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7. 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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8. Linking a European cohort of children born with congenital anomalies to vital statistics and mortality records: A EUROlinkCAT study

Author

Loane, M., primary, Given, J. E., additional, Tan, J., additional, Reid, A., additional, Akhmedzhanova, D., additional, Astolfi, G., additional, Barišić, I., additional, Bertille, N., additional, Bonet, L. B., additional, Carbonell, C. C., additional, Carollo, O. Mokoroa, additional, Coi, A., additional, Densem, J., additional, Draper, E., additional, Garne, E., additional, Gatt, M., additional, Glinianaia, S. V., additional, Heino, A., additional, Hond, E. Den, additional, Jordan, S., additional, Khoshnood, B., additional, Kiuru-Kuhlefelt, S., additional, Klungsøyr, K., additional, Lelong, N., additional, Lutke, L. R., additional, Neville, A. J., additional, Ostapchuk, L., additional, Puccini, A., additional, Rissmann, A., additional, Santoro, M., additional, Scanlon, I., additional, Thys, G., additional, Tucker, D., additional, Urhoj, S. K., additional, de Walle, H. E. K., additional, Wellesley, D., additional, Zurriaga, O., additional, and Morris, J. K., additional

Published
2021
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9. Linking a European cohort of children born with congenital anomalies to vital statistics and mortality records:A EUROlinkCAT study

Author

Loane, M., Given, J. E., Tan, J., Reid, A., Akhmedzhanova, D., Astolfi, G., Barišić, I., Bertille, N., Bonet, L. B., Carbonell, C. C., Carollo, O. Mokoroa, Coi, A., Densem, J., Draper, E., Gatt, M., Glinianaia, S. V., Heino, A., Hond, E. Den, Jordan, S., Khoshnood, B., Kiuru-Kuhlefelt, S., Klungsøyr, K., Lelong, N., Lutke, L. R., Neville, A. J., Ostapchuk, L., Puccini, A., Rissmann, A., Santoro, M., Scanlon, I., Thys, G., Tucker, D., Urhoj, S. K., De Walle, H. E.K., Wellesley, D., Zurriaga, O., Morris, J. K., Loane, M., Given, J. E., Tan, J., Reid, A., Akhmedzhanova, D., Astolfi, G., Barišić, I., Bertille, N., Bonet, L. B., Carbonell, C. C., Carollo, O. Mokoroa, Coi, A., Densem, J., Draper, E., Gatt, M., Glinianaia, S. V., Heino, A., Hond, E. Den, Jordan, S., Khoshnood, B., Kiuru-Kuhlefelt, S., Klungsøyr, K., Lelong, N., Lutke, L. R., Neville, A. J., Ostapchuk, L., Puccini, A., Rissmann, A., Santoro, M., Scanlon, I., Thys, G., Tucker, D., Urhoj, S. K., De Walle, H. E.K., Wellesley, D., Zurriaga, O., and Morris, J. K.

Abstract

EUROCAT is a European network of population-based congenital anomaly (CA) registries. Twenty-one registries agreed to participate in the EUROlinkCAT study to determine if reliable information on the survival of children born with a major CA between 1995 and 2014 can be obtained through linkage to national vital statistics or mortality records. Live birth children with a CA could be linked using personal identifiers to either their national vital statistics (including birth records, death records, hospital records) or to mortality records only, depending on the data available within each region. In total, 18 of 21 registries with data on 192,862 children born with congenital anomalies participated in the study. One registry was unable to get ethical approval to participate and linkage was not possible for two registries due to local reasons. Eleven registries linked to vital statistics and seven registries linked to mortality records only; one of the latter only had identification numbers for 78% of cases, hence it was excluded from further analysis. For registries linking to vital statistics: six linked over 95% of their cases for all years and five were unable to link at least 85% of all live born CA children in the earlier years of the study. No estimate of linkage success could be calculated for registries linking to mortality records. Irrespective of linkage method, deaths that occurred during the first week of life were over three times less likely to be linked compared to deaths occurring after the first week of life. Linkage to vital statistics can provide accurate estimates of survival of children with CAs in some European countries. Bias arises when linkage is not successful, as early neonatal deaths were less likely to be linked. Linkage to mortality records only cannot be recommended, as linkage quality, and hence bias, cannot be assessed.

Published
2021

10. Maternal risk factors for the VACTERL association: A EUROCAT case-control study

Author

Putte, R. van de, Rooij, I.A.L.M. van, Haanappel, C.P., Marcelis, C.L.M., Brunner, H.G., Addor, M.C., Cavero-Carbonell, C., Dias, C.M., Draper, E.S., Etxebarriarteun, L., Gatt, M., Khoshnood, B., Kinsner-Ovaskainen, A., Klungsoyr, K., Kurinczuk, J.J., Latos-Bielenska, A., Luyt, K., O'Mahony, M.T., Miller, N., Mullaney, C., Nelen, V., Neville, A.J., Perthus, I., Pierini, A., Randrianaivo, H., Rankin, J., Rissmann, A., Rouget, F., Schaub, B., Tucker, D., Wellesley, D., Wiesel, A., Zymak-Zakutnia, N., Loane, M., Barisic, I., Walle, H.E. de, Bergman, J.E., Roeleveld, N., Putte, R. van de, Rooij, I.A.L.M. van, Haanappel, C.P., Marcelis, C.L.M., Brunner, H.G., Addor, M.C., Cavero-Carbonell, C., Dias, C.M., Draper, E.S., Etxebarriarteun, L., Gatt, M., Khoshnood, B., Kinsner-Ovaskainen, A., Klungsoyr, K., Kurinczuk, J.J., Latos-Bielenska, A., Luyt, K., O'Mahony, M.T., Miller, N., Mullaney, C., Nelen, V., Neville, A.J., Perthus, I., Pierini, A., Randrianaivo, H., Rankin, J., Rissmann, A., Rouget, F., Schaub, B., Tucker, D., Wellesley, D., Wiesel, A., Zymak-Zakutnia, N., Loane, M., Barisic, I., Walle, H.E. de, Bergman, J.E., and Roeleveld, N.

Abstract

Contains fulltext : 220449.pdf (Publisher’s version ) (Open Access), BACKGROUND: The VACTERL association (VACTERL) is the nonrandom occurrence of at least three of these congenital anomalies: vertebral, anal, cardiac, tracheoesophageal, renal, and limb anomalies. Despite suggestions for involvement of several genes and nongenetic risk factors from small studies, the etiology of VACTERL remains largely unknown. OBJECTIVE: To identify maternal risk factors for VACTERL in offspring in a large European study. METHODS: A case-control study was performed using data from 28 EUROCAT registries over the period 1997-2015 with case and control ascertainment through hospital records, birth and death certificates, questionnaires, and/or postmortem examinations. Cases were diagnosed with VACTERL, while controls had a genetic syndrome and/or chromosomal abnormality. Data collected included type of birth defect and maternal characteristics, such as age, use of assisted reproductive techniques (ART), and chronic illnesses. Multivariable logistic regression analyses were performed to estimate confounder adjusted odds ratios (aOR) with 95% confidence intervals (95% CI). RESULTS: The study population consisted of 329 VACTERL cases and 49,724 controls with recognized syndromes or chromosomal abnormality. For couples who conceived through ART, we found an increased risk of VACTERL (aOR 2.3 [95% CI 1.3, 3.9]) in offspring. Pregestational diabetes (aOR 3.1 [95% CI 1.1, 8.6]) and chronic lower obstructive pulmonary diseases (aOR 3.9 [95% CI 2.2, 6.7]) also increased the risk of having a child with VACTERL. Twin pregnancies were not associated with VACTERL (aOR 0.6 [95% CI 0.3, 1.4]). CONCLUSION: We identified several maternal risk factors for VACTERL in offspring befitting a multifactorial etiology.

Published
2020

11. Trends in the prevalence, risk and pregnancy outcome of multiple births with congenital anomaly: a registry-based study in 14 European countries 1984–2007

Author

Boyle, B, McConkey, R, Garne, E, Loane, M, Addor, M C, Bakker, M K, Boyd, P A, Gatt, M, Greenlees, R, Haeusler, M, Klungsyr, K, Latos-Bielenska, A, Lelong, N, McDonnell, R, Métneki, J, Mullaney, C, Nelen, V, OʼMahony, M, Pierini, A, Rankin, J, Rissmann, A, Tucker, D, Wellesley, D, and Dolk, H

Published
2013
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14. The Relationship between Neonatal Gastroschisis, Maternal BMI and Social Deprivation in a UK Population

Author

Derbyshire A, Howe Dt, Hale J, Osmond C, Taylor A, and Wellesley D

Subjects
education.field_of_study, Social deprivation, business.industry, Gastroschisis, Fetal abnormality, Population, Medicine, Multiple deprivation, education, business, medicine.disease, Demography
Abstract

In this paper, we examine the association between social deprivation and gastroschisis in a UK population. We used the UK postcode to determine social deprivation using the government Index of Multiple Deprivation (IMD). IMD ranks areas from 1 being the most deprived to 32,844 as the least socially deprived area. This is the first time that IMD has been used to examine a potential link between social deprivation and any fetal abnormality. Our findings suggest that social deprivation is associated with low maternal age, but is not an additional risk for fetal gastroschisis.

Published
2019
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20. 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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22. Clinical, biochemical and genetic spectrum of 70 patients with ACAD9 deficiency: Is riboflavin supplementation effective?

Author

Repp, B.M. (Birgit M.), Mastantuono, E. (Elisa), Alston, C.L. (Charlotte L.), Schiff, M. (Manuel), Haack, T.B. (Tobias B.), Rötig, A. (Agns), Ardissone, A. (Anna), Lombès, A. (Anne), Catarino, C.F.B.S., Diodato, D. (Daria), Schottmann, G. (Gudrun), Poulton, J. (Joanna), Burlina, A.B. (Alberto), Jonckheere, A. (An), Munnich, A. (Arnold), Rolinski, B. (Boris), Ghezzi, D. (Daniele), Rokicki, D. (Dariusz), Wellesley, D. (Diana), Martinelli, D. (Diego), Wenhong, D. (Ding), Lamantea, E. (Eleonora), Østergaard, E. (Elsebet), Pronicka, E. (Ewa), Pierre, G. (Germaine), Smeets, H.J.M. (Hubert), Wittig, I. (Ilka), Scurr, I. (Ingrid), Coo, I.F.M. (René) de, Moroni, I. (Isabella), Smet, J. (Joél), Mayr, J.A. (Johannes A.), Dai, L. (Lifang), Meirleir, L. (Linda) de, Schuelke, M. (Markus), Zeviani, M. (Massimo), Morscher, R.J. (Raphael J.), McFarland, R. (Robert), Seneca, S. (S.), Klopstock, T. (Thomas), Meitinger, T. (Thomas), Wieland, T. (Thomas), Strom, T.M. (Tim), Herberg, U. (Ulrike), Ahting, U. (Uwe), Sperl, W. (Wolfgang), Nassogne, M.C. (M.), Ling, H. (Han), Fang, F. (Fang), Freisinger, P. (Peter), Coster, R.N.A. (R. N A) van, Strecker, V. (Valentina), Taylor, R.W. (Robert William), Häberle, J. (Johannes), Vockley, J. (Jerry), Prokisch, H. (Holger), Wortmann, S.B. (S.), Repp, B.M. (Birgit M.), Mastantuono, E. (Elisa), Alston, C.L. (Charlotte L.), Schiff, M. (Manuel), Haack, T.B. (Tobias B.), Rötig, A. (Agns), Ardissone, A. (Anna), Lombès, A. (Anne), Catarino, C.F.B.S., Diodato, D. (Daria), Schottmann, G. (Gudrun), Poulton, J. (Joanna), Burlina, A.B. (Alberto), Jonckheere, A. (An), Munnich, A. (Arnold), Rolinski, B. (Boris), Ghezzi, D. (Daniele), Rokicki, D. (Dariusz), Wellesley, D. (Diana), Martinelli, D. (Diego), Wenhong, D. (Ding), Lamantea, E. (Eleonora), Østergaard, E. (Elsebet), Pronicka, E. (Ewa), Pierre, G. (Germaine), Smeets, H.J.M. (Hubert), Wittig, I. (Ilka), Scurr, I. (Ingrid), Coo, I.F.M. (René) de, Moroni, I. (Isabella), Smet, J. (Joél), Mayr, J.A. (Johannes A.), Dai, L. (Lifang), Meirleir, L. (Linda) de, Schuelke, M. (Markus), Zeviani, M. (Massimo), Morscher, R.J. (Raphael J.), McFarland, R. (Robert), Seneca, S. (S.), Klopstock, T. (Thomas), Meitinger, T. (Thomas), Wieland, T. (Thomas), Strom, T.M. (Tim), Herberg, U. (Ulrike), Ahting, U. (Uwe), Sperl, W. (Wolfgang), Nassogne, M.C. (M.), Ling, H. (Han), Fang, F. (Fang), Freisinger, P. (Peter), Coster, R.N.A. (R. N A) van, Strecker, V. (Valentina), Taylor, R.W. (Robert William), Häberle, J. (Johannes), Vockley, J. (Jerry), Prokisch, H. (Holger), and Wortmann, S.B. (S.)

Abstract

Background: Mitochondrial acyl-CoA dehydrogenase family member 9 (ACAD9) is essential for the assembly of mitochondrial respiratory chain complex I. Disease causing biallelic variants in ACAD9 have been reported in individuals presenting with lactic acidosis and cardiomyopathy. Results: We describe the genetic, clinical and biochemical findings in a cohort of 70 patients, of whom 29 previously unpublished. We found 34 known and 18 previously unreported variants in ACAD9. No patients harbored biallelic loss of function mutations, indicating that this combination is unlikely to be compatible with life. Causal pathogenic variants were distributed throughout the entire gene, and there was no obvious genotype-phenotype correlation. Most of the patients presented in the first year of life. For this subgroup the survival was poor (50% not surviving the first 2 years) comparing to patients with a later presentation (more than 90% surviving 10 years). The most common clinical findings were cardiomyopathy (85%), muscular weakness (75%) and exercise intolerance (72%). Interestingly, severe intellectual deficits were only reported in one patient and s

Published
2018
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23. Clinical, biochemical and genetic spectrum of 70 patients with ACAD9 deficiency: Is riboflavin supplementation effective?

Author

Repp, B, Mastantuono, E, Alston, C, Schiff, M, Haack, T, Rötig, A, Ardissone, A, Lombès, A, Catarino, C, Diodato, D, Schottmann, G, Poulton, J, Burlina, A, Jonckheere, A, Munnich, A, Rolinski, B, Ghezzi, D, Rokicki, D, Wellesley, D, Martinelli, D, Wenhong, D, Lamantea, E, Ostergaard, E, Pronicka, E, Pierre, G, Smeets, H, Wittig, I, Scurr, I, De Coo, I, Moroni, I, Smet, J, Mayr, J, Dai, L, De Meirleir, L, Schuelke, M, Zeviani, M, Morscher, R, Mcfarland, R, Seneca, S, Klopstock, T, Meitinger, T, Wieland, T, Strom, T, Herberg, U, Ahting, U, Sperl, W, Nassogne, M, Ling, H, Fang, F, Freisinger, P, Van Coster, R, Strecker, V, Taylor, R, Häberle, J, Vockley, J, Prokisch, H, Wortmann, S, Repp, Birgit M., Mastantuono, Elisa, Alston, Charlotte L., Schiff, Manuel, Haack, Tobias B., Rötig, Agnes, Ardissone, Anna, Lombès, Anne, Catarino, Claudia B., Diodato, Daria, Schottmann, Gudrun, Poulton, Joanna, Burlina, Alberto, Jonckheere, An, Munnich, Arnold, Rolinski, Boris, Ghezzi, Daniele, Rokicki, Dariusz, Wellesley, Diana, Martinelli, Diego, Wenhong, Ding, Lamantea, Eleonora, Ostergaard, Elsebet, Pronicka, Ewa, Pierre, Germaine, Smeets, Hubert J. M., Wittig, Ilka, Scurr, Ingrid, De Coo, Irenaeus F. M., Moroni, Isabella, Smet, Joél, Mayr, Johannes A., Dai, Lifang, De Meirleir, Linda, Schuelke, Markus, Zeviani, Massimo, Morscher, Raphael J., McFarland, Robert, Seneca, Sara, Klopstock, Thomas, Meitinger, Thomas, Wieland, Thomas, Strom, Tim M., Herberg, Ulrike, Ahting, Uwe, Sperl, Wolfgang, Nassogne, Marie-Cecile, Ling, Han, Fang, Fang, Freisinger, Peter, Van Coster, Rudy, Strecker, Valentina, Taylor, Robert W., Häberle, Johannes, Vockley, Jerry, Prokisch, Holger, Wortmann, Saskia, Repp, B, Mastantuono, E, Alston, C, Schiff, M, Haack, T, Rötig, A, Ardissone, A, Lombès, A, Catarino, C, Diodato, D, Schottmann, G, Poulton, J, Burlina, A, Jonckheere, A, Munnich, A, Rolinski, B, Ghezzi, D, Rokicki, D, Wellesley, D, Martinelli, D, Wenhong, D, Lamantea, E, Ostergaard, E, Pronicka, E, Pierre, G, Smeets, H, Wittig, I, Scurr, I, De Coo, I, Moroni, I, Smet, J, Mayr, J, Dai, L, De Meirleir, L, Schuelke, M, Zeviani, M, Morscher, R, Mcfarland, R, Seneca, S, Klopstock, T, Meitinger, T, Wieland, T, Strom, T, Herberg, U, Ahting, U, Sperl, W, Nassogne, M, Ling, H, Fang, F, Freisinger, P, Van Coster, R, Strecker, V, Taylor, R, Häberle, J, Vockley, J, Prokisch, H, Wortmann, S, Repp, Birgit M., Mastantuono, Elisa, Alston, Charlotte L., Schiff, Manuel, Haack, Tobias B., Rötig, Agnes, Ardissone, Anna, Lombès, Anne, Catarino, Claudia B., Diodato, Daria, Schottmann, Gudrun, Poulton, Joanna, Burlina, Alberto, Jonckheere, An, Munnich, Arnold, Rolinski, Boris, Ghezzi, Daniele, Rokicki, Dariusz, Wellesley, Diana, Martinelli, Diego, Wenhong, Ding, Lamantea, Eleonora, Ostergaard, Elsebet, Pronicka, Ewa, Pierre, Germaine, Smeets, Hubert J. M., Wittig, Ilka, Scurr, Ingrid, De Coo, Irenaeus F. M., Moroni, Isabella, Smet, Joél, Mayr, Johannes A., Dai, Lifang, De Meirleir, Linda, Schuelke, Markus, Zeviani, Massimo, Morscher, Raphael J., McFarland, Robert, Seneca, Sara, Klopstock, Thomas, Meitinger, Thomas, Wieland, Thomas, Strom, Tim M., Herberg, Ulrike, Ahting, Uwe, Sperl, Wolfgang, Nassogne, Marie-Cecile, Ling, Han, Fang, Fang, Freisinger, Peter, Van Coster, Rudy, Strecker, Valentina, Taylor, Robert W., Häberle, Johannes, Vockley, Jerry, Prokisch, Holger, and Wortmann, Saskia

Abstract

Background: Mitochondrial acyl-CoA dehydrogenase family member 9 (ACAD9) is essential for the assembly of mitochondrial respiratory chain complex I. Disease causing biallelic variants in ACAD9 have been reported in individuals presenting with lactic acidosis and cardiomyopathy. Results: We describe the genetic, clinical and biochemical findings in a cohort of 70 patients, of whom 29 previously unpublished. We found 34 known and 18 previously unreported variants in ACAD9. No patients harbored biallelic loss of function mutations, indicating that this combination is unlikely to be compatible with life. Causal pathogenic variants were distributed throughout the entire gene, and there was no obvious genotype-phenotype correlation. Most of the patients presented in the first year of life. For this subgroup the survival was poor (50% not surviving the first 2 years) comparing to patients with a later presentation (more than 90% surviving 10 years). The most common clinical findings were cardiomyopathy (85%), muscular weakness (75%) and exercise intolerance (72%). Interestingly, severe intellectual deficits were only reported in one patient and severe developmental delays in four patients. More than 70% of the patients were able to perform the same activities of daily living when compared to peers. Conclusions: Our data show that riboflavin treatment improves complex I activity in the majority of patient-derived fibroblasts tested. This effect was also reported for most of the treated patients and is mirrored in the survival data. In the patient group with disease-onset below 1 year of age, we observed a statistically-significant better survival for patients treated with riboflavin.

Published
2018

24. Clinical, biochemical and genetic spectrum of 70 patients with ACAD9 deficiency: is riboflavin supplementation effective?

Author

Repp, BM, Mastantuono, E, Alston, CL, Schiff, M, Haack, TB, Rotig, A, Ardissone, A, Lombes, A, Catarino, CB, Diodato, D, Schottmann, G, Poulton, J, Burlina, A, Jonckheere, A, Munnich, A, Rolinski, B, Ghezzi, D, Rokicki, D, Wellesley, D, Martinelli, D, Ding, WH, Lamantea, E, Ostergaard, E, Pronicka, E, Pierre, G, Smeets, HJM, Wittig, I, Scurr, I, Coo, IFM, Moroni, I, Smet, J, Mayr, JA, Dai, LF, de Meirleir, L, Schuelke, M, Zeviani, M, Morscher, RJ, McFarland, R, Seneca, S, Klopstock, T, Meitinger, T, Wieland, T, Strom, TM, Herberg, U, Ahting, U, Sperl, W, Nassogne, MC, Ling, H, Fang, F, Freisinger, P, Van Coster, R, Strecker, V, Taylor, RW, Haberle, J, Vockley, J, Prokisch, H, Wortmann, S, Repp, BM, Mastantuono, E, Alston, CL, Schiff, M, Haack, TB, Rotig, A, Ardissone, A, Lombes, A, Catarino, CB, Diodato, D, Schottmann, G, Poulton, J, Burlina, A, Jonckheere, A, Munnich, A, Rolinski, B, Ghezzi, D, Rokicki, D, Wellesley, D, Martinelli, D, Ding, WH, Lamantea, E, Ostergaard, E, Pronicka, E, Pierre, G, Smeets, HJM, Wittig, I, Scurr, I, Coo, IFM, Moroni, I, Smet, J, Mayr, JA, Dai, LF, de Meirleir, L, Schuelke, M, Zeviani, M, Morscher, RJ, McFarland, R, Seneca, S, Klopstock, T, Meitinger, T, Wieland, T, Strom, TM, Herberg, U, Ahting, U, Sperl, W, Nassogne, MC, Ling, H, Fang, F, Freisinger, P, Van Coster, R, Strecker, V, Taylor, RW, Haberle, J, Vockley, J, Prokisch, H, and Wortmann, S

Published
2018

26. Use of hierarchical models to analyse European trends in congenital anomaly prevalence

Author

Cavadino, A, Prieto-Merino, D, Addor, M-C, Arriola, L, Draper, E, Garne, E, Greenlees, R, Haeusler, M, Khoshnood, Kurinczuk, J, McDonnell, B, Nelen, V, O'Mahoney, M, Randrianaivo, H, Rankin, J, Rissman, A, Tucker, D, Verrelen-Dumouli, C, de Walle, H, Wellesley, D, Morris, J, and Bianchi, F

Abstract

Background: Surveillance of congenital anomalies is important to identify potential teratogens. Despite known associations between different anomalies, current surveillance methods examine trends within each subgroup separately. We aimed to evaluate whether hierarchical statistical methods that combine information from several subgroups simultaneously would enhance current surveillance methods using data collected by EUROCAT, a European network of population-based congenital anomaly registries. Methods: Ten year trends (2003 to 2012) in 18 EUROCAT registries over 11 countries were analysed for the following groups of anomalies: neural tube defects, congenital heart defects, digestive system and chromosomal anomalies. Hierarchical Poisson regression models that combined related subgroups together according to EUROCAT’s hierarchy of subgroup coding were applied. Results from hierarchical models were compared to those from Poisson models that consider each congenital anomaly separately. Results: Hierarchical models gave similar results as those obtained when considering each anomaly subgroup in a separate analysis. Hierarchical models that included only around three subgroups showed poor convergence and were generally found to be over-parameterised. Larger sets of anomaly subgroups were found to be too heterogeneous to group together in this way. Conclusions: There were no substantial differences between independent analyses of each subgroup and hierarchical models when using the EUROCAT anomaly subgroups. Considering each anomaly separately therefore remains an appropriate method for the detection of potential changes in prevalence by surveillance systems. Hierarchical models do, however, remain an interesting alternative method of analysis when considering the risks of specific exposures in relation to the prevalence of congenital anomalies, which could be investigated in other studies.

Published
2016

27. Use of topiramate in relation to the risk of orofacial clefts

Author

Wang, H., Loane, M., Morris, J., Garne, E., Nelen, V., Khoshnood, B., Rismann, A., Wiesel, A., O'Mahony, M., Pierini, A., Neville, A., Gatt, M., De Walle, H., Addor, M. C., Tucker, D., Klungsoyr, K., Latos-Bielenska, A., Mejnartowicz, J., Verellen-Dumoulin, C., Doray, B., Arriola, L., Barisic, I., Calzolari, E., Wellesley, D., Dolk, H., and De Jong-Van Den Berg, L.

Subjects
risk *pharmacoepidemiology *risk management registration female therapy human cleft palate exposure monotherapy congenital malformation pregnancy cleft lip first trimester pregnancy population United States drug database population based case control study prevalence pregnant woman mother infant control group drug administration food Europe register palate safety *topiramate lamotrigine carbamazepine valproic acid anticonvulsive agent
Abstract

Background: The use of topiramate (TPM) has been increased among pregnant women. Safety data for TPM in human pregnancy are limited. Recent studies have suggested that exposure to TPM early in gestation has a higher risk of orofacial clefts (OCs), particularly cleft lip with or without palate, and there has been a Food Drug Administration (FDA) alert. Objectives: The aim of this study was to assess the risk of OCs relative to other malformations in infants whose mothers had taken TPM during the first trimester of pregnancy. Methods: A population-based case-control study with malformed controls was performed using the EUROCAT Antiepileptic (AED) Drug Database including data from 19 population-based registries of congenital anomaly in Europe with a total coverage of 8.0 million births from 1995 to 2011. Cases were 10 802 nonsyndromic OC registrations, of whom 8919 were isolated, and 6827 were cleft lip with or without cleft palate (CL/P). Controls were 136 838 nonchromosomal, non-OC registrations. We compared first trimester TPM use versus no-AED use, for monotherapy and polytherapy. Results: Exposure to TPM monotherapy was recorded for a total of 12 registrations, with one registration in the case group (isolated cleft palate) and 11 in the control group (odds ratio (OR) 1.15, 95% CI 0.03-7.95 for OC relative to other malformations, OR 4.03, 95%CI 0.09-27.8 for isolated cleft palate). No registration of CL/P was in TPM monotherapy exposure. There were 36 registrations exposed to TPM polytherapy, of whom six with isolated CL/P, three with cleft palate. Out of 36 of TPM polytherapy, 19 included valproic acid, 8 included carbamazepine and 4 included lamotrigine. The OR for TPM polytherapy versus no-AED use was 4.23 (95%CI 1.75-9.28) for OC, 4.35 (95%CI 1.31- 11.5) for isolated CL/P and 3.85 (95%CI 0.75- 12.5) for isolated cleft palate. Conclusions: The prevalence of TPM monotherapy exposure was five times lower in these data than reported in the United States, which limited our ability to confirm or refute previous findings. We found an excess of OCs, particularly CL/P, associated with TPM polytherapy. Further attention to TPM polytherapy is warranted.

Published
2015
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29. 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

31. Exome sequencing identifies DYNC2H1 mutations as a common cause of asphyxiating thoracic dystrophy (Jeune syndrome) without major polydactyly, renal or retinal involvement

Author

Schmidts, M., Arts, H.H., Bongers, E.M., Yap, Z., Oud, M.M., Antony, D., Duijkers, L., Emes, R.D., Stalker, J., Yntema, J.B., Plagnol, V., Hoischen, A., Gilissen, C., Forsythe, E., Lausch, E., Veltman, J.A., Roeleveld, N., Superti-Furga, A., Kutkowska-Kazmierczak, A., Kamsteeg, E.J., Elçioglu, N., van Maarle, M.C., Graul-Neumann, L.M., Devriendt, K., Smithson, S.F., Wellesley, D., Verbeek, N.E., Hennekam, R.C., Kayserili, H., Scambler, P.J., Beales, P.L., UK10K, Knoers, N.V., Roepman, R., Mitchison, H.M., Schmidts, Miriam, Arts, Heleen H., Bongers, Ernie M. H. F., Yap, Zhimin, Oud, Machteld M., Antony, Dinu, Duijkers, Lonneke, Emes, Richard D., Stalker, Jim, Yntema, Jan-Bart L., Plagnol, Vincent, Hoischen, Alexander, Gilissen, Christian, Forsythe, Elisabeth, Lausch, Ekkehart, Veltman, Joris A., Roeleveld, Nel, Superti-Furga, Andrea, Kutkowska-Kazmierczak, Anna, Kamsteeg, Erik-Jan, Elcioglu, Nursel, van Maarle, Merel C., Graul-Neumann, Luitgard M., Devriendt, Koenraad, Smithson, Sarah F., Wellesley, Diana, Verbeek, Nienke E., Hennekam, Raoul C. M., Kayserili, Hulya, Scambler, Peter J., Beales, Philip L., Knoers, Nine V. A. M., Roepman, Ronald, Mitchison, Hannah M., Human Genetics, ANS - Amsterdam Neuroscience, APH - Amsterdam Public Health, Paediatrics, and UK10K

Subjects
Exome/genetics, Cytoplasmic Dyneins, Models, Molecular, Genetics and epigenetic pathways of disease [NCMLS 6], Protein Conformation, Bioinformatics, medicine.disease_cause, 0302 clinical medicine, Models, Genetic Screening/Counselling, Missense mutation, Developmental, Exome, CRYSTAL-STRUCTURE, Diagnostics, Genetics (clinical), Exome sequencing, Renal disorder [IGMD 9], Genetics, Microscopy, 0303 health sciences, Mutation, Polydactyly, Developmental Defects, DEFECTS, Polymorphism, Single Nucleotide/genetics, 3. Good health, Gene Components, Ellis-Van Creveld Syndrome/genetics, PELVIC-PHALANGEAL DYSTROPHY, Single Nucleotide/genetics, Sequence Analysis, Mutation/genetics, Ellis-Van Creveld Syndrome, Molecular Sequence Data, IFT, Biology, DYNEIN MOTOR DOMAIN, Polymorphism, Single Nucleotide, Fluorescence, Frameshift mutation, Genomic disorders and inherited multi-system disorders [IGMD 3], Molecular Genetics, 03 medical and health sciences, Intraflagellar transport, CYTOPLASMIC DYNEIN, medicine, RETROGRADE INTRAFLAGELLAR TRANSPORT, Humans, Polymorphism, 030304 developmental biology, Clinical Genetics, Base Sequence, Genetic heterogeneity, Molecular, DNA, Sequence Analysis, DNA, Human Reproducion Genomic disorders and inherited multi-system disorders [NCEBP 12], medicine.disease, LIGHT INTERMEDIATE CHAIN, Microscopy, Fluorescence, Cytoplasmic Dyneins/chemistry, Genetics and epigenetic pathways of disease Renal disorder [NCMLS 6], PRIMARY CILIARY DYSKINESIA, Genetics and epigenetic pathways of disease Genomic disorders and inherited multi-system disorders [NCMLS 6], CAENORHABDITIS-ELEGANS, 030217 neurology & neurosurgery
Abstract

Contains fulltext : 116495.pdf (Publisher’s version ) (Open Access) BACKGROUND: Jeune asphyxiating thoracic dystrophy (JATD) is a rare, often lethal, recessively inherited chondrodysplasia characterised by shortened ribs and long bones, sometimes accompanied by polydactyly, and renal, liver and retinal disease. Mutations in intraflagellar transport (IFT) genes cause JATD, including the IFT dynein-2 motor subunit gene DYNC2H1. Genetic heterogeneity and the large DYNC2H1 gene size have hindered JATD genetic diagnosis. AIMS AND METHODS: To determine the contribution to JATD we screened DYNC2H1 in 71 JATD patients JATD patients combining SNP mapping, Sanger sequencing and exome sequencing. RESULTS AND CONCLUSIONS: We detected 34 DYNC2H1 mutations in 29/71 (41%) patients from 19/57 families (33%), showing it as a major cause of JATD especially in Northern European patients. This included 13 early protein termination mutations (nonsense/frameshift, deletion, splice site) but no patients carried these in combination, suggesting the human phenotype is at least partly hypomorphic. In addition, 21 missense mutations were distributed across DYNC2H1 and these showed some clustering to functional domains, especially the ATP motor domain. DYNC2H1 patients largely lacked significant extra-skeletal involvement, demonstrating an important genotype-phenotype correlation in JATD. Significant variability exists in the course and severity of the thoracic phenotype, both between affected siblings with identical DYNC2H1 alleles and among individuals with different alleles, which suggests the DYNC2H1 phenotype might be subject to modifier alleles, non-genetic or epigenetic factors. Assessment of fibroblasts from patients showed accumulation of anterograde IFT proteins in the ciliary tips, confirming defects similar to patients with other retrograde IFT machinery mutations, which may be of undervalued potential for diagnostic purposes. 15 p.

Published
2013

35. Epidemiological study of Beckwith Wiedemann syndrome in European population

Author

Odak, Ljubica, Barišić, Ingeborg, Loane, M, Calzolari, E, Garne, E, Wellesley, D, and Dolk, H

Subjects
Beckwith Wiedemann syndrome
Abstract

Beckwith Wiedemann syndrome (BWS) is an overgrowth syndrome characterized by growth disregulation, risk of tumour development and congenital anomalies. In this study we analysed 197 patients registered in EUROCAT network of congenital anomaly registries in 1980-2007 period by monitoring population of 13 546 771 births. The prevalence was 1.45 per 100 000 births. Male to female ratio was 1.3:1. High proportion of patients was diagnosed by prenatal ultrasound examination (70/166 ; 42.1%), 41 patient was discovered at birth (41/166 ; 24.69%) and 55 patients (33.3%) were diagnosed during the first month of life. Most patients were live births (177/197 ; 89.8%), eight were stillbirths (8/166 ; 4.81%), and twelve pregnancies were terminated after prenatal diagnosis (12/70 ; 17.4%) due to heart, kidney or limb anomalies. Seven live births didn’t survive the first week of life (7/177 ; 3.9%). In 148 (75.12 %) of patients major malformations were present, with the hallmarks of the syndrome, omphalocele (54.72% ; 81/148) and macroglossia (52.7% ; 78/148), being the most common. Other associated anomalies were present in 68 (46%) patients: cardiovascular in 20.28 % (30/148), urinary in 17.56% (26/148), limb defects in 9.15% (14/148), and central nervous system malformations and cleft lip in 2.0% (3/148). In thirteen patients more than one congenital anomaly was present. In conclusion, with estimated frequency of 1 in 69930 births, BWS is a rare congenital anomaly disorder, often associated with major congenital anomalies. Pregnancies that are carried out to term mainly result in live births with high survival rate.

Published
2011

37. Congenital anomaly surveillance in England--ascertainment deficiencies in the national system

Author

Boyd, PA, Armstrong, B, Dolk, H, Botting, B, Pattenden, S, Abramsky, L, Rankin, J, Vrijheid, M, and Wellesley, D

Abstract

OBJECTIVE: Firstly, to assess the completeness of ascertainment in the National Congenital Anomaly System (NCAS), the basis for congenital anomaly surveillance in England and Wales, and its variation by defect, geographical area, and socioeconomic deprivation. Secondly, to assess the impact of the lack of data on pregnancies terminated because of fetal anomaly. DESIGN: Comparison of the NCAS with four local congenital anomaly registers in England. SETTING: Four regions in England covering some 109,000 annual births. PARTICIPANTS: Cases of congenital anomalies registered in the NCAS (live births and stillbirths) and independently registered in the four local registers (live births, stillbirths, fetal losses from 20 weeks' gestation, and pregnancies terminated after prenatal diagnosis of fetal anomaly). MAIN OUTCOME MEASURE: The ratio of cases identified by the national register to those in local registry files, calculated for different specified anomalies, for whole registry areas, and for hospital catchment areas within registry boundaries. RESULTS: Ascertainment by the NCAS (compared with data from local registers, from which terminations of pregnancy were removed) was 40% (34% for chromosomal anomalies and 42% for non-chromosomal anomalies) and varied markedly by defect, by local register, and by hospital catchment area, but not by area deprivation. When terminations of pregnancy were included in the register data, ascertainment by NCAS was 27% (19% for chromosomal anomalies and 31% for non-chromosomal anomalies), and the geographical variation was of a similar magnitude. CONCLUSION: The surveillance of congenital anomalies in England is currently inadequate because ascertainment to the national register is low and non-uniform and because no data exist on termination of pregnancy resulting from prenatal diagnosis of fetal anomaly.

Published
2005

39. The European recommendations for primary prevention of congenital anomalies

Author

Taruscio, D., primary, Arriola, L., additional, Baldi, F., additional, Barisic, I., additional, Bermejo-Sánchez, E., additional, Bianchi, F., additional, Calzolari, E., additional, Carbone, P., additional, Curran, R., additional, Garne, E., additional, Gatt, M., additional, Irgens, L., additional, Latos-Bieleńska, A., additional, Khoshnood, B., additional, Mantovani, A., additional, Martínez-Frías, M.L., additional, Neville, A., additional, Rißmann, A., additional, Ruggeri, S., additional, Wellesley, D., additional, and Dolk, H., additional

Published
2014
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42. Exome sequencing identifies DYNC2H1 mutations as a common cause of asphyxiating thoracic dystrophy (Jeune syndrome) without major polydactyly, renal or retinal involvement.

Author

UK10K, Schmidts, M., Arts, H.H., Bongers, E.M., Yap, Z., Oud, M.M., Antony, D., Duijkers, L., Emes, R.D., Stalker, J., Yntema, J.B., Plagnol, V., Hoischen, A., Gilissen, C., Forsythe, E., Lausch, E., Veltman, J.A., Roeleveld, N., Superti-Furga, A., Kutkowska-Kazmierczak, A., Kamsteeg, E.J., Elçioglu, N., van Maarle, M.C., Graul-Neumann, L.M., Devriendt, K., Smithson, S.F., Wellesley, D., Verbeek, N.E., Hennekam, R.C., Kayserili, H., Scambler, P.J., Beales, P.L., Knoers, N.V., Roepman, R., Mitchison, H.M., UK10K, Schmidts, M., Arts, H.H., Bongers, E.M., Yap, Z., Oud, M.M., Antony, D., Duijkers, L., Emes, R.D., Stalker, J., Yntema, J.B., Plagnol, V., Hoischen, A., Gilissen, C., Forsythe, E., Lausch, E., Veltman, J.A., Roeleveld, N., Superti-Furga, A., Kutkowska-Kazmierczak, A., Kamsteeg, E.J., Elçioglu, N., van Maarle, M.C., Graul-Neumann, L.M., Devriendt, K., Smithson, S.F., Wellesley, D., Verbeek, N.E., Hennekam, R.C., Kayserili, H., Scambler, P.J., Beales, P.L., Knoers, N.V., Roepman, R., and Mitchison, H.M.

Abstract

BACKGROUND: Jeune asphyxiating thoracic dystrophy (JATD) is a rare, often lethal, recessively inherited chondrodysplasia characterised by shortened ribs and long bones, sometimes accompanied by polydactyly, and renal, liver and retinal disease. Mutations in intraflagellar transport (IFT) genes cause JATD, including the IFT dynein-2 motor subunit gene DYNC2H1. Genetic heterogeneity and the large DYNC2H1 gene size have hindered JATD genetic diagnosis. AIMS AND METHODS: To determine the contribution to JATD we screened DYNC2H1 in 71 JATD patients JATD patients combining SNP mapping, Sanger sequencing and exome sequencing. RESULTS AND CONCLUSIONS: We detected 34 DYNC2H1 mutations in 29/71 (41%) patients from 19/57 families (33%), showing it as a major cause of JATD especially in Northern European patients. This included 13 early protein termination mutations (nonsense/frameshift, deletion, splice site) but no patients carried these in combination, suggesting the human phenotype is at least partly hypomorphic. In addition, 21 missense mutations were distributed across DYNC2H1 and these showed some clustering to functional domains, especially the ATP motor domain. DYNC2H1 patients largely lacked significant extra-skeletal involvement, demonstrating an important genotype-phenotype correlation in JATD. Significant variability exists in the course and severity of the thoracic phenotype, both between affected siblings with identical DYNC2H1 alleles and among individuals with different alleles, which suggests the DYNC2H1 phenotype might be subject to modifier alleles, non-genetic or epigenetic factors. Assessment of fibroblasts from patients showed accumulation of anterograde IFT proteins in the ciliary tips, confirming defects similar to patients with other retrograde IFT machinery mutations, which may be of undervalued potential for diagnostic purposes.

Published
2013

47. Prevention of neural tube defects in the UK: a missed opportunity.

Author

Morris, J. K., Rankin, J., Draper, E. S., Kurinczuk, J. J., Springett, A., Tucker, D., Wellesley, D., Wreyford, B., and Wald, N. J.

Subjects
NEURAL tube defects, PREGNANCY complications
Abstract

Objective In 1991, the Medical Research Council (MRC) Vitamin Study demonstrated that folic acid taken before pregnancy and in early pregnancy reduced the risk of a neural tube defect (NTD). We aimed to estimate the number of NTD pregnancies that would have been prevented if flour had been fortified with folic acid in the UK from 1998 as it had been in the USA. Design Estimates of NTD prevalence, the preventive effect of folic acid and the proportion of women taking folic acid supplements before pregnancy were used to predict the number of NTD pregnancies that would have been prevented if folic acid fortification had been implemented. Setting Eight congenital anomaly registers in England and Wales. Main outcome measures The prevalence of pregnancies with an NTD in the UK and the number of these pregnancies that would have been prevented if folic acid fortification had been implemented. Results From 1991 to 2012, the prevalence of NTD pregnancies was 1.28 (95% CI 1.24 to 1.31) per 1000 total births (19% live births, 81% terminations and 0.5% stillbirths and fetal deaths =20 weeks' gestation). If the USA levels of folic acid fortification from 1998 onwards had been adopted in the UK, an estimated 2014 fewer NTD pregnancies would have occurred. Conclusions Failure to implement folic acid fortification in the UK has caused, and continues to cause, avoidable terminations of pregnancy, stillbirths, neonatal deaths and permanent serious disability in surviving children. [ABSTRACT FROM AUTHOR]

Published
2016
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