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1. 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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3. 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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6. 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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7. Mutation Analysis of Core Binding Factor A1 in Patients with Cleidocranial Dysplasia

Author

Quack, I., Vonderstrass, B., Stock, M., Aylsworth, A.S., Becker, A., Brueton, L., Lee, P.J., Majewski, F., Mulliken, J.B., Suri, M., Zenker, M., Mundlos, S., and Otto, F.

Subjects
Dysplasia -- Genetic aspects, Skeleton -- Abnormalities, Gene mutations -- Identification and classification, Biological sciences
Published
1999

8. Further clinical and molecular delineation of the 9q subtelomeric deletion syndrome supports a major contribution of EHMT1 haploinsufficiency to the core phenotype

Author

Kleefstra, T, van Zelst-Stams, W A, Nillesen, W M, Cormier-Daire, V, Houge, G, Foulds, N, van Dooren, M, Willemsen, M H, Pfundt, R, Turner, A, Wilson, M, McGaughran, J, Rauch, A, Zenker, M, Adam, M P, Innes, M, Davies, C, López, González-Meneses A, Casalone, R, Weber, A, Brueton, L A, Navarro, Delicado A, Bralo, Palomares M, Venselaar, H, Stegmann, S P A, Yntema, H G, van Bokhoven, H, and Brunner, H G

Published
2009
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14. 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
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15. Spectrum of clinical features associated with interstitial chromosome 22q11 deletions: a European collaborative study

Author

Ryan, A. K., Goodship, J. A., Wilson, D. I., Philip, N., Levy, A., Seidel, H., Schuffenhauer, S., Oechsler, H., Belohradsky, B., Prieur, M., Aurias, A., Raymond, F. L., Clayton-Smith, J., Hatchwell, E., McKeown, C., Beemer, F. A., Dallapiccola, B., Novelli, G., Hurst, J. A., Ignatius, J., Green, A. J., Winter, R. M., Brueton, L., Brondum-Nielsen, K., Stewart, F., Van Essen, T., Patton, M., Paterson, J., and Scambler, P. J.

Published
1997

17. The SMAD-binding domain of SKI: A hotspot for de novo mutations causing Shprintzen-Goldberg syndrome

Author

Schepers, D. Doyle, A.J. Oswald, G. Sparks, E. Myers, L. Willems, P.J. Mansour, S. Simpson, M.A. Frysira, H. Maat-Kievit, A. Van Minkelen, R. Hoogeboom, J.M. Mortier, G.R. Titheradge, H. Brueton, L. Starr, L. Stark, Z. Ockeloen, C. Lourenco, C.M. Blair, E. Hobson, E. Hurst, J. Maystadt, I. Destrée, A. Girisha, K.M. Miller, M. Dietz, H.C. Loeys, B. Van Laer, L.

Subjects
human activities
Abstract

Shprintzen-Goldberg syndrome (SGS) is a rare, systemic connective tissue disorder characterized by craniofacial, skeletal, and cardiovascular manifestations that show a significant overlap with the features observed in the Marfan (MFS) and Loeys-Dietz syndrome (LDS). A distinguishing observation in SGS patients is the presence of intellectual disability, although not all patients in this series present this finding. Recently, SGS was shown to be due to mutations in the SKI gene, encoding the oncoprotein SKI, a repressor of TGFβ activity. Here, we report eight recurrent and three novel SKI mutations in eleven SGS patients. All were heterozygous missense mutations located in the R-SMAD binding domain, except for one novel in-frame deletion affecting the DHD domain. Adding our new findings to the existing data clearly reveals a mutational hotspot, with 73% (24 out of 33) of the hitherto described unrelated patients having mutations in a stretch of five SKI residues (from p.(Ser31) to p.(Pro35)). This implicates that the initial molecular testing could be focused on mutation analysis of the first half of exon 1 of SKI. As the majority of the known mutations are located in the R-SMAD binding domain of SKI, our study further emphasizes the importance of TGFβ signaling in the pathogenesis of SGS. © 2015 Macmillan Publishers Limited All rights reserved.

Published
2015

18. The 2q23.1 microdeletion syndrome: clinical and behavioural phenotype

Author

Bon, B.W.M. van, Koolen, D.A., Brueton, L., McMullan, D., Lichtenbelt, K.D., Ades, L.C., Peters, G., Gibson, K., Moloney, S., Novara, F., Pramparo, T., Bernardina, B. Dalla, Zoccante, L., Balottin, U., Piazza, F., Pecile, V., Gasparini, P., Guerci, V., Kets, M., Pfundt, R., Brouwer, A.P.M. de, Veltman, J.A., Leeuw, N. de, Wilson, M., Antony, J., Reitano, S., Luciano, D., Fichera, M., Romano, C, Brunner, H.G., Zuffardi, O., Vries, L.B.A. de, VAN BON, Bw, Koolen, Da, Brueton, L, Mcmullan, D, Lichtenbelt, Kd, Adès, Lc, Peters, G, Gibson, K, Novara, F, Pramparo, T, Bernardina, Bd, Zoccante, L, Balottin, U, Piazza, F, Pecile, V, Gasparini, Paolo, Guerci, V, Kets, M, Pfundt, R, DE BROUWER, Ap, Veltman, Ja, DE LEEUW, N, Wilson, M, Antony, J, Reitano, S, Luciano, D, Fichera, M, Romano, C, Brunner, Hg, Zuffardi, O, and DE VRIES, Bb

