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101. A detailed clinical analysis of 13 patients with AUTS2 syndrome further delineates the phenotypic spectrum and underscores the behavioural phenotype

Author

Beunders, Gea, van de Kamp, Jiddeke, Vasudevan, Pradeep, Morton, Jenny, Smets, Katrien, Kleefstra, Tjitske, de Munnik, Sonja A., Schuurs-Hoeijmakers, Janneke, Ceulemans, Berten, Zollino, Marcella, Hoffjan, Sabine, Wieczorek, Stefan, So, Joyce, Mercer, Leanne, Walker, Tanya, Velsher, Lea, Parker, Michael J., Magee, Alex C., Elffers, Bart, Frank Kooy, R., Yntema, Helger G., Meijers-Heijboer, Elizabeth J., Sistermans, Erik A., The DDD study, DDD study, Human genetics, Amsterdam Neuroscience - Complex Trait Genetics, and DDD Study

Subjects
0301 basic medicine, Male, Pediatrics, Microcephaly, Haploinsufficiency, Settore MED/03 - GENETICA MEDICA, Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12], Intellectual disability, Developmental, Copy-number variation, Child, Genetics (clinical), Sequence Deletion, Genetics, Psychiatry, Mental Disorders, Exons, Syndrome, Middle Aged, Phenotype, Child, Preschool, Medical genetics, Female, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9], Adult, medicine.medical_specialty, Copy-number, Biology, Clinical genetics, 03 medical and health sciences, Young Adult, Molecular genetics, Intellectual Disability, medicine, Humans, Genetic Association Studies, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Infant, Proteins, medicine.disease, Cytoskeletal Proteins, 030104 developmental biology, Mutation, Autism, Human medicine, Transcription Factors
Abstract

Item does not contain fulltext BACKGROUND: AUTS2 syndrome is an 'intellectual disability (ID) syndrome' caused by genomic rearrangements, deletions, intragenic duplications or mutations disrupting AUTS2. So far, 50 patients with AUTS2 syndrome have been described, but clinical data are limited and almost all cases involved young children. METHODS: We present a detailed clinical description of 13 patients (including six adults) with AUTS2 syndrome who have a pathogenic mutation or deletion in AUTS2. All patients were systematically evaluated by the same clinical geneticist. RESULTS: All patients have borderline to severe ID/developmental delay, 83-100% have microcephaly and feeding difficulties. Congenital malformations are rare, but mild heart defects, contractures and genital malformations do occur. There are no major health issues in the adults; the oldest of whom is now 59 years of age. Behaviour is marked by it is a friendly outgoing social interaction. Specific features of autism (like obsessive behaviour) are seen frequently (83%), but classical autism was not diagnosed in any. A mild clinical phenotype is associated with a small in-frame 5' deletions, which are often inherited. Deletions and other mutations causing haploinsufficiency of the full-length AUTS2 transcript give a more severe phenotype and occur de novo. CONCLUSIONS: The 13 patients with AUTS2 syndrome with unique pathogenic deletions scattered around the AUTS2 locus confirm a phenotype-genotype correlation. Despite individual variations, AUTS2 syndrome emerges as a specific ID syndrome with microcephaly, feeding difficulties, dysmorphic features and a specific behavioural phenotype.

Published
2016

102. De novo, heterozygous, loss-of-function mutations in SYNGAP1 cause a syndromic form of intellectual disability

Author

Parker, Michael J, Fryer, Alan E, Shears, Deborah J, Lachlan, Katherine L, McKee, Shane A, Magee, Alex C, Mohammed, Shehla, Vasudevan, Pradeep C, Park, Soo-Mi, Benoit, Valérie, Lederer, Damien, Maystadt, Isabelle, Study, Ddd, and FitzPatrick, David R

