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2. SPEN haploinsufficiency causes a neurodevelopmental disorder overlapping proximal 1p36 deletion syndrome with an episignature of X chromosomes in females

Author

Radio, F.C., Pang, K., Ciolfi, A., Levy, M.A., Hernández-García, A., Pedace, L., Pantaleoni, F., Liu, Z, Boer, E. de, Jackson, A., Bruselles, A., McConkey, H., Stellacci, E., Cicero, S. Lo, Motta, M., Carrozzo, R., Dentici, M.L., McWalter, K., Desai, M., Monaghan, K.G., Telegrafi, A., Philippe, C., Vitobello, A., Au, M., Grand, K., Sanchez-Lara, P.A., Baez, J., Lindstrom, K., Kulch, P., Sebastian, J., Madan-Khetarpal, S., Roadhouse, C., MacKenzie, J.J., Monteleone, B., Saunders, C.J., Cuevas, J.K. Jean, Cross, L., Zhou, D., Hartley, T., Sawyer, S.L., Monteiro, F.P., Secches, T.V., Kok, F., Schultz-Rogers, L.E., Macke, E.L., Morava, E., Klee, E.W., Kemppainen, J., Iascone, M., Selicorni, A., Tenconi, R., Amor, D.J., Pais, L., Gallacher, L., Turnpenny, P.D., Stals, K., Ellard, S., Cabet, S., Lesca, G., Pascal, J., Steindl, K., Ravid, S., Weiss, K., Castle, A.M.R., Carter, M.T., Kalsner, L., Vries, B.B.A. de, Bon, B.W. van, Wevers, M.R., Pfundt, R.P., Stegmann, A.P.A., Kerr, B., Kingston, H.M., Chandler, K.E., Sheehan, W., Elias, A.F., Shinde, D.N., Towne, M.C., Robin, N.H., Goodloe, D., Vanderver, A., Sherbini, O., Bluske, K., Hagelstrom, R.T., Zanus, C., Faletra, F., Musante, L., Kurtz-Nelson, E.C., Earl, R.K., Anderlid, B.M., Morin, G., Slegtenhorst, M. van, Diderich, K.E.M., Brooks, A.S., Gribnau, J., Boers, R.G., Finestra, T.R., Carter, L.B., Rauch, A., Gasparini, P., Vissers, L.E.L.M., Lloyd Holder, J., Tartaglia, M., Radio, F.C., Pang, K., Ciolfi, A., Levy, M.A., Hernández-García, A., Pedace, L., Pantaleoni, F., Liu, Z, Boer, E. de, Jackson, A., Bruselles, A., McConkey, H., Stellacci, E., Cicero, S. Lo, Motta, M., Carrozzo, R., Dentici, M.L., McWalter, K., Desai, M., Monaghan, K.G., Telegrafi, A., Philippe, C., Vitobello, A., Au, M., Grand, K., Sanchez-Lara, P.A., Baez, J., Lindstrom, K., Kulch, P., Sebastian, J., Madan-Khetarpal, S., Roadhouse, C., MacKenzie, J.J., Monteleone, B., Saunders, C.J., Cuevas, J.K. Jean, Cross, L., Zhou, D., Hartley, T., Sawyer, S.L., Monteiro, F.P., Secches, T.V., Kok, F., Schultz-Rogers, L.E., Macke, E.L., Morava, E., Klee, E.W., Kemppainen, J., Iascone, M., Selicorni, A., Tenconi, R., Amor, D.J., Pais, L., Gallacher, L., Turnpenny, P.D., Stals, K., Ellard, S., Cabet, S., Lesca, G., Pascal, J., Steindl, K., Ravid, S., Weiss, K., Castle, A.M.R., Carter, M.T., Kalsner, L., Vries, B.B.A. de, Bon, B.W. van, Wevers, M.R., Pfundt, R.P., Stegmann, A.P.A., Kerr, B., Kingston, H.M., Chandler, K.E., Sheehan, W., Elias, A.F., Shinde, D.N., Towne, M.C., Robin, N.H., Goodloe, D., Vanderver, A., Sherbini, O., Bluske, K., Hagelstrom, R.T., Zanus, C., Faletra, F., Musante, L., Kurtz-Nelson, E.C., Earl, R.K., Anderlid, B.M., Morin, G., Slegtenhorst, M. van, Diderich, K.E.M., Brooks, A.S., Gribnau, J., Boers, R.G., Finestra, T.R., Carter, L.B., Rauch, A., Gasparini, P., Vissers, L.E.L.M., Lloyd Holder, J., and Tartaglia, M.