Subjects
Male, Microcephaly, Genetics and epigenetic pathways of disease [NCMLS 6], 2q23.1 microdeletion syndrome, Rett syndrome, phenotype, behaviour, Short stature, Article, MECP2, Genomic disorders and inherited multi-system disorders [IGMD 3], Intellectual Disability, Intensive Care Units, Neonatal, Angelman syndrome, Rett Syndrome, Genetics, Humans, Medicine, Child, Genetics (clinical), Sequence Deletion, Cesarean Section, Learning Disabilities, business.industry, Infant, Newborn, Chromosome Mapping, Microdeletion syndrome, medicine.disease, Phenotype, Chromosomes, Human, Pair 2, Speech delay, Female, Angelman Syndrome, medicine.symptom, Corrigendum, business, Haploinsufficiency
Abstract

Contains fulltext : 89008.pdf (Publisher’s version ) (Closed access) Six submicroscopic deletions comprising chromosome band 2q23.1 in patients with severe mental retardation (MR), short stature, microcephaly and epilepsy have been reported, suggesting that haploinsufficiency of one or more genes in the 2q23.1 region might be responsible for the common phenotypic features in these patients. In this study, we report the molecular and clinical characterisation of nine new 2q23.1 deletion patients and a clinical update on two previously reported patients. All patients were mentally retarded with pronounced speech delay and additional abnormalities including short stature, seizures, microcephaly and coarse facies. The majority of cases presented with stereotypic repetitive behaviour, a disturbed sleep pattern and a broad-based gait. These features led to the initial clinical impression of Angelman, Rett or Smith-Magenis syndromes in several patients. The overlapping 2q23.1 deletion region in all 15 patients comprises only one gene, namely, MBD5. Interestingly, MBD5 is a member of the methyl CpG-binding domain protein family, which also comprises MECP2, mutated in Rett's syndrome. Another gene in the 2q23.1 region, EPC2, was deleted in 12 patients who had a broader phenotype than those with a deletion of MBD5 only. EPC2 is a member of the polycomb protein family, involved in heterochromatin formation and might be involved in causing MR. Patients with a 2q23.1 microdeletion present with a variable phenotype and the diagnosis should be considered in mentally retarded children with coarse facies, seizures, disturbed sleeping patterns and additional specific behavioural problems. 01 februari 2010

Published
2009

19. Dysmorphology at a distance: results of a web-based diagnostic service

Author

Douzgou, S, Clayton-Smith, J, Gardner, S, Day, R, Griffiths, P, Strong, K, Amiel, J, Baraitser, M, Brueton, L, Brunner, H, Chrzanowska, K, Dallapiccola, B, Del Campo Casanelles, M, Devriendt, K, Donnai, D, Fitzpatrick, D, Gillessen-Kaesbach, G, Houge, G, Kerr, B, Krajewska-Walasek, M, Lacombe, D, Meinecke, P, Metcalfe, K, Mortier, G, Odent, S, Philip, N, Prescott, T, Raas-Rothschild, A, Rauch, A, Rittinger, O, Salonen, R, Schrander-Stumpel, C, Suri, M, Temple, K, Tolmie, J, Van Der Burgt, I, Verloes, A, Wieczorek, D, Zenker, M, University of Zurich, and Douzgou, S

Subjects
2716 Genetics (clinical), 1311 Genetics, 10039 Institute of Medical Genetics, 570 Life sciences, biology, 610 Medicine & health
Published
2014

