-Garraud, V., additional, Heron, D., additional, Journel, H., additional, Raffo, E., additional, Vigneron, J., additional, Lyonnet, S., additional, Murday, V., additional, Gubser-Mercati, D., additional, Funalot, B., additional, Brueton, L., additional, Sanchez del Pozo, J., additional, Muñoz, E., additional, Gennery, A.R., additional, Salih, M., additional, Noruzinia, M., additional, Prescott, K., additional, Ramos, L., additional, Stark, Z., additional, Fieggen, K., additional, Chabrol, B., additional, Sarda, P., additional, Edery, P., additional, Bloch-Zupan, A., additional, Fawcett, H., additional, Pham, D., additional, Egly, J.M., additional, Lehmann, A.R., additional, Sarasin, A., additional, and Dollfus, H., additional

Published
2010
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41. Lady Beetle (Coleoptera: Coccinellidae) Communities in Soybean and Maize.

Author

Prescott, K. K. and Andow, D. A.

Subjects
LADYBUGS, INSECT communities, SOYBEAN, CORN, HABITATS
Abstract

Coccinellids provide the most effective natural control of soybean aphid, but outbreaks remain common. Previous work suggests that native coccinellids are rare in soybean, potentially limiting soybean aphid control. We compared the coccinellid community in soybean with that of maize to identify differences in how coccinellid species use these habitats. As maize has long been used by coccinellids in the Americas, we hypothesized that coccinellids native to the Americas would use maize habitats, while exotic coccinellids would be more common in soybean. We identified and quantified aphids and all species and stages of coccinellids in a randomized complete block experiment with four blocks of 10 by 10 -m plots of soybean and maize in central Minnesota during 2008 and 2009. Coccinellid egg masses were identified by hatching in the laboratory. We used repeated-measures ANOVA to identify the dominant species in each habitat and compared species richness and Shannon's diversity with a paired t-test. Aphids and coccinellids had a similar phenology across habitats, but the coccinellid species composition differed significantly between soybean and maize. In soybean, the exotic, Harmonia axyridis Pallas, was the dominant species, while in maize, H. axyridis and the native, Coleomegilla maculata De Geer, were co-dominant. Eggs of H. axyridis were abundant in both habitats. In contrast, C. maculata eggs were very rare in soybean, despite being abundant in adjacent plots of maize. Species diversity was higher in maize. These findings were consistent with other published studies of coccinellid communities in these habitats. [ABSTRACT FROM AUTHOR]

Published
2016
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47. Ankylosing spondylitis: the difficulty and importance of early diagnosis.

Author

Prescott K and Taurog JD

Abstract

The physical findings and radiological features of ankylosing spondylitis (AS) often shown in textbooks typically are late disease manifestations. However, early diagnosis requires knowledge of the early manifestations. Low back pain is the usual first manifestation; physicians distinguish between inflammatory and noninflammatory back pain as a key to recognizing AS. The findings on physical examination include limitation of lumbar spinal motion and decreased chest expansion. MRI helps detect early sacroiliitis and spondylitis. In most patients, plain x-ray films of the sacroiliac joints should be obtained first. No laboratory test is diagnostic of AS. About 90% of patients with AS have inherited the HLA-B27 gene. Significant advances have been made in the development of questionnaires and other clinical assessments. [ABSTRACT FROM AUTHOR]

Published
2007

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