Abstract

Contains fulltext : 231702.pdf (Publisher’s version ) (Closed access), Deletion 1p36 (del1p36) syndrome is the most common human disorder resulting from a terminal autosomal deletion. This condition is molecularly and clinically heterogeneous. Deletions involving two non-overlapping regions, known as the distal (telomeric) and proximal (centromeric) critical regions, are sufficient to cause the majority of the recurrent clinical features, although with different facial features and dysmorphisms. SPEN encodes a transcriptional repressor commonly deleted in proximal del1p36 syndrome and is located centromeric to the proximal 1p36 critical region. Here, we used clinical data from 34 individuals with truncating variants in SPEN to define a neurodevelopmental disorder presenting with features that overlap considerably with those of proximal del1p36 syndrome. The clinical profile of this disease includes developmental delay/intellectual disability, autism spectrum disorder, anxiety, aggressive behavior, attention deficit disorder, hypotonia, brain and spine anomalies, congenital heart defects, high/narrow palate, facial dysmorphisms, and obesity/increased BMI, especially in females. SPEN also emerges as a relevant gene for del1p36 syndrome by co-expression analyses. Finally, we show that haploinsufficiency of SPEN is associated with a distinctive DNA methylation episignature of the X chromosome in affected females, providing further evidence of a specific contribution of the protein to the epigenetic control of this chromosome, and a paradigm of an X chromosome-specific episignature that classifies syndromic traits. We conclude that SPEN is required for multiple developmental processes and SPEN haploinsufficiency is a major contributor to a disorder associated with deletions centromeric to the previously established 1p36 critical regions.

Published
2021

4. The ophthalmic findings in Cohen syndrome. (Clinical Science)

Author

Chandler, K.E., Biswas, S., Lloyd, I.C., Parry, N., Clayton-Smith, J., and Black, G.C.M.

Subjects
Chromosome abnormalities -- Research -- Physiological aspects, Health, Physiological aspects, Research
Abstract

Aim: Cohen syndrome is an uncommon autosomal recessive condition comprising a characteristic facial appearance, mental retardation, benign neutropenia, and retinal dystrophy. This study aimed to identify patients with Cohen syndrome [...]

Published
2002

5. Diagnostic criteria, clinical characteristics, and natural history of Cohen syndrome. (Original Article)

Author

Chandler, K.E., Kidd, A., Al-Gazali, L., Kolehmainen, J., Lehesjoki, A-E, Black, G.C.M., and Clayton-Smith, J.

Subjects
Genetic disorders -- Research -- Genetic aspects, Eye -- Abnormalities -- Research -- Genetic aspects, Child development deviations -- Genetic aspects -- Research, Face -- Abnormalities -- Genetic aspects -- Research, Medical genetics -- Research, Developmental disabilities -- Genetic aspects -- Research, Health, Research, Genetic aspects, Abnormalities
Abstract

Cohen syndrome is a rare, recessively inherited condition associated with facial dysmorphism, developmental delay, and visual disability. A delay in making the diagnosis commonly occurs, contributed to by the lack [...]

Published
2003

6. PURA syndrome: clinical delineation and genotype-phenotype study in 32 individuals with review of published literature

Author

Reijnders, M.R.F., Janowski, R., Alvi, M., Self, J.E., Essen, T.J. van, Vreeburg, M., Rouhl, R.P.W., Stevens, S.J.C., Stegmann, A.P.A., Schieving, J.H., Pfundt, R.P., Dijk, K van, Smeets, E., Stumpel, C., Bok, L.A, Cobben, J.M., Engelen, M., Mansour, S., Whiteford, M., Chandler, K.E., Douzgou, S., Cooper, N.S., Tan, Ene-Choo, Foo, R., Lai, A.H., Rankin, J., Green, A., Lonnqvist, T., Isohanni, P., Williams, S., Ruhoy, I., Carvalho, K.S., Dowling, J.J., Lev, D.L., Sterbova, K., Lassuthova, P., Neupauerova, J., Waugh, J.L., Keros, S., Clayton-Smith, J., Smithson, S.F., Brunner, H.G., Hoeckel, C. van, Anderson, M., Clowes, V.E., Siu, V.M., Study, T. Ddd, Selber, P., Leventer, R.J., Nellaker, C., Niessing, D., Hunt, D., Baralle, D., Reijnders, M.R.F., Janowski, R., Alvi, M., Self, J.E., Essen, T.J. van, Vreeburg, M., Rouhl, R.P.W., Stevens, S.J.C., Stegmann, A.P.A., Schieving, J.H., Pfundt, R.P., Dijk, K van, Smeets, E., Stumpel, C., Bok, L.A, Cobben, J.M., Engelen, M., Mansour, S., Whiteford, M., Chandler, K.E., Douzgou, S., Cooper, N.S., Tan, Ene-Choo, Foo, R., Lai, A.H., Rankin, J., Green, A., Lonnqvist, T., Isohanni, P., Williams, S., Ruhoy, I., Carvalho, K.S., Dowling, J.J., Lev, D.L., Sterbova, K., Lassuthova, P., Neupauerova, J., Waugh, J.L., Keros, S., Clayton-Smith, J., Smithson, S.F., Brunner, H.G., Hoeckel, C. van, Anderson, M., Clowes, V.E., Siu, V.M., Study, T. Ddd, Selber, P., Leventer, R.J., Nellaker, C., Niessing, D., Hunt, D., and Baralle, D.