20. 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

21. 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

23. The SMAD-binding domain of SKI: a hotspot for de novo mutations causing Shprintzen-Goldberg syndrome

Author

Schepers, D. (Dorien), Doyle, A.J. (Alexander), Oswald, P., Sparks, D.L. (David), Myers, L.A. (Loretha), Willems, P.J. (Patrick), Mansour, M.R. (Marc), Simpson, M.A. (Michael A), Frysira, H. (Helena), Maat-Kievit, A.A. (Anneke), Thornton, A.S. (Andrew), Hoogeboom, A.J.M. (Jeannette), Mortier, G. (Geert), Titheradge, H. (Hannah), Brueton, L. (Louise), Starr, L. (Lois), Stark, Z. (Zornitza), Ockeloen, C. (Charlotte), Lourenco, T. (Tania), Blair, E.M. (Ed), Hobson, K.A. (Keith), Hurst, J.A. (Jane), Maystadt, I. (Isabelle), Destrée, A. (Anne), Girisha, K.M. (Katta M), Miller, M. (Michelle), Dietz, H.C. (Harry ), Loeys, B.L. (Bart), Laer, L. (Lut) van, Schepers, D. (Dorien), Doyle, A.J. (Alexander), Oswald, P., Sparks, D.L. (David), Myers, L.A. (Loretha), Willems, P.J. (Patrick), Mansour, M.R. (Marc), Simpson, M.A. (Michael A), Frysira, H. (Helena), Maat-Kievit, A.A. (Anneke), Thornton, A.S. (Andrew), Hoogeboom, A.J.M. (Jeannette), Mortier, G. (Geert), Titheradge, H. (Hannah), Brueton, L. (Louise), Starr, L. (Lois), Stark, Z. (Zornitza), Ockeloen, C. (Charlotte), Lourenco, T. (Tania), Blair, E.M. (Ed), Hobson, K.A. (Keith), Hurst, J.A. (Jane), Maystadt, I. (Isabelle), Destrée, A. (Anne), Girisha, K.M. (Katta M), Miller, M. (Michelle), Dietz, H.C. (Harry ), Loeys, B.L. (Bart), and Laer, L. (Lut) van

Published
2014
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24. Screening and cell-based assessment of mutations in the Aristaless-related homeobox (ARX) gene

Author

Fullston, T., Finnis, M., Hackett, A., Hodgson, B., Brueton, L., Baynam, G., Norman, A., Reish, O., Shoubridge, C., Gecz, J., Fullston, T., Finnis, M., Hackett, A., Hodgson, B., Brueton, L., Baynam, G., Norman, A., Reish, O., Shoubridge, C., and Gecz, J.

Abstract

ARX mutations cause a diverse spectrum of human disorders, ranging from severe brain and genital malformations to non-syndromic intellectual disability (ID). ARX is a transcription factor with multiple domains that include four polyalanine (pA) tracts, the first two of which are frequently expanded by mutations. We progressively screened DNA samples from 613 individuals with ID initially for the most frequent ARX mutations (c.304ins(GCG)7‘expansion’ of pA1 and c.429_452dup ‘dup24bp’ of pA2). Five hundred samples without pA1 or pA2 mutations had the entire ARX ORF screened by single stranded polymorphism conformation (SSCP) and/or denaturing high pressure liquid chromatography (dHPLC) analysis. Overall, eight families with six mutations in ARX were identified (1.31%): five duplication mutations in pA2 (0.82%) with three new clinical reports of families with the dup24bp and two duplications larger than the dup24bp mutation discovered (dup27bp, dup33bp); and three point mutations (0.6%), including one novel mutation in the homeodomain (c.1074G>T). Four ultraconserved regions distal to ARX (uc466–469) were also screened in a subset of 94 patients, with three unique nucleotide changes identified in two (uc466, uc467). The subcellular localization of full length ARX proteins was assessed for 11 variants. Protein mislocalization increased as a function of pA2 tract length and phenotypic severity, as has been previously suggested for pA1. Similarly, protein mislocalization of the homeodomain mutations also correlated with clinical severity, suggesting an emerging genotype vs cellular phenotype correlation.

Published
2011

25. Deletions of the RUNX2 gene are present in about 10% of individuals with cleidocranial dysplasia.

Author

Ott, C.E., Leschik, G., Trotier, F., Brueton, L., Brunner, H.G., Brussel, W., Guillen-Navarro, E., Haase, C., Kohlhase, J., Kotzot, D., Lane, A., Lee-Kirsch, M.A., Morlot, S., Simon, M.E., Steichen-Gersdorf, E., Tegay, D.H., Peters, J.P.W., Mundlos, S., Klopocki, E., Ott, C.E., Leschik, G., Trotier, F., Brueton, L., Brunner, H.G., Brussel, W., Guillen-Navarro, E., Haase, C., Kohlhase, J., Kotzot, D., Lane, A., Lee-Kirsch, M.A., Morlot, S., Simon, M.E., Steichen-Gersdorf, E., Tegay, D.H., Peters, J.P.W., Mundlos, S., and Klopocki, E.

Abstract

1 augustus 2010, Contains fulltext : 88233.pdf (publisher's version ) (Closed access), Cleidocranial Dysplasia (CCD) is an autosomal dominant skeletal disorder characterized by hypoplastic or absent clavicles, increased head circumference, large fontanels, dental anomalies, and short stature. Hand malformations are also common. Mutations in RUNX2 cause CCD, but are not identified in all CCD patients. In this study we screened 135 unrelated patients with the clinical diagnosis of CCD for RUNX2 mutations by sequencing analysis and demonstrated 82 mutations 48 of which were novel. By quantitative PCR we screened the remaining 53 unrelated patients for copy number variations in the RUNX2 gene. Heterozygous deletions of different size were identified in 13 patients, and a duplication of the exons 1 to 4 of the RUNX2 gene in one patient. Thus, heterozygous deletions or duplications affecting the RUNX2 gene may be present in about 10% of all patients with a clinical diagnosis of CCD which corresponds to 26% of individuals with normal results on sequencing analysis. We therefore suggest that screening for intragenic deletions and duplications by qPCR or MLPA should be considered for patients with CCD phenotype in whom DNA sequencing does not reveal a causative RUNX2 mutation.

Published
2010

26. The 2q23.1 microdeletion syndrome: clinical and behavioural phenotype.

Author

Bon, B.W.M. van, Koolen, D.A., Brueton, L., McMullan, D., Lichtenbelt, K.D., Ades, L.C., Peters, G., Gibson, K., Moloney, S., Novara, F., Pramparo, T., Bernardina, B. Dalla, Zoccante, L., Balottin, U., Piazza, F., Pecile, V., Gasparini, P., Guerci, V., Kets, M., Pfundt, R., Brouwer, A.P.M. de, Veltman, J.A., Leeuw, N. de, Wilson, M., Antony, J., Reitano, S., Luciano, D., Fichera, M., Romano, C, Brunner, H.G., Zuffardi, O., Vries, L.B.A. de, Bon, B.W.M. van, Koolen, D.A., Brueton, L., McMullan, D., Lichtenbelt, K.D., Ades, L.C., Peters, G., Gibson, K., Moloney, S., Novara, F., Pramparo, T., Bernardina, B. Dalla, Zoccante, L., Balottin, U., Piazza, F., Pecile, V., Gasparini, P., Guerci, V., Kets, M., Pfundt, R., Brouwer, A.P.M. de, Veltman, J.A., Leeuw, N. de, Wilson, M., Antony, J., Reitano, S., Luciano, D., Fichera, M., Romano, C, Brunner, H.G., Zuffardi, O., and Vries, L.B.A. de

Abstract

1 februari 2010, Contains fulltext : 89008.pdf (publisher's version ) (Closed access), Six submicroscopic deletions comprising chromosome band 2q23.1 in patients with severe mental retardation (MR), short stature, microcephaly and epilepsy have been reported, suggesting that haploinsufficiency of one or more genes in the 2q23.1 region might be responsible for the common phenotypic features in these patients. In this study, we report the molecular and clinical characterisation of nine new 2q23.1 deletion patients and a clinical update on two previously reported patients. All patients were mentally retarded with pronounced speech delay and additional abnormalities including short stature, seizures, microcephaly and coarse facies. The majority of cases presented with stereotypic repetitive behaviour, a disturbed sleep pattern and a broad-based gait. These features led to the initial clinical impression of Angelman, Rett or Smith-Magenis syndromes in several patients. The overlapping 2q23.1 deletion region in all 15 patients comprises only one gene, namely, MBD5. Interestingly, MBD5 is a member of the methyl CpG-binding domain protein family, which also comprises MECP2, mutated in Rett's syndrome. Another gene in the 2q23.1 region, EPC2, was deleted in 12 patients who had a broader phenotype than those with a deletion of MBD5 only. EPC2 is a member of the polycomb protein family, involved in heterochromatin formation and might be involved in causing MR. Patients with a 2q23.1 microdeletion present with a variable phenotype and the diagnosis should be considered in mentally retarded children with coarse facies, seizures, disturbed sleeping patterns and additional specific behavioural problems.

Published
2010

27. Further clinical and molecular delineation of the 9q subtelomeric deletion syndrome supports a major contribution of EHMT1 haploinsufficiency to the core phenotype.

Author

Kleefstra, T., Zelst-Stams, W.A.G. van, Nillesen, W.M., Cormier-Daire, V., Houge, G., Foulds, N., Dooren, M. van, Willemsen, M.H., Pfundt, R.P., Turner, A., Wilson, M., McGaughran, J., Rauch, A., Zenker, M., Adam, M.P., Innes, M., Davies, C., Lopez, A.G., Casalone, R., Weber, A., Brueton, L., Navarro, A.D., Bralo, M.P., Venselaar, H., Stegmann, S.P., Yntema, H.G., Bokhoven, J.H.L.M. van, Brunner, H.G., Kleefstra, T., Zelst-Stams, W.A.G. van, Nillesen, W.M., Cormier-Daire, V., Houge, G., Foulds, N., Dooren, M. van, Willemsen, M.H., Pfundt, R.P., Turner, A., Wilson, M., McGaughran, J., Rauch, A., Zenker, M., Adam, M.P., Innes, M., Davies, C., Lopez, A.G., Casalone, R., Weber, A., Brueton, L., Navarro, A.D., Bralo, M.P., Venselaar, H., Stegmann, S.P., Yntema, H.G., Bokhoven, J.H.L.M. van, and Brunner, H.G.