Abstract

De novo mutations (DNM) in SYNGAP1, encoding Ras/Rap GTPase-activating protein SynGAP, have been reported in individuals with nonsyndromic intellectual disability (ID). We identified 10 previously unreported individuals with SYNGAP1 DNM; seven via the Deciphering Developmental Disorders (DDD) Study, one through clinical analysis for copy number variation and the remaining two (monozygotic twins) via a research multi-gene panel analysis. Seven of the nine heterozygous mutations are likely to result in loss-of-function (3 nonsense; 3 frameshift; 1 whole gene deletion). The remaining two mutations, one of which affected the monozygotic twins, were missense variants. Each individual carrying a DNM in SYNGAP1 had moderate-to-severe ID and 7/10 had epilepsy; typically myoclonic seizures, absences or drop attacks. 8/10 had hypotonia, 5/10 had significant constipation, 7/10 had wide-based/unsteady gait, 3/10 had strabismus, and 2/10 had significant hip dysplasia. A proportion of the affected individuals had a similar, myopathic facial appearance, with broad nasal bridge, relatively long nose and full lower lip vermilion. A distinctive behavioral phenotype was also observed with aggressive/challenging behavior and significant sleep problems being common. 7/10 individuals had MR imaging of the brain each of which was reported as normal. The clinical features of the individuals reported here show significant overlap with those associated with 6p21.3 microdeletions, confirming that haploinsufficiency for SYNGAP1 is responsible for both disorders. © 2015 Wiley Periodicals, Inc.

Published
2015

104. Mutations in the Chromatin Regulator Gene BRPF1 Cause Syndromic Intellectual Disability and Deficient Histone Acetylation

Author

Yan, Kezhi, primary, Rousseau, Justine, additional, Littlejohn, Rebecca Okashah, additional, Kiss, Courtney, additional, Lehman, Anna, additional, Rosenfeld, Jill A., additional, Stumpel, Constance T.R., additional, Stegmann, Alexander P.A., additional, Robak, Laurie, additional, Scaglia, Fernando, additional, Nguyen, Thi Tuyet Mai, additional, Fu, He, additional, Ajeawung, Norbert F., additional, Camurri, Maria Vittoria, additional, Li, Lin, additional, Gardham, Alice, additional, Panis, Bianca, additional, Almannai, Mohammed, additional, Sacoto, Maria J. Guillen, additional, Baskin, Berivan, additional, Ruivenkamp, Claudia, additional, Xia, Fan, additional, Bi, Weimin, additional, Cho, Megan T., additional, Potjer, Thomas P., additional, Santen, Gijs W.E., additional, Parker, Michael J., additional, Canham, Natalie, additional, McKinnon, Margaret, additional, Potocki, Lorraine, additional, MacKenzie, Jennifer J., additional, Roeder, Elizabeth R., additional, Campeau, Philippe M., additional, and Yang, Xiang-Jiao, additional

Published
2017
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105. Coupling Nuclear Induced Phonon Propagation with Conversion Electron Mössbauer Spectroscopy

Author

Parker, Michael J.

Subjects
Nuclear Engineering
Abstract

Mössbauer spectroscopy is a very sensitive measurement technique (10 (exp -8) eV) which prompted motivation for the experiment described in this thesis. Namely, can a sensitive detection system be developed to detect nuclear recoils on the order of 10 to 100 of eVs? The hypothesis that this thesis tests is: Nuclear induced phonon bursts caused by Rutherford scattered alphas, decayed from Am241, in a type-310 stainless steel material can couple with 7.3keV conversion electron Mössbauer events at the other end of the material which will have a statistically significant effect on a Mössbauer spectrum. The phonon bursts produced by the alpha collisions are expected to be very low energy at the other end of length of material. Since Mössbauer spectroscopy is sensitive and can detect the very low energy phonons, the spectrum is expected to change in at least one of the five areas after coupling occurs: broadening in the spectrum peaks, increased/decreased background counting rate, Mossbauer peak asymmetry, increased/decreased counting rate under the peak, and/or a peak centroid shift. This research aims to determine the significance of changes between spectra with phonon bursts and with no phonon bursts through hypothesis testing, where the null hypothesis is where phonons do not affect Mössbauer spectra in one of the five areas mentioned previously. After the spectra and results were analyze using an f-test and t-test comparisons, this experiment failed to reject the null result. Leading to the conclusion that additional research must be conducted.

Published
2015

106. The CHD8overgrowth syndrome: A detailed evaluation of an emerging overgrowth phenotype in 27 patients

Author

Ostrowski, Philip J., Zachariou, Anna, Loveday, Chey, Beleza‐Meireles, Ana, Bertoli, Marta, Dean, John, Douglas, Andrew G. L., Ellis, Ian, Foster, Alison, Graham, John M., Hague, Jennifer, Hilhorst‐Hofstee, Yvonne, Hoffer, Mariette, Johnson, Diana, Josifova, Dragana, Kant, Sarina G., Kini, Usha, Lachlan, Katherine, Lam, Wayne, Lees, Melissa, Lynch, Sally, Maitz, Silvia, McKee, Shane, Metcalfe, Kay, Nathanson, Katherine, Ockeloen, Charlotte W., Parker, Michael J., Pierson, Tyler M., Rahikkala, Elisa, Sanchez‐Lara, Pedro A., Spano, Alice, Van Maldergem, Lionel, Cole, Trevor, Douzgou, Sofia, and Tatton‐Brown, Katrina

Abstract

CHD8has been reported as an autism susceptibility/intellectual disability gene but emerging evidence suggests that it additionally causes an overgrowth phenotype. This study reports 27 unrelated patients with pathogenic or likely pathogenic CHD8variants (25 null variants, two missense variants) and a male:female ratio of 21:6 (3.5:1, p< .01). All patients presented with intellectual disability, with 85% in the mild or moderate range, and 85% had a height and/or head circumference ≥2 standard deviations above the mean, meeting our clinical criteria for overgrowth. Behavioral problems were reported in the majority of patients (78%), with over half (56%) either formally diagnosed with an autistic spectrum disorder or described as having autistic traits. Additional clinical features included neonatal hypotonia (33%), and less frequently seizures, pes planus, scoliosis, fifth finger clinodactyly, umbilical hernia, and glabellar hemangioma (≤15% each). These results suggest that, in addition to its established link with autism and intellectual disability, CHD8causes an overgrowth phenotype, and should be considered in the differential diagnosis of patients presenting with increased height and/or head circumference in association with intellectual disability.

Published
2019
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107. Refining the Primrose syndrome phenotype: A study of five patients with ZBTB20 de novo variants and a review of the literature.

Author

Cleaver, Ruth, Berg, Jonathan, Craft, Emily, Foster, Alison, Gibbons, Richard J., Hobson, Emma, Lachlan, Katherine, Naik, Swati, Sampson, Julian R., Sharif, Saba, Smithson, Sarah, Parker, Michael J., and Tatton‐Brown, Katrina

Abstract

Primrose syndrome is a rare autosomal dominant condition caused by heterozygous missense variants within ZBTB20. Through an exome sequencing approach (as part of the Deciphering Developmental Disorders [DDD] study) we have identified five unrelated individuals with previously unreported, de novo ZBTB20 pathogenic missense variants. All five missense variants targeted the C2H2 zinc finger domains. This genotype‐up approach has allowed further refinement of the Primrose syndrome phenotype. Major characteristics (>90% individuals) include an intellectual disability (most frequently in the moderate range), a recognizable facial appearance and brain MRI abnormalities, particularly abnormalities of the corpus callosum. Other frequent clinical associations (in 50–90% individuals) include sensorineural hearing loss (83%), hypotonia (78%), cryptorchidism in males (75%), macrocephaly (72%), behavioral issues (56%), and dysplastic/hypoplastic nails (57%). Based upon these clinical data we discuss our current management of patients with Primrose syndrome. [ABSTRACT FROM AUTHOR]

Published
2019
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108. Biallelic Variants in UBA5 Link Dysfunctional UFM1 Ubiquitin-like Modifier Pathway to Severe Infantile-Onset Encephalopathy

Author

Muona, Mikko, primary, Ishimura, Ryosuke, additional, Laari, Anni, additional, Ichimura, Yoshinobu, additional, Linnankivi, Tarja, additional, Keski-Filppula, Riikka, additional, Herva, Riitta, additional, Rantala, Heikki, additional, Paetau, Anders, additional, Pöyhönen, Minna, additional, Obata, Miki, additional, Uemura, Takefumi, additional, Karhu, Thomas, additional, Bizen, Norihisa, additional, Takebayashi, Hirohide, additional, McKee, Shane, additional, Parker, Michael J., additional, Akawi, Nadia, additional, McRae, Jeremy, additional, Hurles, Matthew E., additional, Kuismin, Outi, additional, Kurki, Mitja I., additional, Anttonen, Anna-Kaisa, additional, Tanaka, Keiji, additional, Palotie, Aarno, additional, Waguri, Satoshi, additional, Lehesjoki, Anna-Elina, additional, and Komatsu, Masaaki, additional

Published
2016
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109. Prevalence, phenotype and architecture of developmental disorders caused by de novo mutation: The Deciphering Developmental Disorders Study

Author

McRae, Jeremy F, primary, Clayton, Stephen, additional, Fitzgerald, Tomas W, additional, Kaplanis, Joanna, additional, Prigmore, Elena, additional, Rajan, Diana, additional, Sifrim, AlejandroW, additional, Aitken, Stuart, additional, Akawi, Nadia, additional, Alvi, Mohsan, additional, Ambridge, Kirsty, additional, Barrett, Daniel M, additional, Bayzetinova, Tanya, additional, Jones, Philip, additional, Jones, Wendy D, additional, King, Daniel, additional, Krishnappa, Netravathi, additional, Mason, Laura E, additional, Singh, Tarjinder, additional, Tivey, Adrian R, additional, Ahmed, Munaza, additional, Anjum, Uruj, additional, Archer, Hayley, additional, Armstrong, Ruth, additional, Awada, Jana, additional, Balasubramanian, Meena, additional, Banka, Siddharth, additional, Baralle, Diana, additional, Barnicoat, Angela, additional, Batstone, Paul, additional, Baty, David, additional, Bennett, Chris, additional, Berg, Jonathan, additional, Bernhard, Birgitta, additional, Bevan, A Paul, additional, Bitner-Glindzicz, Maria, additional, Blair, Edward, additional, Blyth, Moira, additional, Bohanna, David, additional, Bourdon, Louise, additional, Bourn, David, additional, Bradley, Lisa, additional, Brady, Angela, additional, Brent, Simon, additional, Brewer, Carole, additional, Brunstrom, Kate, additional, Bunyan, David J, additional, Burn, John, additional, Canham, Natalie, additional, Castle, Bruce, additional, Chandler, Kate, additional, Chatzimichali, Elena, additional, Cilliers, Deirdre, additional, Clarke, Angus, additional, Clasper, Susan, additional, Clayton-Smith, Jill, additional, Clowes, Virginia, additional, Coates, Andrea, additional, Cole, Trevor, additional, Colgiu, Irina, additional, Collins, Amanda, additional, Collinson, Morag N, additional, Connell, Fiona, additional, Cooper, Nicola, additional, Cox, Helen, additional, Cresswell, Lara, additional, Cross, Gareth, additional, Crow, Yanick, additional, D'Alessandro, Mariella, additional, Dabir, Tabib, additional, Davidson, Rosemarie, additional, Davies, Sally, additional, de Vries, Dylan, additional, Dean, John, additional, Deshpande, Charu, additional, Devlin, Gemma, additional, Dixit, Abhijit, additional, Dobbie, Angus, additional, Donaldson, Alan, additional, Donnai, Dian, additional, Donnelly, Deirdre, additional, Donnelly, Carina, additional, Douglas, Angela, additional, Douzgou, Sofia, additional, Duncan, Alexis, additional, Eason, Jacqueline, additional, Ellard, Sian, additional, Ellis, Ian, additional, Elmslie, Frances, additional, Evans, Karenza, additional, Everest, Sarah, additional, Fendick, Tina, additional, Fisher, Richard, additional, Flinter, Frances, additional, Foulds, Nicola, additional, Fry, AndrewW, additional, Fryer, Alan, additional, Gardiner, Carol, additional, Gaunt, Lorraine, additional, Ghali, Neeti, additional, Gibbons, Richard, additional, Gill, Harinder, additional, Goodship, Judith, additional, Goudie, David, additional, Gray, Emma, additional, Green, Andrew, additional, Greene, Philip, additional, Greenhalgh, Lynn, additional, Gribble, Susan, additional, Harrison, Lucy, additional, Harrison, Victoria, additional, Hawkins, Rose, additional, He, Liu, additional, Hellens, Stephen, additional, Henderson, Alex, additional, Hewitt, Sarah, additional, Hildyard, Lucy, additional, Hobson, Emma, additional, Holden, Simon, additional, Holder, Muriel, additional, Holder, Susan, additional, Hollingsworth, Georgina, additional, Homfray, Tessa, additional, Humphreys, Mervyn, additional, Hurst, Jane, additional, Hutton, Ben, additional, Ingram, Stuart, additional, Irving, Melita, additional, Islam, Lily, additional, Jackson, Andrew, additional, Jarvis, Joanna, additional, Jenkins, Lucy, additional, Johnson, Diana, additional, Jones, Elizabeth, additional, Josifova, Dragana, additional, Joss, Shelagh, additional, Kaemba, Beckie, additional, Kazembe, Sandra, additional, Kelsell, Rosemary, additional, Kerr, Bronwyn, additional, Kingston, Helen, additional, Kini, Usha, additional, Kinning, Esther, additional, Kirby, Gail, additional, Kirk, Claire, additional, Kivuva, Emma, additional, Kraus, Alison, additional, Kumar, Dhavendra, additional, Kumar, V.K Ajith, additional, Lachlan, Katherine, additional, Lam, Wayne, additional, Lampe, Anne, additional, Langman, Caroline, additional, Lees, Melissa, additional, Lim, Derek, additional, Longman, Cheryl, additional, Lowther, Gordon, additional, Lynch, Sally A, additional, Magee, Alex, additional, Maher, Eddy, additional, Male, Alison, additional, Mansour, Sahar, additional, Marks, Karen, additional, Martin, Katherine, additional, Maye, Una, additional, McCann, Emma, additional, McConnell, Vivienne, additional, McEntagart, Meriel, additional, McGowan, Ruth, additional, McKay, Kirsten, additional, McKee, Shane, additional, McMullan, Dominic J, additional, McNerlan, Susan, additional, McWilliam, Catherine, additional, Mehta, Sarju, additional, Metcalfe, Kay, additional, Middleton, Anna, additional, Miedzybrodzka, Zosia, additional, Miles, Emma, additional, Mohammed, Shehla, additional, Montgomery, Tara, additional, Moore, David, additional, Morgan, Sian, additional, Morton, Jenny, additional, Mugalaasi, Hood, additional, Murday, Victoria, additional, Murphy, Helen, additional, Naik, Swati, additional, Nemeth, Andrea, additional, Nevitt, Louise, additional, Newbury-Ecob, Ruth, additional, Norman, Andrew, additional, O'Shea, Rosie, additional, Ogilvie, Caroline, additional, Ong, Kai-Ren, additional, Park, Soo-Mi, additional, Parker, Michael J, additional, Patel, Chirag, additional, Paterson, Joan, additional, Payne, Stewart, additional, Perrett, Daniel, additional, Phipps, Julie, additional, Pilz, Daniela T, additional, Pollard, Martin, additional, Pottinger, Caroline, additional, Poulton, Joanna, additional, Pratt, Norman, additional, Prescott, Katrina, additional, Price, Sue, additional, Pridham, Abigail, additional, Procter, Annie, additional, Purnell, Hellen, additional, Quarrell, Oliver, additional, Ragge, Nicola, additional, Rahbari, Raheleh, additional, Randall, Josh, additional, Rankin, Julia, additional, Raymond, Lucy, additional, Rice, Debbie, additional, Robert, Leema, additional, Roberts, Eileen, additional, Roberts, Jonathan, additional, Roberts, Paul, additional, Roberts, Gillian, additional, Ross, Alison, additional, Rosser, Elisabeth, additional, Saggar, Anand, additional, Samant, Shalaka, additional, Sampson, Julian, additional, Sandford, Richard, additional, Sarkar, Ajoy, additional, Schweiger, Susann, additional, Scott, Richard, additional, Scurr, Ingrid, additional, Selby, Ann, additional, Seller, Anneke, additional, Sequeira, Cheryl, additional, Shannon, Nora, additional, Sharif, Saba, additional, Shaw-Smith, Charles, additional, Shearing, Emma, additional, Shears, Debbie, additional, Sheridan, Eamonn, additional, Simonic, Ingrid, additional, Singzon, Roldan, additional, Skitt, Zara, additional, Smith, Audrey, additional, Smith, Kath, additional, Smithson, Sarah, additional, Sneddon, Linda, additional, Splitt, Miranda, additional, Squires, Miranda, additional, Stewart, Fiona, additional, Stewart, Helen, additional, Straub, Volker, additional, Suri, Mohnish, additional, Sutton, Vivienne, additional, Swaminathan, Ganesh Jawahar, additional, Sweeney, Elizabeth, additional, Tatton-Brown, Kate, additional, Taylor, Cat, additional, Taylor, Rohan, additional, Tein, Mark, additional, Temple, I Karen, additional, Thomson, Jenny, additional, Tischkowitz, Marc, additional, Tomkins, Susan, additional, Torokwa, Audrey, additional, Treacy, Becky, additional, Turner, Claire, additional, Turnpenny, Peter, additional, Tysoe, Carolyn, additional, Vandersteen, Anthony, additional, Varghese, Vinod, additional, Vasudevan, Pradeep, additional, Vijayarangakannan, Parthiban, additional, Vogt, Julie, additional, Wakeling, Emma, additional, Wallwark, Sarah, additional, Waters, Jonathon, additional, Weber, Astrid, additional, Wellesley, Diana, additional, Whiteford, Margo, additional, Widaa, Sara, additional, Wilcox, Sarah, additional, Wilkinson, Emily, additional, Williams, Denise, additional, Williams, Nicola, additional, Wilson, Louise, additional, Woods, Geoff, additional, Wragg, Christopher, additional, Wright, Michael, additional, Yates, Laura, additional, Yau, Michael, additional, Nellaker, Chris, additional, Firth, Helen V, additional, Wright, Caroline F, additional, FitzPatrick, David R, additional, Barrett, Jeffrey C, additional, and Hurles, Matthew E, additional

Published
2016
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110. Extending the phenotype associated with the <italic>CSNK2A1‐</italic>related Okur–Chung syndrome—A clinical study of 11 individuals.

Author

Owen, Ceris I., Bowden, Ramsay, Parker, Michael J., Patterson, Jo, Patterson, Joan, Price, Sue, Sarkar, Ajoy, Castle, Bruce, Deshpande, Charulatha, Splitt, Miranda, Ghali, Neeti, Dean, John, Green, Andrew J., Crosby, Charlene, Deciphering Developmental Disorders Study, and Tatton‐Brown, Katrina

Abstract

Variants in the Protein Kinase CK2 alpha subunit, encoding the CSNK2A1 gene, have previously been reported in children with an intellectual disability and dysmorphic facial features syndrome: now termed the Okur–Chung neurodevelopmental syndrome. More recently, through trio‐based exome sequencing undertaken by the Deciphering Developmental Disorders Study (DDD study), a further 11 children with de novo CSNK2A1 variants have been identified. We have undertaken detailed phenotyping of these patients. Consistent with previously reported patients, patients in this series had apparent intellectual disability, swallowing difficulties, and hypotonia. While there are some shared facial characteristics, the gestalt is neither consistent nor readily recognized. Congenital heart abnormalities were identified in nearly 30% of the patients, representing a newly recognized CSNK2A1 clinical association. Based upon the clinical findings from this study and the previously reported patients, we suggest an initial approach to the management of patients with this recently described intellectual disability syndrome. [ABSTRACT FROM AUTHOR]

Published
2018
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111. De novo and biallelic DEAF1variants cause a phenotypic spectrum

Author

Nabais Sá, Maria J., Jensik, Philip J., McGee, Stacey R., Parker, Michael J., Lahiri, Nayana, McNeil, Evan P., Kroes, Hester Y., Hagerman, Randi J., Harrison, Rachel E., Montgomery, Tara, Splitt, Miranda, Palmer, Elizabeth E., Sachdev, Rani K., Mefford, Heather C., Scott, Abbey A., Martinez-Agosto, Julian A., Lorenz, Rüdiger, Orenstein, Naama, Berg, Jonathan N., Amiel, Jeanne, Heron, Delphine, Keren, Boris, Cobben, Jan-Maarten, Menke, Leonie A., Marco, Elysa J., Graham, John M., Pierson, Tyler Mark, Karimiani, Ehsan Ghayoor, Maroofian, Reza, Manzini, M. Chiara, Cauley, Edmund S., Colombo, Roberto, Odent, Sylvie, Dubourg, Christele, Phornphutkul, Chanika, de Brouwer, Arjan P.M., de Vries, Bert B.A., and Vulto-vanSilfhout, Anneke T.

Abstract

To investigate the effect of different DEAF1variants on the phenotype of patients with autosomal dominant and recessive inheritance patterns and on DEAF1 activity in vitro.

Published
2019
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112. Mutations in DDX3X Are a Common Cause of Unexplained Intellectual Disability with Gender-Specific Effects on Wnt Signaling

Author

Snijders Blok, Lot, primary, Madsen, Erik, additional, Juusola, Jane, additional, Gilissen, Christian, additional, Baralle, Diana, additional, Reijnders, Margot R.F., additional, Venselaar, Hanka, additional, Helsmoortel, Céline, additional, Cho, Megan T., additional, Hoischen, Alexander, additional, Vissers, Lisenka E.L.M., additional, Koemans, Tom S., additional, Wissink-Lindhout, Willemijn, additional, Eichler, Evan E., additional, Romano, Corrado, additional, Van Esch, Hilde, additional, Stumpel, Connie, additional, Vreeburg, Maaike, additional, Smeets, Eric, additional, Oberndorff, Karin, additional, van Bon, Bregje W.M., additional, Shaw, Marie, additional, Gecz, Jozef, additional, Haan, Eric, additional, Bienek, Melanie, additional, Jensen, Corinna, additional, Loeys, Bart L., additional, Van Dijck, Anke, additional, Innes, A. Micheil, additional, Racher, Hilary, additional, Vermeer, Sascha, additional, Di Donato, Nataliya, additional, Rump, Andreas, additional, Tatton-Brown, Katrina, additional, Parker, Michael J., additional, Henderson, Alex, additional, Lynch, Sally A., additional, Fryer, Alan, additional, Ross, Alison, additional, Vasudevan, Pradeep, additional, Kini, Usha, additional, Newbury-Ecob, Ruth, additional, Chandler, Kate, additional, Male, Alison, additional, Dijkstra, Sybe, additional, Schieving, Jolanda, additional, Giltay, Jacques, additional, van Gassen, Koen L.I., additional, Schuurs-Hoeijmakers, Janneke, additional, Tan, Perciliz L., additional, Pediaditakis, Igor, additional, Haas, Stefan A., additional, Retterer, Kyle, additional, Reed, Patrick, additional, Monaghan, Kristin G., additional, Haverfield, Eden, additional, Natowicz, Marvin, additional, Myers, Angela, additional, Kruer, Michael C., additional, Stein, Quinn, additional, Strauss, Kevin A., additional, Brigatti, Karlla W., additional, Keating, Katherine, additional, Burton, Barbara K., additional, Kim, Katherine H., additional, Charrow, Joel, additional, Norman, Jennifer, additional, Foster-Barber, Audrey, additional, Kline, Antonie D., additional, Kimball, Amy, additional, Zackai, Elaine, additional, Harr, Margaret, additional, Fox, Joyce, additional, McLaughlin, Julie, additional, Lindstrom, Kristin, additional, Haude, Katrina M., additional, van Roozendaal, Kees, additional, Brunner, Han, additional, Chung, Wendy K., additional, Kooy, R. Frank, additional, Pfundt, Rolph, additional, Kalscheuer, Vera, additional, Mehta, Sarju G., additional, Katsanis, Nicholas, additional, and Kleefstra, Tjitske, additional

Published
2015
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116. Dominant Mutations in KAT6A Cause Intellectual Disability with Recognizable Syndromic Features

Author

Tham, Emma, primary, Lindstrand, Anna, additional, Santani, Avni, additional, Malmgren, Helena, additional, Nesbitt, Addie, additional, Dubbs, Holly A., additional, Zackai, Elaine H., additional, Parker, Michael J., additional, Millan, Francisca, additional, Rosenbaum, Kenneth, additional, Wilson, Golder N., additional, and Nordgren, Ann, additional

Published
2015
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117. CRTAPmutation in a patient with Cole-Carpenter syndrome

Author

Balasubramanian, Meena, primary, Pollitt, Rebecca C., additional, Chandler, Kate E., additional, Mughal, M. Z., additional, Parker, Michael J., additional, Dalton, Ann, additional, Arundel, Paul, additional, Offiah, Amaka C., additional, and Bishop, Nicholas J., additional

Published
2015
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118. Philosophical reflections

Author

Parker, Michael J., Ashcroft, R., Verkerk, Marian, Widdershoven, Guy A. M., Lucassen, A., Parker, M., Verkerk, M.A., Widdershoven, G.A., and Faculteit Medische Wetenschappen/UMCG

Published
2005

119. Mutations specific to the Rac-GEF domain of TRIO cause intellectual disability and microcephaly.

Author

Pengelly, Reuben J., Greville-Heygate, Stephanie, Schmidt, Susanne, Seaby, Eleanor G., Jabalameli, M. Reza, Mehta, Sarju G., Parker, Michael J., Goudie, David, Fagotto-Kaufmann, Christine, Mercer, Catherine, Debant, Anne, Ennis, Sarah, and Baralle, Diana

Abstract

Background Neurodevelopmental disorders have challenged clinical genetics for decades, with over 700 genes implicated and many whose function remains unknown. The application of whole-exome sequencing is proving pivotal in closing the genotype/phenotype gap through the discovery of new genes and variants that help to unravel the pathogenic mechanisms driving neuropathogenesis. One such discovery includes TRIO, a gene recently implicated in neurodevelopmental delay. Trio is a Dbl family guanine nucleotide exchange factor (GEF) and a major regulator of neuronal development, controlling actin cytoskeleton dynamics by activating the GTPase Rac1. Methods Whole-exome sequencing was undertaken on a family presenting with global developmental delay, microcephaly and mild dysmorphism. Father/daughter exome analysis was performed, followed by confirmatory Sanger sequencing and segregation analysis on four individuals. Three further patients were recruited through the deciphering developmental disorders (DDD) study. Functional studies were undertaken using patient-specific Trio protein mutations. Results We identified a frameshift deletion in TRIO that segregated autosomal dominantly. By scrutinising data from DDD, we further identified three unrelated children with a similar phenotype who harboured de novo missense mutations in TRIO. Biochemical studies demonstrated that in three out of four families, the Trio mutations led to a markedly reduced Rac1 activation. Conclusions We describe an inherited global developmental delay phenotype associated with a frameshift deletion in TRIO. Additionally, we identify pathogenic de novo missense mutations in TRIO associated with the same consistent phenotype, intellectual disability, microcephaly and dysmorphism with striking digital features. We further functionally validate the importance of the GEF domain in Trio protein function. Our study demonstrates how genomic technologies are yet again proving prolific in diagnosing and advancing the understanding of neurodevelopmental disorders. [ABSTRACT FROM AUTHOR]

Published
2016
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122. De Novo Loss-of-Function Mutations in SETD5, Encoding a Methyltransferase in a 3p25 Microdeletion Syndrome Critical Region, Cause Intellectual Disability

Author

Grozeva, Detelina, primary, Carss, Keren, additional, Spasic-Boskovic, Olivera, additional, Parker, Michael J., additional, Archer, Hayley, additional, Firth, Helen V., additional, