Author: "Newbury-Ecob R" - Searchworks@Jio Institute Digital Library Search Results

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234 results on '"Newbury-Ecob R"'

1. De novo variants in CNOT3 cause a variable neurodevelopmental disorder

Author: Martin, R., Splitt, M., Genevieve, D., Aten, E., Collins, A., de Bie, C. I., Faivre, L., Foulds, N., Giltay, J., Ibitoye, R., Joss, S., Kennedy, J., Kerr, B., Kivuva, E., Koopmans, M., Newbury-Ecob, R., Jean-Marçais, N., Peeters, E. A. J., Smithson, S., Tomkins, S., Tranmauthem, F., Piton, A., and van Haeringen, A.
Published: 2019
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2. Expanding the phenotype of ASXL3-related syndrome: A comprehensive description of 45 unpublished individuals with inherited and de novo pathogenic variants in ASXL3

Author: Schirwani, S., Albaba, S., Carere, D.A., Sacoto, M.J. Guillen, Zamora, F. Milan, Si, Y., Rabin, R., Pappas, J., Renaud, D.L., Hauser, N., Reid, E., Blanchet, P., Foulds, N., Dixit, A., Fisher, R., Armstrong, R., Isidor, B., Cogne, B., Vergano, S. Schrier, Demirdas, S., Dykzeul, N., Cohen, J.S., Grand, K., Morel, D., Slavotinek, A., Albassam, H.F., Naik, S., Dean, J., Ragge, N., Cinzia, C., Tedesco, M.G., Harrison, R.E., Bouman, A., Palen, E., Challman, T.D., Willemsen, M.H., Vogt, J., Cunniff, C., Bergstrom, K., Walia, J.S., Bruel, A.L., Kini, U., Alkuraya, F.S., Slegesky, V., Meeks, N., Girotto, P., Johnson, D., Newbury-Ecob, R., Ockeloen, C.W., Prontera, P., Lynch, S.A., Li, D., Graham, J.M., Balasubramanian, M., and Clinical Genetics
Subjects: Adult, Male, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Adolescent, Hypertelorism, Developmental Disabilities, speech impairment, Genetic Variation, ASXL3, BRPS, Young Adult, Phenotype, ASXL3-related syndrome, Bainbridge–Ropers syndrome, Neurodevelopmental Disorders, intellectual disability, Child, Preschool, Mutation, Humans, Muscle Hypotonia, Female, Genetic Predisposition to Disease, Child, Transcription Factors
Abstract: Item does not contain fulltext The study aimed at widening the clinical and genetic spectrum of ASXL3-related syndrome, a neurodevelopmental disorder, caused by truncating variants in the ASXL3 gene. In this international collaborative study, we have undertaken a detailed clinical and molecular analysis of 45 previously unpublished individuals with ASXL3-related syndrome, as well as a review of all previously published individuals. We have reviewed the rather limited functional characterization of pathogenic variants in ASXL3 and discuss current understanding of the consequences of the different ASXL3 variants. In this comprehensive analysis of ASXL3-related syndrome, we define its natural history and clinical evolution occurring with age. We report familial ASXL3 pathogenic variants, characterize the phenotype in mildly affected individuals and discuss nonpenetrance. We also discuss the role of missense variants in ASXL3. We delineate a variable but consistent phenotype. The most characteristic features are neurodevelopmental delay with consistently limited speech, significant neuro-behavioral issues, hypotonia, and feeding difficulties. Distinctive features include downslanting palpebral fissures, hypertelorism, tubular nose with a prominent nasal bridge, and low-hanging columella. The presented data will inform clinical management of individuals with ASXL3-related syndrome and improve interpretation of new ASXL3 sequence variants.
Published: 2021

3. Expanding the genotypic spectrum of Perrault syndrome

Author: Demain, L.A.M., Urquhart, J.E., OʼSullivan, J., Williams, S.G., Bhaskar, S.S., Jenkinson, E.M., Lourenco, C.M., Heiberg, A., Pearce, S.H., Shalev, S.A., Yue, W.W., Mackinnon, S., Munro, K.J., Newbury‐Ecob, R., Becker, K., Kim, M.J., Oʼ Keefe, R.T., and Newman, W.G.
Published: 2017
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4. 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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5. Comprehensive study of 28 individuals with SIN3A-related disorder underscoring the associated mild cognitive and distinctive facial phenotype

Author: Balasubramanian, M., Dingemans, A.J.M., Albaba, S., Richardson, R., Yates, T.M., Cox, H., Douzgou, S., Armstrong, R., Sansbury, F.H., Burke, K.B., Fry, A.E., Ragge, N., Sharif, S., Foster, A., Sandre-Giovannoli, A. De, Elouej, S., Vasudevan, P., Mansour, S., Wilson, K., Stewart, H., Heide, S. van der, Nava, C., Keren, B., Demirdas, S., Brooks, A.S., Vincent, M., Isidor, B., Küry, S., Schouten, M.I., Leenders, E.K.S.M., Chung, W.K., Haeringen, A.V., Scheffner, T., Debray, F.G., White, S.M., Palafoll, M.I.V., Pfundt, R.P., Newbury-Ecob, R., Kleefstra, T., Balasubramanian, M., Dingemans, A.J.M., Albaba, S., Richardson, R., Yates, T.M., Cox, H., Douzgou, S., Armstrong, R., Sansbury, F.H., Burke, K.B., Fry, A.E., Ragge, N., Sharif, S., Foster, A., Sandre-Giovannoli, A. De, Elouej, S., Vasudevan, P., Mansour, S., Wilson, K., Stewart, H., Heide, S. van der, Nava, C., Keren, B., Demirdas, S., Brooks, A.S., Vincent, M., Isidor, B., Küry, S., Schouten, M.I., Leenders, E.K.S.M., Chung, W.K., Haeringen, A.V., Scheffner, T., Debray, F.G., White, S.M., Palafoll, M.I.V., Pfundt, R.P., Newbury-Ecob, R., and Kleefstra, T.
Abstract: Contains fulltext : 245024.pdf (Publisher’s version ) (Open Access), Witteveen-Kolk syndrome (OMIM 613406) is a recently defined neurodevelopmental syndrome caused by heterozygous loss-of-function variants in SIN3A. We define the clinical and neurodevelopmental phenotypes related to SIN3A-haploinsufficiency in 28 unreported patients. Patients with SIN3A variants adversely affecting protein function have mild intellectual disability, growth and feeding difficulties. Involvement of a multidisciplinary team including a geneticist, paediatrician and neurologist should be considered in managing these patients. Patients described here were identified through a combination of clinical evaluation and gene matching strategies (GeneMatcher and Decipher). All patients consented to participate in this study. Mean age of this cohort was 8.2 years (17 males, 11 females). Out of 16 patients ≥ 8 years old assessed, eight (50%) had mild intellectual disability (ID), four had moderate ID (22%), and one had severe ID (6%). Four (25%) did not have any cognitive impairment. Other neurological symptoms such as seizures (4/28) and hypotonia (12/28) were common. Behaviour problems were reported in a minority. In patients ≥2 years, three were diagnosed with Autism Spectrum Disorder (ASD) and four with Attention Deficit Hyperactivity Disorder (ADHD). We report 27 novel variants and one previously reported variant. 24 were truncating variants; three were missense variants and one large in-frame gain including exons 10-12.
Published: 2021

6. Mutation-specific pathophysiological mechanisms define different neurodevelopmental disorders associated with SATB1 dysfunction

Author: Hoed, J. den, Boer, E. de, Voisin, N., Dingemans, A.J.M., Guex, N., Wiel, L.J.M. van de, Nellaker, C., Amudhavalli, S.M., Banka, S., Bena, F.S., Ben-Zeev, B., Bonagura, V.R., Bruel, A.L., Brunet, T., Brunner, H.G., Chew, H.B., Chrast, J., Cimbalistienė, L., Coon, H., Délot, E.C., Démurger, F., Denommé-Pichon, A.S., Depienne, C., Donnai, D., Dyment, D.A., Elpeleg, O., Faivre, L., Gilissen, C.F., Granger, L., Haber, B., Hachiya, Y., Abedi, Y.H., Hanebeck, J., Hehir-Kwa, J.Y., Horist, B., Itai, T., Jackson, A., Jewell, R., Jones, K.L., Joss, S., Kashii, H., Kato, M., Kattentidt-Mouravieva, A.A., Kok, F., Kotzaeridou, U., Krishnamurthy, V., Kučinskas, V., Kuechler, A., Lavillaureix, A., Liu, P, Manwaring, L., Matsumoto, N., Mazel, B., McWalter, K., Meiner, V., Mikati, M.A., Miyatake, S., Mizuguchi, T., Moey, L.H., Mohammed, S, Mor-Shaked, H., Mountford, H., Newbury-Ecob, R., Odent, S., Orec, L., Osmond, M., Palculict, T.B., Parker, M., Petersen, A.K., Pfundt, R.P., Preikšaitienė, E., Radtke, K., Ranza, E., Rosenfeld, J.A., Santiago-Sim, T., Schwager, C., Sinnema, M., Snijders Blok, L., Spillmann, R.C., Stegmann, A.P.A., Thiffault, I., Tran, L., Vaknin-Dembinsky, A., Vedovato-Dos-Santos, J.H., Schrier Vergano, S.A., Vilain, E., Vitobello, A., Wagner, M., Waheeb, A., Willing, M., Zuccarelli, B., Kini, U., Newbury, D.F., Kleefstra, T., Reymond, A., Fisher, S.E., Vissers, L.E.L.M., Hoed, J. den, Boer, E. de, Voisin, N., Dingemans, A.J.M., Guex, N., Wiel, L.J.M. van de, Nellaker, C., Amudhavalli, S.M., Banka, S., Bena, F.S., Ben-Zeev, B., Bonagura, V.R., Bruel, A.L., Brunet, T., Brunner, H.G., Chew, H.B., Chrast, J., Cimbalistienė, L., Coon, H., Délot, E.C., Démurger, F., Denommé-Pichon, A.S., Depienne, C., Donnai, D., Dyment, D.A., Elpeleg, O., Faivre, L., Gilissen, C.F., Granger, L., Haber, B., Hachiya, Y., Abedi, Y.H., Hanebeck, J., Hehir-Kwa, J.Y., Horist, B., Itai, T., Jackson, A., Jewell, R., Jones, K.L., Joss, S., Kashii, H., Kato, M., Kattentidt-Mouravieva, A.A., Kok, F., Kotzaeridou, U., Krishnamurthy, V., Kučinskas, V., Kuechler, A., Lavillaureix, A., Liu, P, Manwaring, L., Matsumoto, N., Mazel, B., McWalter, K., Meiner, V., Mikati, M.A., Miyatake, S., Mizuguchi, T., Moey, L.H., Mohammed, S, Mor-Shaked, H., Mountford, H., Newbury-Ecob, R., Odent, S., Orec, L., Osmond, M., Palculict, T.B., Parker, M., Petersen, A.K., Pfundt, R.P., Preikšaitienė, E., Radtke, K., Ranza, E., Rosenfeld, J.A., Santiago-Sim, T., Schwager, C., Sinnema, M., Snijders Blok, L., Spillmann, R.C., Stegmann, A.P.A., Thiffault, I., Tran, L., Vaknin-Dembinsky, A., Vedovato-Dos-Santos, J.H., Schrier Vergano, S.A., Vilain, E., Vitobello, A., Wagner, M., Waheeb, A., Willing, M., Zuccarelli, B., Kini, U., Newbury, D.F., Kleefstra, T., Reymond, A., Fisher, S.E., and Vissers, L.E.L.M.
Abstract: Contains fulltext : 231687.pdf (Publisher’s version ) (Closed access), Whereas large-scale statistical analyses can robustly identify disease-gene relationships, they do not accurately capture genotype-phenotype correlations or disease mechanisms. We use multiple lines of independent evidence to show that different variant types in a single gene, SATB1, cause clinically overlapping but distinct neurodevelopmental disorders. Clinical evaluation of 42 individuals carrying SATB1 variants identified overt genotype-phenotype relationships, associated with different pathophysiological mechanisms, established by functional assays. Missense variants in the CUT1 and CUT2 DNA-binding domains result in stronger chromatin binding, increased transcriptional repression, and a severe phenotype. In contrast, variants predicted to result in haploinsufficiency are associated with a milder clinical presentation. A similarly mild phenotype is observed for individuals with premature protein truncating variants that escape nonsense-mediated decay, which are transcriptionally active but mislocalized in the cell. Our results suggest that in-depth mutation-specific genotype-phenotype studies are essential to capture full disease complexity and to explain phenotypic variability.
Published: 2021

7. Comprehensive study of 28 individuals with SIN3A-related disorder underscoring the associated mild cognitive and distinctive facial phenotype

Author: Balasubramanian, M. (Meena), Dingemans, A.J.M. (Alexander J. M.), Albaba, S. (Shadi), Richardson, R. (Ruth), Yates, T.M. (Thabo M.), Cox, H. (H.), Douzgou, S. (Sofia), Armstrong, R. (Ruth), Sansbury, F.H. (Francis H.), Burke, K.B. (Katherine B.), Fry, A.E. (Andrew E.), Ragge, N. (Nicola), Sharif, S. (Saba), Foster, A. (Alison), Sandre-Giovannoli, A. (Annachiara) de, Elouej, S. (Sahar), Vasudevan, P. (Pradeep), Mansour, S. (Sahar), Wilson, K. (Kate), Stewart, H. (Helen), Heide, S. (Solveig), Nava, C. (Caroline), Keren, B. (Boris), Demirdas, S. (Serwet), Brooks, A.S. (Alice S.), Vincent, M. (Marie), Isidor, B. (Bertrand), Küry, S. (Sebastien), Schouten, M. (Meyke), Leenders, E. (Erika), Chung, W. (Wendy), Haeringen, A. (Arie van), Scheffner, T. (Thomas), Debray, F.-G. (Francois-Guillaume), White, S.M. (Susan M.), Palafoll, M.I.V. (Maria Irene Valenzuela), Pfundt, R. (Rolph), Newbury-Ecob, R. (Ruth), Kleefstra, T. (Tjitske), Balasubramanian, M. (Meena), Dingemans, A.J.M. (Alexander J. M.), Albaba, S. (Shadi), Richardson, R. (Ruth), Yates, T.M. (Thabo M.), Cox, H. (H.), Douzgou, S. (Sofia), Armstrong, R. (Ruth), Sansbury, F.H. (Francis H.), Burke, K.B. (Katherine B.), Fry, A.E. (Andrew E.), Ragge, N. (Nicola), Sharif, S. (Saba), Foster, A. (Alison), Sandre-Giovannoli, A. (Annachiara) de, Elouej, S. (Sahar), Vasudevan, P. (Pradeep), Mansour, S. (Sahar), Wilson, K. (Kate), Stewart, H. (Helen), Heide, S. (Solveig), Nava, C. (Caroline), Keren, B. (Boris), Demirdas, S. (Serwet), Brooks, A.S. (Alice S.), Vincent, M. (Marie), Isidor, B. (Bertrand), Küry, S. (Sebastien), Schouten, M. (Meyke), Leenders, E. (Erika), Chung, W. (Wendy), Haeringen, A. (Arie van), Scheffner, T. (Thomas), Debray, F.-G. (Francois-Guillaume), White, S.M. (Susan M.), Palafoll, M.I.V. (Maria Irene Valenzuela), Pfundt, R. (Rolph), Newbury-Ecob, R. (Ruth), and Kleefstra, T. (Tjitske)
Abstract: Witteveen-Kolk syndrome (OMIM 613406) is a recently defined neurodevelopmental syndrome caused by heterozygous loss-of-function variants in SIN3A. We define the clinical and neurodevelopmental phenotypes related to SIN3A-haploinsufficiency in 28 unreported patients. Patients with SIN3A variants adversely affecting protein function have mild intellectual disability, growth and feeding difficulties. Involvement of a multidisciplinary team including a geneticist, paediatrician and neurologist should be considered in managing these patients. Patients described here were identified through a combination of clinical evaluation and gene matching strategies (GeneMatcher and Decipher). All patients consented to participate in this study. Mean age of this cohort was 8.2 years (17 males, 11 females). Out of 16 patients ≥ 8 years old assessed, eight (50%) had mild intellectual disability (ID), four had moderate ID (22%), and one had severe ID (6%). Four (25%) did not have any cognitive impairment. Other neurological symptoms such as seizures (4/28) and hypotonia (12/28) were common. Behaviour problems were reported in a minority. In patients ≥2 years, three were diagnosed with Autism Spectrum Disorder (ASD) and four with Attention Deficit Hyperactivity Disorder (ADHD). We report 27 novel variants and one previously reported variant. 24 were truncating variants; three were missense variants and one large in-frame gain including exons 10–12.
Published: 2021
Full Text: View/download PDF

8. Comprehensive study of 28 individuals with SIN3A-related disorder underscoring the associated mild cognitive and distinctive facial phenotype

Author: Balasubramanian, M, Dingemans, AJM, Albaba, S, Richardson, R, Yates, TM, Cox, H, Douzgou, S, Armstrong, R, Sansbury, FH, Burke, KB, Fry, AE, Ragge, N, Sharif, S, Foster, A, De Sandre-Giovannoli, A, Elouej, S, Vasudevan, P, Mansour, S, Wilson, K, Stewart, H, Heide, S, Nava, C, Keren, B, Demirdas, S, Brooks, AS, Vincent, M, Isidor, B, Kury, S, Schouten, M, Leenders, E, Chung, WK, Haeringen, AV, Scheffner, T, Debray, F-G, White, SM, Palafoll, MIV, Pfundt, R, Newbury-Ecob, R, Kleefstra, T, Balasubramanian, M, Dingemans, AJM, Albaba, S, Richardson, R, Yates, TM, Cox, H, Douzgou, S, Armstrong, R, Sansbury, FH, Burke, KB, Fry, AE, Ragge, N, Sharif, S, Foster, A, De Sandre-Giovannoli, A, Elouej, S, Vasudevan, P, Mansour, S, Wilson, K, Stewart, H, Heide, S, Nava, C, Keren, B, Demirdas, S, Brooks, AS, Vincent, M, Isidor, B, Kury, S, Schouten, M, Leenders, E, Chung, WK, Haeringen, AV, Scheffner, T, Debray, F-G, White, SM, Palafoll, MIV, Pfundt, R, Newbury-Ecob, R, and Kleefstra, T
Abstract: Witteveen-Kolk syndrome (OMIM 613406) is a recently defined neurodevelopmental syndrome caused by heterozygous loss-of-function variants in SIN3A. We define the clinical and neurodevelopmental phenotypes related to SIN3A-haploinsufficiency in 28 unreported patients. Patients with SIN3A variants adversely affecting protein function have mild intellectual disability, growth and feeding difficulties. Involvement of a multidisciplinary team including a geneticist, paediatrician and neurologist should be considered in managing these patients. Patients described here were identified through a combination of clinical evaluation and gene matching strategies (GeneMatcher and Decipher). All patients consented to participate in this study. Mean age of this cohort was 8.2 years (17 males, 11 females). Out of 16 patients ≥ 8 years old assessed, eight (50%) had mild intellectual disability (ID), four had moderate ID (22%), and one had severe ID (6%). Four (25%) did not have any cognitive impairment. Other neurological symptoms such as seizures (4/28) and hypotonia (12/28) were common. Behaviour problems were reported in a minority. In patients ≥2 years, three were diagnosed with Autism Spectrum Disorder (ASD) and four with Attention Deficit Hyperactivity Disorder (ADHD). We report 27 novel variants and one previously reported variant. 24 were truncating variants; three were missense variants and one large in-frame gain including exons 10-12.
Published: 2021

9. Comprehensive study of 28 individuals with SIN3A-related disorder underscoring the associated mild cognitive and distinctive facial phenotype

Author: Balasubramanian M, Dingemans AJM, lbaba S, Richardson R, Yates TM, Cox H, Douzgou S, Armstrong R, Sansbury FH, Burke KB, Fry AE, Ragge N, Sharif S, Foster A, De Sandre-Giovannoli A, Elouej S, Vasudevan P, Mansour S, Wilson K, Stewart H, Heide S, Nava C, Keren B, Demirdas S, Brooks AS, Vincent M, Isidor B, Küry S, Schouten M, Leenders E, Chung WK, van Haeringen A, Scheffner T, Debray F, White SM, Valenzuela Palafoll MI, Pfundt R, Newbury-Ecob R, Kleefstra T, Balasubramanian M, Dingemans AJM, lbaba S, Richardson R, Yates TM, Cox H, Douzgou S, Armstrong R, Sansbury FH, Burke KB, Fry AE, Ragge N, Sharif S, Foster A, De Sandre-Giovannoli A, Elouej S, Vasudevan P, Mansour S, Wilson K, Stewart H, Heide S, Nava C, Keren B, Demirdas S, Brooks AS, Vincent M, Isidor B, Küry S, Schouten M, Leenders E, Chung WK, van Haeringen A, Scheffner T, Debray F, White SM, Valenzuela Palafoll MI, Pfundt R, Newbury-Ecob R, and Kleefstra T
Abstract: Witteveen-Kolk syndrome (OMIM 613406) is a recently defined neurodevelopmental syndrome caused by heterozygous loss-of-function variants in SIN3A. We define the clinical and neurodevelopmental phenotypes related to SIN3A-haploinsufficiency in 28 unreported patients. Patients with SIN3A variants adversely affecting protein function have mild intellectual disability, growth and feeding difficulties. Involvement of a multidisciplinary team including a geneticist, pediatrician and neurologist should be considered in managing these patients. Patients described here were identified through a combination of clinical evaluation and gene matching strategies (GeneMatcher and Decipher). All patients consented to participate in this study. Mean age of this cohort was 8.2 years (17 males, 11 females). Out of 16 patients ≥ eight years old assessed, eight (50%) had mild intellectual disability (ID), four had moderate ID (22%), and one had severe ID (6%). Four (25%) did not have any cognitive impairment. Other neurological symptoms such as seizures (4/28) and hypotonia (12/28) were common. Behaviour problems were reported in a minority. In patients ≥2 years, three were diagnosed with Autism Spectrum Disorder (ASD) and four with Attention Deficit Hyperactivity Disorder (ADHD). We report 27 novel variants and one previously reported variant. 24 were truncating variants; three were missense variants and one large in-frame gain including exons 10-12.
Published: 2021

10. KAT6A Syndrome

Author: Kennedy, J., Goudie, D., Blair, E., Chandler, K., Joss, S., McKay, V., Green, A., Armstrong, R., Lees, M., Kamien, B., Hopper, B., Tan, T.Y., Yap, P., Stark, Z., Okamoto, N., Miyake, N., Matsumoto, N., Macnamara, E., Murphy, J.L., McCormick, E., Hakonarson, H., Falk, M.J., Li, D., Blackburn, P., Klee, E., Babovic-Vuksanovic, D., Schelley, S., Hudgins, L., Kant, S., Isidor, B., Cogne, B., Bradbury, K., Williams, M., Patel, C., Heussler, H., Duff-Farrier, C., Lakeman, P., Scurr, I., Kini, U., Elting, M., Reijnders, M., Schuurs-Hoeijmakers, J., Wafik, M., Blomhoff, A., Ruivenkamp, C.A.L., Nibbeling, E., Dingemans, A.J.M., Douine, E.D., Nelson, S.F., Hempel, M., Bierhals, T., Lessel, D., Johannsen, J., Arboleda, V.A., Newbury-Ecob, R., and DDD Study
Abstract: An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Published: 2020

11. Mutation-specific pathophysiological mechanisms in a new SATB1-associated neurodevelopmental disorder

Author: den Hoed, J., De Boer, E., Voisin, N., Guex, N., Blok, L. Snijders, Chrast, J., Manwaring, L., Willing, M., Waheeb, A., Osmond, M., McWalter, K., Vitobello, A., Demurger, F., Lavillaureix, A., Odent, S., Mazel, B., Faivre, L., Thiffault, I., Schwager, C., Amudhavalli, S. M., Rosenfeld, J. A., Radtke, K., Preiksaitiene, E., Ranza, E., Depienne, C., Kuechler, A., Mohammed, S., Abedi, Y. Hamzavi, Bonagura, V. R., Zuccarelli, B., Horist, B., Krishnamurthy, V., Kattentidt-Mouravieva, A. A., Granger, L., Petersen, A., Jones, K. L., Sinnema, M., Stegmann, A. P. A., Newbury-Ecob, R., Kini, U., Newbury, D. F., Gilissen, C., Brunner, H., Kleefstra, T., Reymond, A., Vissers, L. E. L. M., Fisher, S. E., Donders Institute for Brain, Cognition and Behaviour, Radboud university [Nijmegen], Université de Lausanne (UNIL), Washington University in Saint Louis (WUSTL), GeneDx [Gaithersburg, MD, USA], Université Bourgogne Franche-Comté [COMUE] (UBFC), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Groupe Hospitalier Bretagne Sud (GHBS), Institut de Génétique et Développement de Rennes (IGDR), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Ambry Genetics [Aliso Viejo, CA, USA], University of Kansas [Lawrence] (KU), Maastricht University [Maastricht], Radboud University [Nijmegen], Université de Lausanne = University of Lausanne (UNIL), and Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )
Subjects: [SDV]Life Sciences [q-bio], ComputingMilieux_MISCELLANEOUS
Abstract: International audience
Published: 2020

12. Thrombocytopenia with Absent Radii (TAR) syndrome is cause by compound inheritance of low-frequency regulatory SNPs and a rare null mutation in exon-junction complex subunit RBM8A: 18

Author: Albers, C A, Paul, D S, Schulze, H, Freson, K, Stephens, J C, Smethurst, P A, Jolley, J D, Cvejic, A, Kostadima, M, Bertone, P, Breuning, M H, Debili, N, Deloukas, P, Favier, R, Fiedler, J, Hobbs, C M, Huang, N, Hurles, M E, Kiddle, G, Krapels, I, Nurden, P, Ruivenkamp, C AL, Sambrook, J G, Smith, K, Stemple, D L, Strauss, G, Thys, C, van Geet, C, Newbury-Ecob, R, Ouwehand, W H, and Ghevaert, C
Published: 2012

13. Barth syndrome: an X-linked cause of fetal cardiomyopathy and stillbirth

Author: Steward, C. G., Newbury-Ecob, R. A., Hastings, R., Smithson, S. F., Tsai-Goodman, B., Quarrell, O. W., Kulik, W., Wanders, R., Pennock, M., Williams, M., Cresswell, J. L., Gonzalez, I. L., and Brennan, P.
Published: 2010
Full Text: View/download PDF

14. Delineation of dominant and recessive forms of LZTR1‐associated Noonan syndrome

Author: Pagnamenta, A, Kaisaki, P, Bennett, F, Burkitt-Wright, E, Martin, H, Ferla, M, Taylor, J, Gompertz, L, Lahiri, N, Tatton-Brown, K, Newbury-Ecob, R, Henderson, A, Joss, S, Weber, A, Carmichael, J, Turnpenny, P, McKee, S, Forzano, F, Ashraf, T, Bradbury, K, Shears, D, Kini, U, De Burca, A, Study, The DDD, Blair, E, and Stewart, H
Subjects: Male, Heterozygote, Adolescent, Infant, Genes, Recessive, Original Articles, Pedigree, Cohort Studies, Gene Ontology, Phenotype, Child, Preschool, Mutation, RAS‐MAPK signalling, Humans, Noonan syndrome, Female, Original Article, Exome, LZTR1, Child, Alleles, developmental disorder, Transcription Factors, Genes, Dominant
Abstract: Noonan syndrome (NS) is characterised by distinctive facial features, heart defects, variable degrees of intellectual disability and other phenotypic manifestations. Although the mode of inheritance is typically dominant, recent studies indicate LZTR1 may be associated with both dominant and recessive forms. Seeking to describe the phenotypic characteristics of LZTR1‐associated NS, we searched for likely pathogenic variants using two approaches. First, scrutiny of exomes from 9624 patients recruited by the Deciphering Developmental Disorders (DDDs) study uncovered six dominantly‐acting mutations (p.R97L; p.Y136C; p.Y136H, p.N145I, p.S244C; p.G248R) of which five arose de novo, and three patients with compound‐heterozygous variants (p.R210*/p.V579M; p.R210*/p.D531N; c.1149+1G>T/p.R688C). One patient also had biallelic loss‐of‐function mutations in NEB, consistent with a composite phenotype. After removing this complex case, analysis of human phenotype ontology terms indicated significant phenotypic similarities (P = 0.0005), supporting a causal role for LZTR1. Second, targeted sequencing of eight unsolved NS‐like cases identified biallelic LZTR1 variants in three further subjects (p.W469*/p.Y749C, p.W437*/c.‐38T>A and p.A461D/p.I462T). Our study strengthens the association of LZTR1 with NS, with de novo mutations clustering around the KT1‐4 domains. Although LZTR1 variants explain ~0.1% of cases across the DDD cohort, the gene is a relatively common cause of unsolved NS cases where recessive inheritance is suspected.
Published: 2019

15. CDKL5 mutations cause infantile spasms, early onset seizures, and severe mental retardation in female patients

Author: Archer, H L, Evans, J, Edwards, S, Colley, J, Newbury-Ecob, R, O’Callaghan, F, Huyton, M, O’Regan, M, Tolmie, J, Sampson, J, Clarke, A, and Osborne, J
Published: 2006

16. The importance of seeking ALMS1 mutations in infants with dilated cardiomyopathy

Author: Bond, J, Flintoff, K, Higgins, J, Scott, S, Bennet, C, Parsons, J, Mannon, J, Jafri, H, Rashid, Y, Barrow, M, Trembath, R, Woodruff, G, Rossa, E, Lynch, S, Sheilds, J, Newbury-Ecob, R, Falconer, A, Holland, P, Cockburn, D, Karbani, G, Malik, S, Ahmed, M, Roberts, E, Taylor, G, and Woods, C G
Published: 2005

17. Growth disrupting mutations in epigenetic regulatory molecules are associated with abnormalities of epigenetic aging.

Author: Mill J., Yachelevich N., Tatton-Brown K., Crosby A.H., Hunter M.F., Baple E.L., Jeffries A.R., Maroofian R., Salter C.G., Chioza B.A., Cross H.E., Patton M.A., Dempster E., Karen Temple I., Mackay D.J.G., Rezwan F.I., Aksglaede L., Baralle D., Dabir T., Kamath A., Kumar A., Newbury-Ecob R., Selicorni A., Springer A., Van Maldergem L., Varghese V., Mill J., Yachelevich N., Tatton-Brown K., Crosby A.H., Hunter M.F., Baple E.L., Jeffries A.R., Maroofian R., Salter C.G., Chioza B.A., Cross H.E., Patton M.A., Dempster E., Karen Temple I., Mackay D.J.G., Rezwan F.I., Aksglaede L., Baralle D., Dabir T., Kamath A., Kumar A., Newbury-Ecob R., Selicorni A., Springer A., Van Maldergem L., and Varghese V.
Abstract: Germline mutations in fundamental epigenetic regulatory molecules including DNA methyltransferase 3 alpha (DNMT3A) are commonly associated with growth disorders, whereas somatic mutations are often associated with malignancy. We profiled genome-wide DNA methylation patterns in DNMT3A c.2312G > A; p.(Arg771Gln) carriers in a large Amish sibship with Tatton-Brown-Rahman syndrome (TBRS), their mosaic father, and 15 TBRS patients with distinct pathogenic de novo DNMT3A variants. This defined widespread DNA hypomethylation at specific genomic sites enriched at locations annotated as genes involved in morphogenesis, development, differentiation, and malignancy predisposition pathways. TBRS patients also displayed highly accelerated DNA methylation aging. These findings were most marked in a carrier of the AML-associated driver mutation p.Arg882Cys. Our studies additionally defined phenotype-related accelerated and decelerated epigenetic aging in two histone methyltransferase disorders: NSD1 Sotos syndrome overgrowth disorder and KMT2D Kabuki syndrome growth impairment. Together, our findings provide fundamental new insights into aberrant epigenetic mechanisms, the role of epigenetic machinery maintenance, and determinants of biological aging in these growth disorders.Copyright © 2019 Jeffries et al. This article, published in Genome Research, is available under a Creative Commons License (Attribution 4.0 International), as described at http://creativecommons.org/licenses/by/4.0/.
Published: 2019

18. De novo variants in CNOT3 cause a variable neurodevelopmental disorder

Author: Sectie Morfologie/CMC, Genetica Klinische Genetica, Child Health, Martin, R., Splitt, M., Genevieve, D., Aten, E., Collins, A., de Bie, C. I., Faivre, L., Foulds, N., Giltay, J., Ibitoye, R., Joss, S., Kennedy, J., Kerr, B., Kivuva, E., Koopmans, M., Newbury-Ecob, R., Jean-Marçais, N., Peeters, E. A.J., Smithson, S., Tomkins, S., Tranmauthem, F., Piton, A., van Haeringen, A., Sectie Morfologie/CMC, Genetica Klinische Genetica, Child Health, Martin, R., Splitt, M., Genevieve, D., Aten, E., Collins, A., de Bie, C. I., Faivre, L., Foulds, N., Giltay, J., Ibitoye, R., Joss, S., Kennedy, J., Kerr, B., Kivuva, E., Koopmans, M., Newbury-Ecob, R., Jean-Marçais, N., Peeters, E. A.J., Smithson, S., Tomkins, S., Tranmauthem, F., Piton, A., and van Haeringen, A.
Published: 2019

19. Mutations at the SALL4 locus on chromosome 20 result in a range of clinically overlapping phenotypes, including Okihiro syndrome, Holt-Oram syndrome, acro-renal-ocular syndrome, and patients previously reported to represent thalidomide embryopathy

Author: Kohlhase, J, Schubert, L, Liebers, M, Rauch, A, Becker, K, Mohammed, S N, Newbury-Ecob, R, and Reardon, W
Published: 2003

20. Thrombocytopenia-absent radius syndrome: a clinical genetic study

Author: Greenhalgh, K L, Howell, R T, Bottani, A, Ancliff, P J, Brunner, H G, Verschuuren-Bemelmans, C C, Vernon, E, Brown, K W, and Newbury-Ecob, R A
Published: 2002

21. Mutations at the SALL4 locus on chromosome 20 result in a range of clinically overlapping phenotypes. (Original Article)

Author: Kohlhase, J., Schubert, L., Liebers, M., Rauch, A., Becker, K., Mohammed, S.N., Newbury-Ecob, R., and Reardon, W.
Subjects: Gene mutations -- Analysis -- Research -- Genetic aspects, Genetic disorders -- Research -- Genetic aspects, Chromosome abnormalities -- Analysis -- Research -- Genetic aspects, Eye -- Movement disorders, Health, Analysis, Research, Genetic aspects
Abstract: Mutations at the SALL4 locus on chromosome 20 result in a range of clinically overlapping phenotypes, including Okihiro syndrome, Holt-Oram syndrome, acro-renal-ocular syndrome, and patients previously reported to represent thalidomide [...]
Published: 2003

22. Pancreatic dysfunction in severe obesity

Author: Drake, A J, Greenhalgh, L, Newbury-Ecob, R, Crowne, E C, and Shield, J P H
Published: 2001

23. What Syndrome Is This?

Author: Moffitt, D. L., Kennedy, C. T. C., and Newbury-Ecob, R.
Published: 1999

24. Further delineation of an entity caused by CREBBP and EP300 mutations but not resembling Rubinstein-Taybi syndrome

Author: Menke, L.A., Gardeitchik, T., Hammond, P., Heimdal, K.R., Houge, G., Hufnagel, S.B., Ji, J.L., Johansson, S., Kant, S.G., Kinning, E., Leon, E.L., Newbury-Ecob, R., Paolacci, S., Pfundt, R., Ragge, N.K., Rinne, T., Ruivenkamp, C., Saitta, S.C., Sun, Y., Tartaglia, M., Terhal, P.A., Essen, A.J. van, Vigeland, M.D., Xiao, B., Hennekam, R.C., DDD Study, ARD - Amsterdam Reproduction and Development, General Paediatrics, APH - Quality of Care, and Human Genetics
Subjects: Male, Models, Anatomic, 0301 basic medicine, Microcephaly, Intellectual disability, PHENOTYPE, DISEASE, Ptosis, Missense mutation, P300, Child, Genetics (clinical), Exome sequencing, Rubinstein-Taybi Syndrome, Genetics, Sanger sequencing, EP300, Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], CREBBP, CREB-Binding Protein, Child, Preschool, symbols, Female, medicine.symptom, Adolescent, Genotype, PROTEIN CBP, Biology, genotype-phenotype correlation, CBP, Short stature, 03 medical and health sciences, symbols.namesake, Imaging, Three-Dimensional, medicine, Humans, Genetic Predisposition to Disease, Alleles, Genetic Association Studies, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Rubinstein–Taybi syndrome, Facies, Infant, medicine.disease, 030104 developmental biology, Mutation, E1A-Associated p300 Protein, exome sequencing
Abstract: Contains fulltext : 190439.pdf (Publisher’s version ) (Closed access) In 2016, we described that missense variants in parts of exons 30 and 31 of CREBBP can cause a phenotype that differs from Rubinstein-Taybi syndrome (RSTS). Here we report on another 11 patients with variants in this region of CREBBP (between bp 5,128 and 5,614) and two with variants in the homologous region of EP300. None of the patients show characteristics typical for RSTS. The variants were detected by exome sequencing using a panel for intellectual disability in all but one individual, in whom Sanger sequencing was performed upon clinical recognition of the entity. The main characteristics of the patients are developmental delay (90%), autistic behavior (65%), short stature (42%), and microcephaly (43%). Medical problems include feeding problems (75%), vision (50%), and hearing (54%) impairments, recurrent upper airway infections (42%), and epilepsy (21%). Major malformations are less common except for cryptorchidism (46% of males), and cerebral anomalies (70%). Individuals with variants between bp 5,595 and 5,614 of CREBBP show a specific phenotype (ptosis, telecanthi, short and upslanted palpebral fissures, depressed nasal ridge, short nose, anteverted nares, short columella, and long philtrum). 3D face shape demonstrated resemblance to individuals with a duplication of 16p13.3 (the region that includes CREBBP), possibly indicating a gain of function. The other affected individuals show a less specific phenotype. We conclude that there is now more firm evidence that variants in these specific regions of CREBBP and EP300 result in a phenotype that differs from RSTS, and that this phenotype may be heterogeneous.
Published: 2018

25. Finding Diagnostically Useful Patterns in Quantitative Phenotypic Data

Author: Aitken, Stuart, primary, Firth, Helen V., additional, McRae, Jeremy, additional, Halachev, Mihail, additional, Kini, Usha, additional, Parker, Michael J., additional, Lees, Melissa M., additional, Lachlan, Katherine, additional, Sarkar, Ajoy, additional, Joss, Shelagh, additional, Splitt, Miranda, additional, McKee, Shane, additional, Németh, Andrea H., additional, Scott, Richard H., additional, Wright, Caroline F., additional, Marsh, Joseph A., additional, Hurles, Matthew E., additional, FitzPatrick, David R., additional, Fitzgerald, T.W., additional, Gerety, S.S., additional, Jones, W.D., additional, van Kogelenberg, M., additional, King, D.A., additional, McRae, J., additional, Morley, K.I., additional, Parthiban, V., additional, Al-Turki, S., additional, Ambridge, K., additional, Barrett, D.M., additional, Bayzetinova, T., additional, Clayton, S., additional, Coomber, E.L., additional, Gribble, S., additional, Jones, P., additional, Krishnappa, N., additional, Mason, L.E., additional, Middleton, A., additional, Miller, R., additional, Prigmore, E., additional, Rajan, D., additional, Sifrim, A., additional, Tivey, A.R., additional, Ahmed, M., additional, Akawi, N., additional, Andrews, R., additional, Anjum, U., additional, Archer, H., additional, Armstrong, R., additional, Balasubramanian, M., additional, Banerjee, R., additional, Barelle, D., additional, Batstone, P., additional, Baty, D., additional, Bennett, C., additional, Berg, J., additional, Bernhard, B., additional, Bevan, A.P., additional, Blair, E., additional, Blyth, M., additional, Bohanna, D., additional, Bourdon, L., additional, Bourn, D., additional, Brady, A., additional, Bragin, E., additional, Brewer, C., additional, Brueton, L., additional, Brunstrom, K., additional, Bumpstead, S.J., additional, Bunyan, D.J., additional, Burn, J., additional, Burton, J., additional, Canham, N., additional, Castle, B., additional, Chandler, K., additional, Clasper, S., additional, Clayton-Smith, J., additional, Cole, T., additional, Collins, A., additional, Collinson, M.N., additional, Connell, F., additional, Cooper, N., additional, Cox, H., additional, Cresswell, L., additional, Cross, G., additional, Crow, Y., additional, D’Alessandro, P.M., additional, Dabir, T., additional, Davidson, R., additional, Davies, S., additional, Dean, J., additional, Deshpande, C., additional, Devlin, G., additional, Dixit, A., additional, Dominiczak, A., additional, Donnelly, C., additional, Donnelly, D., additional, Douglas, A., additional, Duncan, A., additional, Eason, J., additional, Edkins, S., additional, Ellard, S., additional, Ellis, P., additional, Elmslie, F., additional, Evans, K., additional, Everest, S., additional, Fendick, T., additional, Fisher, R., additional, Flinter, F., additional, Foulds, N., additional, Fryer, A., additional, Fu, B., additional, Gardiner, C., additional, Gaunt, L., additional, Ghali, N., additional, Gibbons, R., additional, Pereira, S.L. Gomes, additional, Goodship, J., additional, Goudie, D., additional, Gray, E., additional, Greene, P., additional, Greenhalgh, L., additional, Harrison, L., additional, Hawkins, R., additional, Hellens, S., additional, Henderson, A., additional, Hobson, E., additional, Holden, S., additional, Holder, S., additional, Hollingsworth, G., additional, Homfray, T., additional, Humphreys, M., additional, Hurst, J., additional, Ingram, S., additional, Irving, M., additional, Jarvis, J., additional, Jenkins, L., additional, Johnson, D., additional, Jones, D., additional, Jones, E., additional, Josifova, D., additional, Joss, S., additional, Kaemba, B., additional, Kazembe, S., additional, Kerr, B., additional, Kini, U., additional, Kinning, E., additional, Kirby, G., additional, Kirk, C., additional, Kivuva, E., additional, Kraus, A., additional, Kumar, D., additional, Lachlan, K., additional, Lam, W., additional, Lampe, A., additional, Langman, C., additional, Lees, M., additional, Lim, D., additional, Lowther, G., additional, Lynch, S.A., additional, Magee, A., additional, Maher, E., additional, Mansour, S., additional, Marks, K., additional, Martin, K., additional, Maye, U., additional, McCann, E., additional, McConnell, V., additional, McEntagart, M., additional, McGowan, R., additional, McKay, K., additional, McKee, S., additional, McMullan, D.J., additional, McNerlan, S., additional, Mehta, S., additional, Metcalfe, K., additional, Miles, E., additional, Mohammed, S., additional, Montgomery, T., additional, Moore, D., additional, Morgan, S., additional, Morris, A., additional, Morton, J., additional, Mugalaasi, H., additional, Murday, V., additional, Nevitt, L., additional, Newbury-Ecob, R., additional, Norman, A., additional, O’Shea, R., additional, Ogilvie, C., additional, Park, S., additional, Parker, M.J., additional, Patel, C., additional, Paterson, J., additional, Payne, S., additional, Phipps, J., additional, Pilz, D.T., additional, Porteous, D., additional, Pratt, N., additional, Prescott, K., additional, Price, S., additional, Pridham, A., additional, Proctor, A., additional, Purnell, H., additional, Ragge, N., additional, Rankin, J., additional, Raymond, L., additional, Rice, D., additional, Robert, L., additional, Roberts, E., additional, Roberts, G., additional, Roberts, J., additional, Roberts, P., additional, Ross, A., additional, Rosser, E., additional, Saggar, A., additional, Samant, S., additional, Sandford, R., additional, Sarkar, A., additional, Schweiger, S., additional, Scott, C., additional, Scott, R., additional, Selby, A., additional, Seller, A., additional, Sequeira, C., additional, Shannon, N., additional, Sharif, S., additional, Shaw-Smith, C., additional, Shearing, E., additional, Shears, D., additional, Simonic, I., additional, Simpkin, D., additional, Singzon, R., additional, Skitt, Z., additional, Smith, A., additional, Smith, B., additional, Smith, K., additional, Smithson, S., additional, Sneddon, L., additional, Splitt, M., additional, Squires, M., additional, Stewart, F., additional, Stewart, H., additional, Suri, M., additional, Sutton, V., additional, Swaminathan, G.J., additional, Sweeney, E., additional, Tatton-Brown, K., additional, Taylor, C., additional, Taylor, R., additional, Tein, M., additional, Temple, I.K., additional, Thomson, J., additional, Tolmie, J., additional, Torokwa, A., additional, Treacy, B., additional, Turner, C., additional, Turnpenny, P., additional, Tysoe, C., additional, Vandersteen, A., additional, Vasudevan, P., additional, Vogt, J., additional, Wakeling, E., additional, Walker, D., additional, Waters, J., additional, Weber, A., additional, Wellesley, D., additional, Whiteford, M., additional, Widaa, S., additional, Wilcox, S., additional, Williams, D., additional, Williams, N., additional, Woods, G., additional, Wragg, C., additional, Wright, M., additional, Yang, F., additional, Yau, M., additional, Carter, N.P., additional, Parker, M., additional, Firth, H.V., additional, FitzPatrick, D.R., additional, Wright, C.F., additional, Barrett, J.C., additional, and Hurles, M.E., additional
Published: 2019
Full Text: View/download PDF

26. Holt-Oram syndrome: a clinical genetic study

Author: Newbury-Ecob, R. A., Leanage, R., and Raeburn, J. A.
Published: 1996

27. HUWE1 variants cause dominant X-linked intellectual disability: a clinical study of 21 patients

Author: Moortgat, S., Berland, S., Aukrust, Ingvild, Maystadt, I., Baker, L.C., Benoit, V., Gardeitchik, T., Pfundt, R.P., Low, Karen J., Newbury-Ecob, R., Moortgat, S., Berland, S., Aukrust, Ingvild, Maystadt, I., Baker, L.C., Benoit, V., Gardeitchik, T., Pfundt, R.P., Low, Karen J., and Newbury-Ecob, R.
Abstract: Contains fulltext : 183870.pdf (publisher's version ) (Closed access)
Published: 2018

28. Diagnosis of lethal or prenatal-onset autosomal recessive disorders by parental exome sequencing.

Author: Stals, KL, Wakeling, M, Baptista, J, Caswell, R, Parrish, A, Rankin, J, Tysoe, C, Jones, G, Gunning, AC, Lango Allen, H, Bradley, L, Brady, AF, Carley, H, Carmichael, J, Castle, B, Cilliers, D, Cox, H, Deshpande, C, Dixit, A, Eason, J, Elmslie, F, Fry, AE, Fryer, A, Holder, M, Homfray, T, Kivuva, E, McKay, V, Newbury-Ecob, R, Parker, M, Savarirayan, R, Searle, C, Shannon, N, Shears, D, Smithson, S, Thomas, E, Turnpenny, PD, Varghese, V, Vasudevan, P, Wakeling, E, Baple, EL, Ellard, S, Stals, KL, Wakeling, M, Baptista, J, Caswell, R, Parrish, A, Rankin, J, Tysoe, C, Jones, G, Gunning, AC, Lango Allen, H, Bradley, L, Brady, AF, Carley, H, Carmichael, J, Castle, B, Cilliers, D, Cox, H, Deshpande, C, Dixit, A, Eason, J, Elmslie, F, Fry, AE, Fryer, A, Holder, M, Homfray, T, Kivuva, E, McKay, V, Newbury-Ecob, R, Parker, M, Savarirayan, R, Searle, C, Shannon, N, Shears, D, Smithson, S, Thomas, E, Turnpenny, PD, Varghese, V, Vasudevan, P, Wakeling, E, Baple, EL, and Ellard, S
Published: 2018

29. Prevalence and architecture of de novo mutations in developmental disorders

Author: McRae, JF, Clayton, S, Fitzgerald, TW, Kaplanis, J, Prigmore, E, Rajan, D, Sifrim, A, Aitken, S, Akawi, N, Alvi, M, Ambridge, K, Barrett, DM, Bayzetinova, T, Jones, P, Jones, WD, King, D, Krishnappa, N, Mason, LE, Singh, T, Tivey, AR, Ahmed, M, Anjum, U, Archer, H, Armstrong, R, Awada, J, Balasubramanian, M, Banka, S, Baralle, D, Barnicoat, A, Batstone, P, Baty, D, Bennett, C, Berg, J, Bernhard, B, Bevan, AP, Bitner-Glindzicz, M, Blair, E, Blyth, M, Bohanna, D, Bourdon, L, Bourn, D, Bradley, L, Brady, A, Brent, S, Brewer, C, Brunstrom, K, Bunyan, DJ, Burn, J, Canham, N, Castle, B, Chandler, K, Chatzimichali, E, Cilliers, D, Clarke, A, Clasper, S, Clayton-Smith, J, Clowes, V, Coates, A, Cole, T, Colgiu, I, Collins, A, Collinson, MN, Connell, F, Cooper, N, Cox, H, Cresswell, L, Cross, G, Crow, Y, D’Alessandro, M, Dabir, T, Davidson, R, Davies, S, de Vries, D, Dean, J, Deshpande, C, Devlin, G, Dixit, A, Dobbie, A, Donaldson, A, Donnai, D, Donnelly, D, Donnelly, C, Douglas, A, Douzgou, S, Duncan, A, Eason, J, Ellard, S, Ellis, I, Elmslie, F, Evans, K, Everest, S, Fendick, T, Fisher, R, Flinter, F, Foulds, N, Fry, A, Fryer, A, Gardiner, C, Gaunt, L, Ghali, N, Gibbons, R, Gill, H, Goodship, J, Goudie, D, Gray, E, Green, A, Greene, P, Greenhalgh, L, Gribble, S, Harrison, R, Harrison, L, Harrison, V, Hawkins, R, He, L, Hellens, S, Henderson, A, Hewitt, S, Hildyard, L, Hobson, E, Holden, S, Holder, M, Holder, S, Hollingsworth, G, Homfray, T, Humphreys, M, Hurst, J, Hutton, B, Ingram, S, Irving, M, Islam, L, Jackson, A, Jarvis, J, Jenkins, L, Johnson, D, Jones, E, Josifova, D, Joss, S, Kaemba, B, Kazembe, S, Kelsell, R, Kerr, B, Kingston, H, Kini, U, Kinning, E, Kirby, G, Kirk, C, Kivuva, E, Kraus, A, Kumar, D, Kumar, VKA, Lachlan, K, Lam, W, Lampe, A, Langman, C, Lees, M, Lim, D, Longman, C, Lowther, G, Lynch, SA, Magee, A, Maher, E, Male, A, Mansour, S, Marks, K, Martin, K, Maye, U, McCann, E, McConnell, V, McEntagart, M, McGowan, R, McKay, K, McKee, S, McMullan, DJ, McNerlan, S, McWilliam, C, Mehta, S, Metcalfe, K, Middleton, A, Miedzybrodzka, Z, Miles, E, Mohammed, S, Montgomery, T, Moore, D, Morgan, S, Morton, J, Mugalaasi, H, Murday, V, Murphy, H, Naik, S, Nemeth, A, Nevitt, L, Newbury-Ecob, R, Norman, A, O’Shea, R, Ogilvie, C, Ong, K-R, Park, S-M, Parker, MJ, Patel, C, Paterson, J, Payne, S, Perrett, D, Phipps, J, Pilz, DT, Pollard, M, Pottinger, C, Poulton, J, Pratt, N, Prescott, K, Price, S, Pridham, A, Procter, A, Purnell, H, Quarrell, O, Ragge, N, Rahbari, R, Randall, J, Rankin, J, Raymond, L, Rice, D, Robert, L, Roberts, E, Roberts, J, Roberts, P, Roberts, G, Ross, A, Rosser, E, Saggar, A, Samant, S, Sampson, J, Sandford, R, Sarkar, A, Schweiger, S, Scott, R, Scurr, I, Selby, A, Seller, A, Sequeira, C, Shannon, N, Sharif, S, Shaw-Smith, C, Shearing, E, Shears, D, Sheridan, E, Simonic, I, Singzon, R, Skitt, Z, Smith, A, Smith, K, Smithson, S, Sneddon, L, Splitt, M, Squires, M, Stewart, F, Stewart, H, Straub, V, Suri, M, Sutton, V, Swaminathan, GJ, Sweeney, E, Tatton-Brown, K, Taylor, C, Taylor, R, Tein, M, Temple, IK, Thomson, J, Tischkowitz, M, Tomkins, S, Torokwa, A, Treacy, B, Turner, C, Turnpenny, P, Tysoe, C, Vandersteen, A, Varghese, V, Vasudevan, P, Vijayarangakannan, P, Vogt, J, Wakeling, E, Wallwark, S, Waters, J, Weber, A, Wellesley, D, Whiteford, M, Widaa, S, Wilcox, S, Wilkinson, E, Williams, D, Williams, N, Wilson, L, Woods, G, Wragg, C, Wright, M, Yates, L, Yau, M, Nellåker, C, Parker, M, Firth, HV, Wright, CF, FitzPatrick, DR, Barrett, JC, and Hurles, ME
Subjects: Male, Parents, Heredity, Developmental Disabilities, GRIN2B, POGZ, Autoantigens, SMAD4, CASK, GATAD2B, 0302 clinical medicine, TRIO, SMARCA2, KCNH1, Average Faces, CTNNB1, SCN1A, Young adult, Casein Kinase II, Child, AUTS2, MEF2C, Exome, ADNP, Exome sequencing, EP300, KCNQ2, KCNQ3, EHMT1, CNKSR2, CREBBP, MYT1L, MED13L, CSNK2A1, Protein Phosphatase 2C, PPP2R1A, ZBTB18, CDKL5, WAC, HNRNPU, Cohort, STXBP1, Medical genetics, SYNGAP1, Mi-2 Nucleosome Remodeling and Deacetylase Complex, Sex characteristics, AHDC1, SCN8A, medicine.medical_specialty, SLC6A1, FOXP1, USP9X, Article, ANKRD11, PUF60, BRAF, 03 medical and health sciences, SATB2, SMC1A, Intellectual Disability, BCL11A, GABRB3, IQSEC2, Humans, TBL1XR1, TCF4, MSL3, TCF20, DNM1, EEF1A2, SUV420H1, DYRK1A, SETD5, COL4A3BP, CTCF, CHD2, R1, CHD4, 030104 developmental biology, NAA10, HDAC8, Mutation, KDM5B, CHAMP1, PhenIcons, 030217 neurology & neurosurgery, Transcription Factors, 0301 basic medicine, ZMYND11, PTEN, De novo mutation, Chromosomal Proteins, Non-Histone, PTPN11, ASXL1, Bioinformatics, medicine.disease_cause, ASXL3, Cohort Studies, DEAD-box RNA Helicases, CHD8, Prevalence, QRICH1, KIF1A, Genetics, Sex Characteristics, GNAI1, Multidisciplinary, WDR45, Middle Aged, KMT2A, PPM1D, MECP2, DNA-Binding Proteins, PPP2R5D, Phenotype, PACS1, ras GTPase-Activating Proteins, DDX3X, Female, FOXG1, SET, Myeloid-Lymphoid Leukemia Protein, Developmental Disease, Adult, KANSL1, Adolescent, NFIX, Nerve Tissue Proteins, PURA, Biology, KAT6B, KAT6A, NSD1, PDHA1, ALG13, Young Adult, Seizures, CDC2 Protein Kinase, medicine, Journal Article, QH426, Homeodomain Proteins, ITPR1, DYNC1H1, GNAO1, Histone-Lysine N-Methyltransferase, Sequence Analysis, DNA, ZC4H2, ARID1B, Repressor Proteins, CNOT3, SCN2A, SLC35A2, CDK13
Abstract: Children with severe, undiagnosed developmental disorders (DDs) are enriched for damaging de novo mutations (DNMs) in developmentally important genes. We exome sequenced 4,294 families with children with DDs, and meta-analysed these data with published data on 3,287 children with similar disorders. We show that the most significant factors influencing the diagnostic yield of de novo mutations are the sex of the child, the relatedness of their parents and the age of both father and mother. We identified 95 genes enriched for damaging de novo mutation at genome-wide significance (P < 5 x 10-7), including fourteen genes for which compelling data for causation was previously lacking. The large number of genome-wide significant findings allow us to demonstrate that, at current cost differentials, exome sequencing has much greater power than genome sequencing for novel gene discovery in genetically heterogeneous disorders. We estimate that 42.5% of our cohort likely carry pathogenic de novo single nucleotide variants (SNVs) and indels in coding sequences, with approximately half operating by a loss-of-function mechanism, and the remainder being gain-of-function. We established that most haploinsufficient developmental disorders have already been identified, but that many gain-of-function disorders remain to be discovered. Extrapolating from the DDD cohort to the general population, we estimate that de novo dominant developmental disorders have an average birth prevalence of 1 in 168 to 1 in 377, depending on parental age.
Published: 2017

30. Hypophosphataemic Rickets After Ifosfamide Treatment

Author: Newbury-Ecob, R. A. and Barbor, P. R. H.
Published: 1989

31. De Novo Truncating Mutations in the Last and Penultimate Exons of PPM1D Cause an Intellectual Disability Syndrome

Author: Jansen, S, Geuer, S., Pfundt, R.P., Brough, R., Ghongane, P., Herkert, J.C., Marco, E.J., Willemsen, M.H., Kleefstra, T., Hannibal, M., Shieh, J.T., Lynch, S.A., Flinter, F., FitzPatrick, D.R., Gardham, A., Bernhard, B., Ragge, N., Newbury-Ecob, R., Bernier, R., Kvarnung, M., Magnusson, E.A., Wessels, M.W., Slegtenhorst, M.A. van, Monaghan, K.G., Vries, P.F. de, Veltman, J.A., Lord, C.J., Vissers, L.E.L.M., Vries, B.B. de, Jansen, S, Geuer, S., Pfundt, R.P., Brough, R., Ghongane, P., Herkert, J.C., Marco, E.J., Willemsen, M.H., Kleefstra, T., Hannibal, M., Shieh, J.T., Lynch, S.A., Flinter, F., FitzPatrick, D.R., Gardham, A., Bernhard, B., Ragge, N., Newbury-Ecob, R., Bernier, R., Kvarnung, M., Magnusson, E.A., Wessels, M.W., Slegtenhorst, M.A. van, Monaghan, K.G., Vries, P.F. de, Veltman, J.A., Lord, C.J., Vissers, L.E.L.M., and Vries, B.B. de
Abstract: Contains fulltext : 174535.pdf (publisher's version ) (Closed access), Intellectual disability (ID) is a highly heterogeneous disorder involving at least 600 genes, yet a genetic diagnosis remains elusive in approximately 35%-40% of individuals with moderate to severe ID. Recent meta-analyses statistically analyzing de novo mutations in >7,000 individuals with neurodevelopmental disorders highlighted mutations in PPM1D as a possible cause of ID. PPM1D is a type 2C phosphatase that functions as a negative regulator of cellular stress-response pathways by mediating a feedback loop of p38-p53 signaling, thereby contributing to growth inhibition and suppression of stress-induced apoptosis. We identified 14 individuals with mild to severe ID and/or developmental delay and de novo truncating PPM1D mutations. Additionally, deep phenotyping revealed overlapping behavioral problems (ASD, ADHD, and anxiety disorders), hypotonia, broad-based gait, facial dysmorphisms, and periods of fever and vomiting. PPM1D is expressed during fetal brain development and in the adult brain. All mutations were located in the last or penultimate exon, suggesting escape from nonsense-mediated mRNA decay. Both PPM1D expression analysis and cDNA sequencing in EBV LCLs of individuals support the presence of a stable truncated transcript, consistent with this hypothesis. Exposure of cells derived from individuals with PPM1D truncating mutations to ionizing radiation resulted in normal p53 activation, suggesting that p53 signaling is unaffected. However, a cell-growth disadvantage was observed, suggesting a possible effect on the stress-response pathway. Thus, we show that de novo truncating PPM1D mutations in the last and penultimate exons cause syndromic ID, which provides additional insight into the role of cell-cycle checkpoint genes in neurodevelopmental disorders.
Published: 2017

32. De Novo Truncating Mutations in the Last and Penultimate Exons of PPM1D Cause an Intellectual Disability Syndrome

Author: Jansen, S. (Sandra), Geuer, S. (Sinje), Pfundt, R. (Rolph), Brough, R. (Rachel), Ghongane, P. (Priyanka), Herkert, J.C. (Johanna), Marco, E.J. (Elysa J.), Willemsen, M.H. (Marjolein), Kleefstra, T. (Tjitske), Hannibal, M. (Mark), Shieh, J.T. (Joseph T.), Lynch, S.A., Flinter, F. (Frances), Fitzpatrick, D.R. (David), Gardham, A. (Alice), Bernhard, B. (Birgitta), Ragge, N. (Nicola), Newbury-Ecob, R. (Ruth), Bernier, R. (Raphael), Kvarnung, M. (Malin), Magnusson, E.A.H. (E.A. Helena), Wessels, M.W. (Marja), Slegtenhorst, M.A. (Marjon) van, Monaghan, K.G. (Kristin G.), de Vries, P. (Petra), Veltman, J.A. (Joris), Lord, C.J. (Christopher ), Vissers, L.E.L.M., Vries, B. (Boukje) de, Jansen, S. (Sandra), Geuer, S. (Sinje), Pfundt, R. (Rolph), Brough, R. (Rachel), Ghongane, P. (Priyanka), Herkert, J.C. (Johanna), Marco, E.J. (Elysa J.), Willemsen, M.H. (Marjolein), Kleefstra, T. (Tjitske), Hannibal, M. (Mark), Shieh, J.T. (Joseph T.), Lynch, S.A., Flinter, F. (Frances), Fitzpatrick, D.R. (David), Gardham, A. (Alice), Bernhard, B. (Birgitta), Ragge, N. (Nicola), Newbury-Ecob, R. (Ruth), Bernier, R. (Raphael), Kvarnung, M. (Malin), Magnusson, E.A.H. (E.A. Helena), Wessels, M.W. (Marja), Slegtenhorst, M.A. (Marjon) van, Monaghan, K.G. (Kristin G.), de Vries, P. (Petra), Veltman, J.A. (Joris), Lord, C.J. (Christopher ), Vissers, L.E.L.M., and Vries, B. (Boukje) de
Abstract: Intellectual disability (ID) is a highly heterogeneous disorder involving at least 600 genes, yet a genetic diagnosis remains elusive in ∼35%-40% of individuals with moderate to severe ID. Recent meta-analyses statistically analyzing de novo mutations in >7,000 individuals with neurodevelopmental disorders highlighted mutations in PPM1D as a possible cause of ID. PPM1D is a type 2C phosphatase that functions as a negative regulator of cellular stress-response pathways by mediating a feedback loop of p38-p53 signaling, thereby contributing to growth inhibition and suppression of stress-induced apoptosis. We identified 14 individuals with mild to severe ID and/or developmental delay and de novo truncating PPM1D mutations. Additionally, deep phenotyping revealed overlapping behavioral problems (ASD, ADHD, and anxiety disorders), hypotonia, broad-based gait, facial dysmorphisms, and periods of fever and vomiting. PPM1D is expressed during fetal brain development and in the adult brain. All mutations were located in the last or penultimate exon, suggesting escape from nonsense-mediated mRNA decay. Both PPM1D expression analysis and cDNA sequencing in EBV LCLs of individuals support the presence of a stable truncated transcript, consistent with this hypothesis. Exposure of cells derived from individuals with PPM1D truncating mutations to ionizing radiation resulted in normal p53 activation, suggesting that p53 signaling is unaffected. However, a cell-growth disadvantage was observed, suggesting a possible effect on the stress-response pathway. Thus, we show that de novo truncating PPM1D mutations in the last and penultimate exons cause syndromic ID, which provides additional insight into the role of cell-cycle checkpoint genes in neurodevelopmental disorders.
Published: 2017
Full Text: View/download PDF

33. Frontometaphyseal dysplasia: Mutations in FLNA and phenotypic diversity (vol 140A, pg 1726, 2006)

Author: Robertson, S, Jenkins, Z, Morgan, T, Ades, L, Aftimos, S, Boute, O, Fiskerstrand, T, Garcia-Minaur, S, Grix, A, Green, A, Kalouistian, V, Lewkonia, R, McInnes, B, Haelst, v, Macini, G, Illes, T, Mortier, G, Newbury-Ecob, R, Nicholson, L, Scott, C, Ochman, K, Brozek, I, Shears, D, Superti-Furga, A, and Suri, M
Published: 2016

34. An unclassified congenital myopathy diagnosed as Snyder Robinson syndrome identified through the deciphering developmental disorders study

Author: Bownass, L., primary, Newbury-Ecob, R., additional, Love, S., additional, Urankar, K., additional, Study, D., additional, Vijayakumar, K., additional, and Majumdar, A., additional
Published: 2017
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35. Genetic analysis of 'PAX6-negative' individuals with aniridia or Gillespie Syndrome

Author: Ansari, M, Rainger, J, Hanson, IM, Williamson, KA, Sharkey, F, Harewood, L, Sandilands, A, Clayton-Smith, J, Dollfus, H, Bitoun, P, Meire, F, Fantes, J, Franco, B, Lorenz, B, Taylor, DS, Stewart, F, Willoughby, CE, McEntagart, M, Khaw, PT, Clericuzio, C, Van Maldergem, L, Williams, D, Newbury-Ecob, R, Traboulsi, EI, Silva, ED, Madlom, MM, Goudie, DR, Fleck, BW, Wieczorek, D, Kohlhase, J, McTrusty, AD, Gardiner, C, Yale, C, Moore, AT, Russell-Eggitt, I, Islam, L, Lees, M, Beales, PL, Tuft, SJ, Solano, JB, Splitt, M, Hertz, JM, Prescott, TE, Shears, DJ, Nischal, KK, Doco-Fenzy, M, Prieur, F, Temple, IK, Lachlan, KL, Damante, G, Morrison, DA, Van Heyningen, V, Fitzpatrick, DR, Ansari, M, Rainger, J, Hanson, IM, Williamson, KA, Sharkey, F, Harewood, L, Sandilands, A, Clayton-Smith, J, Dollfus, H, Bitoun, P, Meire, F, Fantes, J, Franco, B, Lorenz, B, Taylor, DS, Stewart, F, Willoughby, CE, McEntagart, M, Khaw, PT, Clericuzio, C, Van Maldergem, L, Williams, D, Newbury-Ecob, R, Traboulsi, EI, Silva, ED, Madlom, MM, Goudie, DR, Fleck, BW, Wieczorek, D, Kohlhase, J, McTrusty, AD, Gardiner, C, Yale, C, Moore, AT, Russell-Eggitt, I, Islam, L, Lees, M, Beales, PL, Tuft, SJ, Solano, JB, Splitt, M, Hertz, JM, Prescott, TE, Shears, DJ, Nischal, KK, Doco-Fenzy, M, Prieur, F, Temple, IK, Lachlan, KL, Damante, G, Morrison, DA, Van Heyningen, V, and Fitzpatrick, DR
Abstract: We report molecular genetic analysis of 42 affected individuals referred with a diagnosis of aniridia who previously screened as negative for intragenic PAX6 mutations. Of these 42, the diagnoses were 31 individuals with aniridia and 11 individuals referred with a diagnosis of Gillespie syndrome (iris hypoplasia, ataxia and mild to moderate developmental delay). Array-based comparative genomic hybridization identified six whole gene deletions: four encompassing PAX6 and two encompassing FOXC1. Six deletions with plausible cis-regulatory effects were identified: five that were 3′ (telomeric) to PAX6 and one within a gene desert 5′ (telomeric) to PITX2. Sequence analysis of the FOXC1 and PITX2 coding regions identified two plausibly pathogenic de novo FOXC1 missense mutations (p.Pro79Thr and p. Leu101Pro). No intragenic mutations were detected in PITX2. FISH mapping in an individual with Gillespie-like syndrome with an apparently balanced X;11 reciprocal translocation revealed disruption of a gene at each breakpoint: ARHGAP6 on the X chromosome and PHF21A on chromosome 11. In the other individuals with Gillespie syndrome no mutations were identified in either of these genes, or in HCCS which lies close to the Xp breakpoint. Disruption of PHF21A has previously been implicated in the causation of intellectual disability (but not aniridia). Plausibly causative mutations were identified in 15 out of 42 individuals (12/32 aniridia; 3/11 Gillespie syndrome). Fourteen of these mutations presented in the known aniridia genes; PAX6, FOXC1 and PITX2. The large number of individuals in the cohort with no mutation identified suggests greater locus heterogeneity may exist in both isolated and syndromic aniridia than was previously appreciated.
Published: 2016

36. Mutational and Linkage Analyses of Atrial Septal Defect

Author: Ching, Y.H., Cross, S.J., Gilliland-Paterson, A., Dearlove, A., Rhodes, M., Newbury-Ecob, R., Bonnet, D., and Brook, J.D.
Subjects: Human genetics -- Research, Heart diseases -- Genetic aspects, Biological sciences
Published: 2000

37. Expanding the genotypic spectrum of Perrault syndrome

Author: Demain, L.A.M., primary, Urquhart, J.E., additional, O'Sullivan, J., additional, Williams, S.G., additional, Bhaskar, S.S., additional, Jenkinson, E.M., additional, Lourenco, C.M., additional, Heiberg, A., additional, Pearce, S.H., additional, Shalev, S.A., additional, Yue, W.W., additional, Mackinnon, S., additional, Munro, K.J., additional, Newbury‐Ecob, R., additional, Becker, K., additional, Kim, M.J., additional, O' Keefe, R.T., additional, and Newman, W.G., additional
Published: 2016
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38. Mutations in DDX3X Are a Common Cause of Unexplained Intellectual Disability with Gender-Specific Effects on Wnt Signaling

Author: Snijders Blok, C., Madsen, E., Juusola, J., Gilissen, C.F., Baralle, D., Reijnders, M.R.F., Venselaar, H., Helsmoortel, C., Cho, M.T., Hoischen, A., Vissers, L.E., Koemans, T.S., Wissink, W.M., Eichler, E.E., Romano, C, Esch, H. Van, Stumpel, C., Vreeburg, M., Smeets, E., Oberndorff, K., Bon, B.W. van, Shaw, M., Gecz, J., Haan, E., Bienek, M., Jensen, C., Loeys, B.L., Dijck, A. Van, Innes, A.M., Racher, H., Vermeer, S., Donato, N. Di, Rump, A., Tatton-Brown, K., Parker, M.J., Henderson, A., Lynch, S.A., Fryer, A., Ross, A., Vasudevan, P., Kini, U., Newbury-Ecob, R., Chandler, K., Male, A., Dijkstra, S, Schieving, J., Giltay, J., Gassen, K.L. van, Schuurs-Hoeijmakers, J., Tan, P.L., Pediaditakis, I., Haas, S.A., Retterer, K., Reed, P., Monaghan, K.G., Haverfield, E., Natowicz, M., Myers, A., Kruer, M.C., Stein, Q., Strauss, K.A., Brigatti, K.W., Keating, K., Burton, B.K., Kim, K.H., Charrow, J., Norman, J., Foster-Barber, A., Kline, A.D., Kimball, A., Zackai, E., Harr, M., Fox, J., McLaughlin, J., Lindstrom, K., Haude, K.M., Roozendaal, K. van, Brunner, H.G., Chung, W.K., Kooy, R.F., Pfundt, R., Kalscheuer, V., Mehta, S.G., Katsanis, N., Kleefstra, T., Snijders Blok, C., Madsen, E., Juusola, J., Gilissen, C.F., Baralle, D., Reijnders, M.R.F., Venselaar, H., Helsmoortel, C., Cho, M.T., Hoischen, A., Vissers, L.E., Koemans, T.S., Wissink, W.M., Eichler, E.E., Romano, C, Esch, H. Van, Stumpel, C., Vreeburg, M., Smeets, E., Oberndorff, K., Bon, B.W. van, Shaw, M., Gecz, J., Haan, E., Bienek, M., Jensen, C., Loeys, B.L., Dijck, A. Van, Innes, A.M., Racher, H., Vermeer, S., Donato, N. Di, Rump, A., Tatton-Brown, K., Parker, M.J., Henderson, A., Lynch, S.A., Fryer, A., Ross, A., Vasudevan, P., Kini, U., Newbury-Ecob, R., Chandler, K., Male, A., Dijkstra, S, Schieving, J., Giltay, J., Gassen, K.L. van, Schuurs-Hoeijmakers, J., Tan, P.L., Pediaditakis, I., Haas, S.A., Retterer, K., Reed, P., Monaghan, K.G., Haverfield, E., Natowicz, M., Myers, A., Kruer, M.C., Stein, Q., Strauss, K.A., Brigatti, K.W., Keating, K., Burton, B.K., Kim, K.H., Charrow, J., Norman, J., Foster-Barber, A., Kline, A.D., Kimball, A., Zackai, E., Harr, M., Fox, J., McLaughlin, J., Lindstrom, K., Haude, K.M., Roozendaal, K. van, Brunner, H.G., Chung, W.K., Kooy, R.F., Pfundt, R., Kalscheuer, V., Mehta, S.G., Katsanis, N., and Kleefstra, T.
Abstract: Contains fulltext : 153453.pdf (publisher's version ) (Closed access), Intellectual disability (ID) affects approximately 1%-3% of humans with a gender bias toward males. Previous studies have identified mutations in more than 100 genes on the X chromosome in males with ID, but there is less evidence for de novo mutations on the X chromosome causing ID in females. In this study we present 35 unique deleterious de novo mutations in DDX3X identified by whole exome sequencing in 38 females with ID and various other features including hypotonia, movement disorders, behavior problems, corpus callosum hypoplasia, and epilepsy. Based on our findings, mutations in DDX3X are one of the more common causes of ID, accounting for 1%-3% of unexplained ID in females. Although no de novo DDX3X mutations were identified in males, we present three families with segregating missense mutations in DDX3X, suggestive of an X-linked recessive inheritance pattern. In these families, all males with the DDX3X variant had ID, whereas carrier females were unaffected. To explore the pathogenic mechanisms accounting for the differences in disease transmission and phenotype between affected females and affected males with DDX3X missense variants, we used canonical Wnt defects in zebrafish as a surrogate measure of DDX3X function in vivo. We demonstrate a consistent loss-of-function effect of all tested de novo mutations on the Wnt pathway, and we further show a differential effect by gender. The differential activity possibly reflects a dose-dependent effect of DDX3X expression in the context of functional mosaic females versus one-copy males, which reflects the complex biological nature of DDX3X mutations.
Published: 2015

39. 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

40. De novo variants in CNOT3cause a variable neurodevelopmental disorder

Author: Martin, R., Splitt, M., Genevieve, D., Aten, E., Collins, A., de Bie, C. I., Faivre, L., Foulds, N., Giltay, J., Ibitoye, R., Joss, S., Kennedy, J., Kerr, B., Kivuva, E., Koopmans, M., Newbury-Ecob, R., Jean-Marçais, N., Peeters, E. A. J., Smithson, S., Tomkins, S., Tranmauthem, F., Piton, A., and van Haeringen, A.
Abstract: As a result of exome-based sequencing work performed by the DDD study, de novo variants in CNOT3have emerged as a newly recognised cause of a developmental disorder. This paper describes molecular and clinical details of 16 probands with developmental disorders and de novo CNOT3 variants. It is the first such description of the developmental phenotype associated with CNOT3variants. Eight of these cases were discovered as part of the DDD study, while the other eight were found as a result of large-scale sequencing work performed by other groups. A highly specific phenotype was not recognised in these 16 cases. The most consistent phenotypic features seen in subjects with de novo variants in CNOT3were hypotonia, relatively small stature, developmental delay, behavioural problems and intellectual disability. There is no easily recognisable facial phenotype, but some common dysmorphic features such as anteverted nares, thin upper lip and low set eyebrows were shared among some of the probands. Haploinsufficiency appears to be the most likely mechanism of action, with eight cases found to have protein-truncating variants. Of the other eight cases (all missense variants), three share an amino acid substitution at the same position which may therefore represent an important functional domain.
Published: 2019
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41. Thrombocytopenia with Absent Radii (TAR) syndrome is cause by compound inheritance of low-frequency regulatory SNPs and a rare null mutation in exon-junction complex subunit RBM8A

Author: Albers, C. A., Paul, D. S., Schulze, H., Freson, K., Stephens, J. C., Smethurst, P. A., Jolley, J. D., Cvejic, A., Kostadima, M., Paul Bertone, Breuning, M. H., Debili, N., Deloukas, P., Favier, R., Fiedler, J., Hobbs, C. M., Huang, N., Hurles, M. E., Kiddle, G., Krapels, I., Nurden, P., Ruivenkamp, C. A. L., Sambrook, J. G., Smith, K., Stemple, D. L., Strauss, G., Thys, C., Geet, C., Newbury-Ecob, R., Ouwehand, W. H., and Ghevaert, C.
Published: 2012

42. P.294 - An unclassified congenital myopathy diagnosed as Snyder Robinson syndrome identified through the deciphering developmental disorders study

Author: Bownass, L., Newbury-Ecob, R., Love, S., Urankar, K., Study, D., Vijayakumar, K., and Majumdar, A.
Published: 2017
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43. Am. J. Hum. Genet

Author: Klopocki, E., Schulze, H., Strauß, G., Ott, C., Hall, J., Trotier, F., Fleischhauer, S., Greenhalgh, L., Newbury-Ecob, R., Neumann, L., Habenicht, R., König, R., Seemanova, E., Megarbane, A., Ropers, H., Ullmann, R., and Mundlos, S.
Abstract: Thrombocytopenia–absent radius (TAR) syndrome is characterized by hypomegakaryocytic thrombocytopenia and bilateral radial aplasia in the presence of both thumbs. Other frequent associations are congenital heart disease and a high incidence of cow’s milk intolerance. Evidence for autosomal recessive inheritance comes from families with several affected individuals born to unaffected parents, but several other observations argue for a more complex pattern of inheritance. In this study, we describe a common interstitial microdeletion of 200 kb on chromosome 1q21.1 in all 30 investigated patients with TAR syndrome, detected by microarray-based comparative genomic hybridization. Analysis of the parents revealed that this deletion occurred de novo in 25% of affected individuals. Intriguingly, inheritance of the deletion along the maternal line as well as the paternal line was observed. The absence of this deletion in a cohort of control individuals argues for a specific role played by the microdeletion in the pathogenesis of TAR syndrome. We hypothesize that TAR syndrome is associated with a deletion on chromosome 1q21.1 but that the phenotype develops only in the presence of an additional as-yet-unknown modifier (mTAR).
Published: 2007

44. Frontometaphyseal dysplasia: Mutations in FLNA and phenotypic diversity (vol 140A, pg 1726, 2006)

Author: Robertson, SP, Jenkins, ZA, Morgan, T, Ades, L, Aftimos, S, Boute, O, Fiskerstrand, T, Garcia-Minaur, S, Grix, A, Green, A, Kalouistian, VD, Lewkonia, R, McInnes, B, van Haelst, MM, Macini, G, Illes, T, Mortier, G, Newbury-Ecob, R, Nicholson, L, Scott, CI, Ochman, K, Brozek, I, Shears, DJ, Superti-Furga, A, Suri, M, Whiteford, M, Wilkie, AOM, and Krakow, D
Published: 2006

45. Pancreatic dysfunction in severe obesity

Author: Drake, A, Greenhalgh, L, Newbury-Ecob, R, Crowne, E, and Shield, J
Subjects: Male, Adolescent, Puberty, Precocious, Body Mass Index, Obesity, Morbid, Pancreatic Function Tests, Diabetes Mellitus, Type 2, Predictive Value of Tests, Risk Factors, Child, Preschool, Hyperinsulinism, General and Specialist Paediatrics, Diabetes Mellitus, Humans, Female, Obesity, Child, Pancreas
Abstract: AIMS—To investigate pancreatic function in children attending an obesity clinic. METHODS—Thirty six children (of which 34 were white) with severe obesity of prepubertal onset (body mass index more than +2 SDS) were reviewed clinically and dysmorphologically, with assessment of pancreatic function. RESULTS—Eight had dysmorphic features and 13 had learning difficulties. Four of 17 prepubertal children had hyperinsulinaemia and seven had hyperproinsulinaemia. All 19 pubertal children had hyperinsulinaemia, 14 had hyperproinsulinaemia, and one had type II diabetes. CONCLUSIONS—Metabolic abnormalities predictive of type II diabetes occur in severely obese white children.
Published: 2001

46. Compound inheritance of a low-frequency regulatory SNP and a rare null mutation in exon-junction complex subunit RBM8A causes TAR syndrome

Author: Albers, C.A., Paul, D.S., Schulze, H., Freson, K., Stephens, J.C., Smethurst, P.A., Jolley, J.D., Cvejic, A., Kostadima, M., Bertone, P., Breuning, M.H., Debili, N., Deloukas, P., Favier, R., Fiedler, J., Hobbs, C.M., Huang, N., Hurles, M.E., Kiddle, G., Krapels, I., Nurden, P., Ruivenkamp, C.A., Sambrook, J.G., Smith, K., Stemple, D.L., Strauss, G., Thys, C., van Geet, C., Newbury-Ecob, R., Ouwehand, W.H., Ghevaert, C., Albers, C.A., Paul, D.S., Schulze, H., Freson, K., Stephens, J.C., Smethurst, P.A., Jolley, J.D., Cvejic, A., Kostadima, M., Bertone, P., Breuning, M.H., Debili, N., Deloukas, P., Favier, R., Fiedler, J., Hobbs, C.M., Huang, N., Hurles, M.E., Kiddle, G., Krapels, I., Nurden, P., Ruivenkamp, C.A., Sambrook, J.G., Smith, K., Stemple, D.L., Strauss, G., Thys, C., van Geet, C., Newbury-Ecob, R., Ouwehand, W.H., and Ghevaert, C.
Abstract: Item does not contain fulltext, The exon-junction complex (EJC) performs essential RNA processing tasks. Here, we describe the first human disorder, thrombocytopenia with absent radii (TAR), caused by deficiency in one of the four EJC subunits. Compound inheritance of a rare null allele and one of two low-frequency SNPs in the regulatory regions of RBM8A, encoding the Y14 subunit of EJC, causes TAR. We found that this inheritance mechanism explained 53 of 55 cases (P < 5 x 10(-228)) of the rare congenital malformation syndrome. Of the 53 cases with this inheritance pattern, 51 carried a submicroscopic deletion of 1q21.1 that has previously been associated with TAR, and two carried a truncation or frameshift null mutation in RBM8A. We show that the two regulatory SNPs result in diminished RBM8A transcription in vitro and that Y14 expression is reduced in platelets from individuals with TAR. Our data implicate Y14 insufficiency and, presumably, an EJC defect as the cause of TAR syndrome.
Published: 2012

47. The mutation spectrum in Holt-Oram syndrome

Author: Cross, S.J., Ching, Y.H., Li, Q.Y., Armstrong-Buisseret, L., Spranger, S., Lyonnet, S., Bonnet, D., Penttinen, M., Jonveaux, P., Leheup, B., Mortier, G.R., Ravenswaaij-Arts, C.M.A. van, Gardiner, C.A., Brook, J.D., and Newbury-Ecob, R.
Subjects: Breuk-gevoelige plaatsen in chromosomen bij de mens, Heart Defects, Congenital, Male, medicine.medical_specialty, Genotype, Heart malformation, (Fragile) breakage-prone sites in human chromosomes, Genetic counseling, Clinical description and delineation of genetic syndromes, DNA Mutational Analysis, Molecular Sequence Data, Limb Deformities, Congenital, Phocomelia, Biology, Atrial septal defects, Internal medicine, Genetics, medicine, Humans, Genetic Testing, Letters to the Editor, Klinische beschrijving en moleculaire definiëring van genetische syndromen, Genetics (clinical), Polymorphism, Single-Stranded Conformational, Genetic testing, Heart septal defect, Holt–Oram syndrome, Chromosomes, Human, Pair 12, medicine.diagnostic_test, Heart Septal Defects, Chromosome Mapping, Genetic Variation, Exons, Syndrome, medicine.disease, Introns, Pedigree, Heart Block, Phenotype, Mutation, Cardiology, Female, Syndactyly, Abnormality
Abstract: Editor—Holt-Oram syndrome (HOS) is a developmental disorder characterised by malformations of the radial ray of the forelimb and by congenital heart disease.1 The syndrome shows a marked variability in phenotype, with radial ray defects ranging from minor thumb abnormality through to severe reduction defect or phocomelia. The cardiac manifestations of HOS are similarly varied, and patients can present with a variety of structural heart abnormalities, atrial septal defects (ASDs) and ventricular septal defects (VSDs) being the most common, or conduction defects evident on ECG profiles. Previous studies have shown no correlation between the severity of a patient's cardiac and skeletal abnormalities.2 Intrafamilial variation can be wide. HOS shows autosomal dominant inheritance and mutations in the T box transcription factor gene ( TBX5 ) have been shown previously to be responsible for this disorder.3 4There is also evidence for genetic heterogeneity.5 The mechanism by which mutations in TBX5 cause a dominant phenotype is not understood at present, and it is anticipated that knowledge of the type of mutations causing HOS may shed light on this. Knowledge of a large number of mutations and the relation of a person's genotype to phenotype is also useful for genetic counselling. In the face of a growing demand for a molecular diagnostic test for HOS, it is also helpful to have a quantitative estimate of the ability of current methods to detect mutations in TBX5 . Twenty five cases with a clinical diagnosis of Holt-Oram syndrome have been tested for this study, bringing to 47 the total number of cases studied by us. Minimal diagnostic criteria were as described previously2: bilateral radial ray defect, plus either cardiac abnormality or family history of cardiac abnormality. Cases were referred by a variety of clinicians and underwent full clinical assessment including …
Published: 2000

48. De novo nonsense mutations in ASXL1 cause Bohring-Opitz syndrome

Author: Hoischen, A., Bon, B.W. van, Rodriguez-Santiago, B., Gilissen, C.F.H.A., Vissers, L.E.L.M., Vries, P.F. de, Janssen, I.M., Lier, B. van, Hastings, R., Smithson, S.F., Newbury-Ecob, R., Kjaergaard, S., Goodship, J., McGowan, R., Bartholdi, D., Rauch, A., Peippo, M., Cobben, J.M., Wieczorek, D., Gillessen-Kaesbach, G., Veltman, J.A., Brunner, H.G., Vries, L.B.A. de, Hoischen, A., Bon, B.W. van, Rodriguez-Santiago, B., Gilissen, C.F.H.A., Vissers, L.E.L.M., Vries, P.F. de, Janssen, I.M., Lier, B. van, Hastings, R., Smithson, S.F., Newbury-Ecob, R., Kjaergaard, S., Goodship, J., McGowan, R., Bartholdi, D., Rauch, A., Peippo, M., Cobben, J.M., Wieczorek, D., Gillessen-Kaesbach, G., Veltman, J.A., Brunner, H.G., and Vries, L.B.A. de
Abstract: Item does not contain fulltext, Bohring-Opitz syndrome is characterized by severe intellectual disability, distinctive facial features and multiple congenital malformations. We sequenced the exomes of three individuals with Bohring-Opitz syndrome and in each identified heterozygous de novo nonsense mutations in ASXL1, which is required for maintenance of both activation and silencing of Hox genes. In total, 7 out of 13 subjects with a Bohring-Opitz phenotype had de novo ASXL1 mutations, suggesting that the syndrome is genetically heterogeneous.
Published: 2011

49. Heterozygous germline mutations in the P53 homolog P63 are causes of the EEC syndrome

Author: Celli, J., Duijf, P.H., Hamel, B.C.J., Bamshad, M., Kramer, B.M., Smits, A.P.T., Newbury-Ecob, R., Hennekam, R.C.M., Buggenhout, G.J.C.M. van, Haeringen, A. van, Woods, C.G., Essen, A.J. van, Waal, R.M.W. de, Vriend, G., Haber, D.A., Yang, A., McKeon, F., Brunner, H.G., and Bokhoven, J.H.L.M. van
Subjects: Breuk-gevoelige plaatsen in chromosomen bij de mens, Bioinformatics, (Fragile) breakage-prone sites in human chromosomes, Clinical description and delineation of genetic syndromes, Tumor pathology, Tumor pathologie, Klinische beschrijving en moleculaire definiëring van genetische syndromen
Abstract: Item does not contain fulltext
Published: 1999

50. A translocation at 12q2 refines the interval containing the Holt-Oram syndrome 1 gene

Author: Terrett, J. A., Newbury-Ecob, R., Smith, N. M., Li, Q. Y., Garrett, C., Cox, P., Bonnet, D., Lyonnet, S., Munnich, A., Buckler, A. J., and John David Brook
Subjects: Heart Defects, Congenital, Chromosomes, Human, Pair 12, Phenotype, Karyotyping, Arm, Chromosome Mapping, Humans, Female, Syndrome, In Situ Hybridization, Fluorescence, Translocation, Genetic, Research Article
Abstract: A gene for Holt-Oram syndrome (HOS) has been previously mapped to chromosome 12q2 and designated HOS1. We have identified a HOS patient with a de novo chromosomal rearrangement involving 12q. Detailed cytogenetic analysis of this case reveals three breaks on 12q, and two of these are within the HOS1 interval. By using a combination of chromosome painting and FISH with YACs and cosmids, it has been possible to map these breakpoints within the critical HOS1 interval and thus provide a focus for HOS gene-identification efforts.
Published: 1996

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