Abstract

Contains fulltext : 80656.pdf (publisher's version ) (Closed access), BACKGROUND: The 9q subtelomeric deletion syndrome (9qSTDS) is clinically characterised by moderate to severe mental retardation, childhood hypotonia and facial dysmorphisms. In addition, congenital heart defects, urogenital defects, epilepsy and behavioural problems are frequently observed. The syndrome can be either caused by a submicroscopic 9q34.3 deletion or by intragenic EHMT1 mutations leading to haploinsufficiency of the EHMT1 gene. So far it has not been established if and to what extent other genes in the 9q34.3 region contribute to the phenotype observed in deletion cases. This study reports the largest cohort of 9qSTDS cases so far. METHODS AND RESULTS: By a multiplex ligation dependent probe amplification (MLPA) approach, the authors identified and characterised 16 novel submicroscopic 9q deletions. Direct sequence analysis of the EHMT1 gene in 24 patients exhibiting the 9qSTD phenotype without such deletion identified six patients with an intragenic EHMT1 mutation. Five of these mutations predict a premature termination codon whereas one mutation gives rise to an amino acid substitution in a conserved domain of the protein. CONCLUSIONS: The data do not provide any evidence for phenotype-genotype correlations between size of the deletions or type of mutations and severity of clinical features. Therefore, the authors confirm the EHMT1 gene to be the major determinant of the 9qSTDS phenotype. Interestingly, five of six patients who had reached adulthood had developed severe psychiatric pathology, which may indicate that EHMT1 haploinsufficiency is associated with neurodegeneration in addition to neurodevelopmental defect.

Published
2009

28. Molecular karyotyping of patients with unexplained mental retardation by SNP arrays: a multicenter study.

Author

McMullan, D.J., Bonin, M., Hehir-Kwa, J.Y., Vries, L.B.A. de, Dufke, A., Rattenberry, E., Steehouwer, M., Moruz, L.M., Pfundt, R.P., Leeuw, N. de, Riess, A., Altug-Teber, O., Enders, H., Singer, S., Grasshoff, U., Walter, M., Walker, J.M., Lamb, C.V., Davison, E.V., Brueton, L., Riess, O., Veltman, J.A., McMullan, D.J., Bonin, M., Hehir-Kwa, J.Y., Vries, L.B.A. de, Dufke, A., Rattenberry, E., Steehouwer, M., Moruz, L.M., Pfundt, R.P., Leeuw, N. de, Riess, A., Altug-Teber, O., Enders, H., Singer, S., Grasshoff, U., Walter, M., Walker, J.M., Lamb, C.V., Davison, E.V., Brueton, L., Riess, O., and Veltman, J.A.

Abstract

Contains fulltext : 79652.pdf (publisher's version ) (Closed access), Genomic microarrays have been implemented in the diagnosis of patients with unexplained mental retardation. This method, although revolutionizing cytogenetics, is still limited to the detection of rare de novo copy number variants (CNVs). Genome-wide single nucleotide polymorphism (SNP) microarrays provide high-resolution genotype as well as CNV information in a single experiment. We hypothesize that the widespread use of these microarray platforms can be exploited to greatly improve our understanding of the genetic causes of mental retardation and many other common disorders, while already providing a robust platform for routine diagnostics. Here we report a detailed validation of Affymetrix 500k SNP microarrays for the detection of CNVs associated to mental retardation. After this validation we applied the same platform in a multicenter study to test a total of 120 patients with unexplained mental retardation and their parents. Rare de novo CNVs were identified in 15% of cases, showing the importance of this approach in daily clinical practice. In addition, much more genomic variation was observed in these patients as well as their parents. We provide all of these data for the scientific community to jointly enhance our understanding of these genomic variants and their potential role in this common disorder.

Published
2009

29. Fourteen new cases contribute to the characterization of the 7q11.23 microduplication syndrome.

Author

Aa, N. van der, Rooms, L., Vandeweyer, G., Ende, J.J. van den, Reyniers, E., Fichera, M., Romano, C, Chiaie, B. Delle, Mortier, G., Menten, B., Destree, A., Maystadt, I., Mannik, K., Kurg, A., Reimand, T., McMullan, D., Oley, C., Brueton, L., Bongers, E.M.H.F., Bon, B.W.M. van, Pfundt, R.P., Jacquemont, S., Ferrarini, A., Martinet, D., Schrander-Stumpel, C.T.R.M., Stegmann, A.P., Frints, S.G., Vries, L.B.A. de, Ceulemans, B., Kooy, R.F., Aa, N. van der, Rooms, L., Vandeweyer, G., Ende, J.J. van den, Reyniers, E., Fichera, M., Romano, C, Chiaie, B. Delle, Mortier, G., Menten, B., Destree, A., Maystadt, I., Mannik, K., Kurg, A., Reimand, T., McMullan, D., Oley, C., Brueton, L., Bongers, E.M.H.F., Bon, B.W.M. van, Pfundt, R.P., Jacquemont, S., Ferrarini, A., Martinet, D., Schrander-Stumpel, C.T.R.M., Stegmann, A.P., Frints, S.G., Vries, L.B.A. de, Ceulemans, B., and Kooy, R.F.

Abstract

Contains fulltext : 80644.pdf (publisher's version ) (Closed access), Interstitial deletions of 7q11.23 cause Williams-Beuren syndrome, one of the best characterized microdeletion syndromes. The clinical phenotype associated with the reciprocal duplication however is not well defined, though speech delay is often mentioned. We present 14 new 7q11.23 patients with the reciprocal duplication of the Williams-Beuren syndrome critical region, nine familial and five de novo. These were identified by either array-based MLPA or by array-CGH/oligonucleotide analysis in a series of patients with idiopathic mental retardation with an estimated population frequency of 1:13,000-1:20,000. Variable speech delay is a constant finding in our patient group, confirming previous reports. Cognitive abilities range from normal to moderate mental retardation. The association with autism is present in five patients and in one father who also carries the duplication. There is an increased incidence of hypotonia and congenital anomalies: heart defects (PDA), diaphragmatic hernia, cryptorchidism and non-specific brain abnormalities on MRI. Specific dysmorphic features were noted in our patients, including a short philtrum, thin lips and straight eyebrows. Our patient collection demonstrates that the 7q11.23 microduplication not only causes language delay, but is also associated with congenital anomalies and a recognizable face.

Published
2009

30. Clinical and molecular phenotype of Aicardi-Goutieres syndrome.

Author

Rice, G., Patrick, T., Parmar, R, Taylor, C.F., Aeby, A., Aicardi, J., Artuch, R., Montalto, S.A., Bacino, C.A., Borroso, B., Baxter, P., Benko, W.S., Bergmann, C., Bertini, E., Biancheri, R., Blair, E., Blau, N., Bonthron, D.T., Briggs, T., Brueton, L., Brunner, H.G., Burke, C.J., Carr, I., Carvalho, D.R., Chandler, K.E., Christen, H.J., Corry, P.C., Cowan, F.M., Cox, H., D'Arrigo, S., Dean, J., Laet, C.E. de, Praeter, C.M. de, Dery, C., Ferrie, C.D., Flintoff, K., Frints, S.G., Garcia-Cazorla, A., Gener, B., Goizet, C., Goutieres, F., Green, A.J., Guet, A., Hamel, B.C.J., Hayward, B.E., Heiberg, A., Hennekam, R.C.M., Husson, M., Jackson, A.P., Jayatunga, R., Jiang, Y.H., Kant, S., Kao, A., King, M., Kingston, H., Klepper, J., Knaap, M.S. van der, Kornberg, A.J., Kotzot, D., Kratzer, W., Lacombe, D., Lagae, L., Landrieu, P.G., Lanzi, G., Leitch, A., Lim, M.J., Livingston, J.H., Lourenco, C.M., Lyall, E.G.H., Lynch, S.A., Lyons, M.J., Marom, D., McClure, J.P., McWilliam, R., Melancon, S.B., Mewasingh, L.D., Moutard, M.L., Nischal, K.K., Ostergaard, J.R., Prendiville, J., Rasmussen, M., Rogers, R.C., Roland, D., Rosser, E.M., Rostasy, K., Roubertie, A., Sanchis, A, Schiffmann, R., Scholl-Burgi, S., Seal, S., Shalev, S.A., Corcoles, C.S., Sinha, G.P., Soler, D., Spiegel, R., Stephenson, J.B., Tacke, U., Tan, T.Y., Willemsen, M.A.A.P., Rice, G., Patrick, T., Parmar, R, Taylor, C.F., Aeby, A., Aicardi, J., Artuch, R., Montalto, S.A., Bacino, C.A., Borroso, B., Baxter, P., Benko, W.S., Bergmann, C., Bertini, E., Biancheri, R., Blair, E., Blau, N., Bonthron, D.T., Briggs, T., Brueton, L., Brunner, H.G., Burke, C.J., Carr, I., Carvalho, D.R., Chandler, K.E., Christen, H.J., Corry, P.C., Cowan, F.M., Cox, H., D'Arrigo, S., Dean, J., Laet, C.E. de, Praeter, C.M. de, Dery, C., Ferrie, C.D., Flintoff, K., Frints, S.G., Garcia-Cazorla, A., Gener, B., Goizet, C., Goutieres, F., Green, A.J., Guet, A., Hamel, B.C.J., Hayward, B.E., Heiberg, A., Hennekam, R.C.M., Husson, M., Jackson, A.P., Jayatunga, R., Jiang, Y.H., Kant, S., Kao, A., King, M., Kingston, H., Klepper, J., Knaap, M.S. van der, Kornberg, A.J., Kotzot, D., Kratzer, W., Lacombe, D., Lagae, L., Landrieu, P.G., Lanzi, G., Leitch, A., Lim, M.J., Livingston, J.H., Lourenco, C.M., Lyall, E.G.H., Lynch, S.A., Lyons, M.J., Marom, D., McClure, J.P., McWilliam, R., Melancon, S.B., Mewasingh, L.D., Moutard, M.L., Nischal, K.K., Ostergaard, J.R., Prendiville, J., Rasmussen, M., Rogers, R.C., Roland, D., Rosser, E.M., Rostasy, K., Roubertie, A., Sanchis, A, Schiffmann, R., Scholl-Burgi, S., Seal, S., Shalev, S.A., Corcoles, C.S., Sinha, G.P., Soler, D., Spiegel, R., Stephenson, J.B., Tacke, U., Tan, T.Y., and Willemsen, M.A.A.P.

Abstract

Contains fulltext : 52556.pdf (publisher's version ) (Closed access)

Published
2007

31. Mutations in the embryonal subunit of the acetylcholine receptor (CHRNG) cause lethal and Escobar variants of multiple pterygium syndrome.

Author

Morgan, N.V., Brueton, L., Cox, P., Greally, M.T., Tolmie, J.L., Pasha, S., Aligianis, I.A., Bokhoven, J.H.L.M. van, Marton, T., Al-Gazali, L., Morton, J.E., Oley, C.A., Johnson, C.A., Trembath, R.C., Brunner, H.G., Maher, E.R., Morgan, N.V., Brueton, L., Cox, P., Greally, M.T., Tolmie, J.L., Pasha, S., Aligianis, I.A., Bokhoven, J.H.L.M. van, Marton, T., Al-Gazali, L., Morton, J.E., Oley, C.A., Johnson, C.A., Trembath, R.C., Brunner, H.G., and Maher, E.R.

Abstract

Contains fulltext : 50026.pdf (publisher's version ) (Closed access), Multiple pterygium syndromes (MPSs) comprise a group of multiple-congenital-anomaly disorders characterized by webbing (pterygia) of the neck, elbows, and/or knees and joint contractures (arthrogryposis). In addition, a variety of developmental defects (e.g., vertebral anomalies) may occur. MPSs are phenotypically and genetically heterogeneous but are traditionally divided into prenatally lethal and nonlethal (Escobar) types. To elucidate the pathogenesis of MPS, we undertook a genomewide linkage scan of a large consanguineous family and mapped a locus to 2q36-37. We then identified germline-inactivating mutations in the embryonal acetylcholine receptor gamma subunit (CHRNG) in families with both lethal and nonlethal MPSs. These findings extend the role of acetylcholine receptor dysfunction in human disease and provide new insights into the pathogenesis and management of fetal akinesia syndromes.

Published
2006

32. Molecular and clinical analyses of Greig cephalopolysyndactyly and Pallister-Hall syndromes: robust phenotype prediction from the type and position of GLI3 mutations.

Author

Johnston, J.J., Olivos-Glander, I., Killoran, C., Elson, E., Turner, J.T., Peters, K.F., Abbott, M.H., Aughton, D.J., Aylsworth, A.S., Bamshad, M., Booth, C., Curry, C.J., David, A., Dinulos, M.B., Flannery, D.B., Fox, M.A., Graham, J.M., Grange, D.K., Guttmacher, A.E., Hannibal, M.C., Henn, W., Hennekam, R.C.M., Holmes, L.B., Hoyme, H.E., Leppig, K.A., Lin, A.E., Macleod, P., Manchester, D.K., Marcelis, C.L.M., Mazzanti, L., McCann, E., McDonald, M.T., Mendelsohn, N.J., Moeschler, J.B., Moghaddam, B., Neri, G., Newbury-Ecob, R., Pagon, R.A., Phillips, J.A., Sadler, L.S., Stoler, J.M., Tilstra, D., Walsh Vockley, C.M., Zackai, E.H., Zadeh, T.M., Brueton, L., Black, G.C.M., Biesecker, L.G., Johnston, J.J., Olivos-Glander, I., Killoran, C., Elson, E., Turner, J.T., Peters, K.F., Abbott, M.H., Aughton, D.J., Aylsworth, A.S., Bamshad, M., Booth, C., Curry, C.J., David, A., Dinulos, M.B., Flannery, D.B., Fox, M.A., Graham, J.M., Grange, D.K., Guttmacher, A.E., Hannibal, M.C., Henn, W., Hennekam, R.C.M., Holmes, L.B., Hoyme, H.E., Leppig, K.A., Lin, A.E., Macleod, P., Manchester, D.K., Marcelis, C.L.M., Mazzanti, L., McCann, E., McDonald, M.T., Mendelsohn, N.J., Moeschler, J.B., Moghaddam, B., Neri, G., Newbury-Ecob, R., Pagon, R.A., Phillips, J.A., Sadler, L.S., Stoler, J.M., Tilstra, D., Walsh Vockley, C.M., Zackai, E.H., Zadeh, T.M., Brueton, L., Black, G.C.M., and Biesecker, L.G.

Abstract

Contains fulltext : 48832.pdf (publisher's version ) (Closed access), Mutations in the GLI3 zinc-finger transcription factor gene cause Greig cephalopolysyndactyly syndrome (GCPS) and Pallister-Hall syndrome (PHS), which are variable but distinct clinical entities. We hypothesized that GLI3 mutations that predict a truncated functional repressor protein cause PHS and that functional haploinsufficiency of GLI3 causes GCPS. To test these hypotheses, we screened patients with PHS and GCPS for GLI3 mutations. The patient group consisted of 135 individuals: 89 patients with GCPS and 46 patients with PHS. We detected 47 pathological mutations (among 60 probands); when these were combined with previously published mutations, two genotype-phenotype correlations were evident. First, GCPS was caused by many types of alterations, including translocations, large deletions, exonic deletions and duplications, small in-frame deletions, and missense, frameshift/nonsense, and splicing mutations. In contrast, PHS was caused only by frameshift/nonsense and splicing mutations. Second, among the frameshift/nonsense mutations, there was a clear genotype-phenotype correlation. Mutations in the first third of the gene (from open reading frame [ORF] nucleotides [nt] 1-1997) caused GCPS, and mutations in the second third of the gene (from ORF nt 1998-3481) caused primarily PHS. Surprisingly, there were 12 mutations in patients with GCPS in the 3' third of the gene (after ORF nt 3481), and no patients with PHS had mutations in this region. These results demonstrate a robust correlation of genotype and phenotype for GLI3 mutations and strongly support the hypothesis that these two allelic disorders have distinct modes of pathogenesis.

Published
2005

33. Evidence for locus heterogeneity in acrocephalosyndactyly: a refined localization for the Saethre-Chotzen syndrome locus on distal chromosome 7p--and exclusion of Jackson-Weiss syndrome from craniosynostosis loci on 7p and 5q

Author

van Herwerden, L., Rose, C. S., Reardon, W., Brueton, L. A., Weissenbach, J., Malcolm, S., and Winter, R. M.

Subjects
Male, Base Sequence, Genetic Linkage, Molecular Sequence Data, Chromosome Mapping, Sequence Analysis, DNA, Acrocephalosyndactylia, Pedigree, Craniosynostoses, Chromosomes, Human, Pair 5, Humans, Female, Lod Score, Chromosomes, Human, Pair 7, Research Article, Genes, Dominant
Abstract

Craniosynostosis (premature fusion of the skull sutures) occurs as a clinically heterogeneous group of disorders, frequently involving digital abnormalities. We have previously provisionally assigned the gene for one such condition, Saethre-Chotzen syndrome (ACS III), to chromosome 7p. Linkage analysis is now reported between ACS III and dinucleotide repeat loci on distal 7p. The maximum lod scores, Zmax, were 5.57 at a recombination fraction of .05, with D7S488, and 4.74 at a recombination fraction of .05, with D7S493. Only weak linkage, not reaching significance, was found with distal markers (D7S513 and afm281vc9) and a proximal marker (D7S516). Multipoint analysis shows that the disease locus lies between D7S513 and D7S516. Analysis of individual recombinants shows that the most likely position is between D7S493 and D7S516. Linkage data in regard of Jackson-Weiss syndrome demonstrate that this autosomal dominant form of acrocephalosyndactyly does not map to the ACS III region on 7p or to the acrocephalosyndactyly locus on 5q (Boston type). These findings underline the genetic heterogeneity among the different clinical conditions manifesting with acrocephalosyndactyly.

Published
1994

34. 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
Full Text
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41. Clinical and hematologic aspects of the X-linked α-thalassemia/mental retardation syndrome (ATR-X)

Author

Gibbons, R. J., primary, Brueton, L., additional, Buckle, V. J., additional, Burn, J., additional, Clayton-Smith, J., additional, Davison, B. C. C., additional, Gardner, R. J. M., additional, Homfray, T., additional, Kearney, L., additional, Kingston, H. M., additional, Newbury-Ecob, R., additional, Porteous, M. E. P., additional, Wilkie, A. O. M., additional, and Higgs, D. R., additional

Published
1995
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49. Spectrum of clinical features associated with interstitial chromosome 22q11 deletions: A European collaborative study

Author

Ryan, A. K., Goodship, J. A., Wilson, D. I., Philip, N., Levy, A., Seidel, H., Schuffenhauer, S., Oechsler, H., Belohradsky, B., Prieur, M., Aurias, A., Raymond, F. L., Clayton-Smith, J., Hatchwell, E., Mckeown, C., Beemer, F. A., Dallapiccola, B., Giuseppe Novelli, Hurst, J. A., Ignatius, J., Green, A. J., Winter, R. M., Brueton, L., Brøndum-Nielsen, K., Stewart, F., Essen, T., Patton, M., Paterson, J., and Scambler, P. J.

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