Abstract

Contains fulltext : 190731.pdf (publisher's version ) (Open Access), BACKGROUND: De novo mutations in PURA have recently been described to cause PURA syndrome, a neurodevelopmental disorder characterised by severe intellectual disability (ID), epilepsy, feeding difficulties and neonatal hypotonia. OBJECTIVES: To delineate the clinical spectrum of PURA syndrome and study genotype-phenotype correlations. METHODS: Diagnostic or research-based exome or Sanger sequencing was performed in individuals with ID. We systematically collected clinical and mutation data on newly ascertained PURA syndrome individuals, evaluated data of previously reported individuals and performed a computational analysis of photographs. We classified mutations based on predicted effect using 3D in silico models of crystal structures of Drosophila-derived Pur-alpha homologues. Finally, we explored genotype-phenotype correlations by analysis of both recurrent mutations as well as mutation classes. RESULTS: We report mutations in PURA (purine-rich element binding protein A) in 32 individuals, the largest cohort described so far. Evaluation of clinical data, including 22 previously published cases, revealed that all have moderate to severe ID and neonatal-onset symptoms, including hypotonia (96%), respiratory problems (57%), feeding difficulties (77%), exaggerated startle response (44%), hypersomnolence (66%) and hypothermia (35%). Epilepsy (54%) and gastrointestinal (69%), ophthalmological (51%) and endocrine problems (42%) were observed frequently. Computational analysis of facial photographs showed subtle facial dysmorphism. No strong genotype-phenotype correlation was identified by subgrouping mutations into functional classes. CONCLUSION: We delineate the clinical spectrum of PURA syndrome with the identification of 32 additional individuals. The identification of one individual through targeted Sanger sequencing points towards the clinical recognisability of the syndrome. Genotype-phenotype analysis showed no significant correlation between mutation classes and

Published
2018

7. De novo mutations in HNRNPU result in a neurodevelopmental syndrome

Author

Yates, T.M., Vasudevan, P.C., Chandler, K.E., Donnelly, D.E., Stark, Z., Sadedin, S., Willoughby, J., and Balasubramanian, M.

Abstract

Exome sequencing in the context of developmental disorders is a useful technique, but variants found need to be interpreted in the context of detailed phenotypic information. Whole gene deletions and loss-of-function-mutations in the HNRNPU gene have been associated with intellectual disability and seizures in some patients. However, a unifying syndromic phenotype has not been previously elucidated. Here, we report a total of seven patients (six patients identified through the Wellcome Trust Deciphering Developmental Disorders study, with one additional patient), who have heterozygous de novo mutations in HNRNPU. These were found via trio-based exome sequencing. All but one of the mutations is predicted to cause loss-of-function. These patients have dysmorphic features in common, including prominent eyebrows, long palpebral fissures, overhanging columella, and thin upper lip. All patients have developmental delay and intellectual disability (ID), ranging from moderate to severe. Seizures are common from early childhood. These initially occur in the context of febrile episodes. This series demonstrates common phenotypic features, including emerging dysmorphism, associated with heterozygous HNRNPU mutations. This allows us to define a novel neurodevelopmental syndrome, with a likely mechanism of haploinsufficiency.

Published
2017

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

Author

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

Abstract

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

Published
2007

14. Deletions in the VPS13B ( COH1) gene as a cause of Cohen syndrome.

Author

Balikova, I., Lehesjoki, A-E., de Ravel, T.J.L., Thienpont, B., Chandler, K.E., Clayton-Smith, J., Träskelin, A-L., Fryns, J-P., and Vermeesch, J.R.

Abstract

Cohen syndrome is an autosomal recessive disorder that is characterized by mental retardation, facial dysmorphism, microcephaly, retinal dystrophy, truncal obesity, joint laxity and intermittent neutropenia. Mutations in the VPS13B (COH1) gene underlie Cohen syndrome. In approximately 70% of the patients mutations in the gene are identified on both alleles, while in about 30% only a mutation in a single allele or no mutant allele is detected. The VPS13B locus was recently added to the growing list of benign copy number variants. We hypothesized that patients with unexplained Cohen syndrome would harbour deletions affecting the VPS13B locus. We screened 35 patients from 26 families with targeted array CGH and identified 7 copy number alterations: 2 homozygous and 5 heterozygous deletions. Our results show that deletions are an important cause of Cohen syndrome and screening for copy number alterations of VPS13B should be an integral part of the diagnostic work-up of these patients. These findings have important consequences for the diagnosis of patients with genetic disorders in general since, as we highlight, rare benign copy number variants can underly autosomal recessive disorders and lead to disease in homozygous state or in compound heterozygosity with another mutation. © 2009 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Published
2009
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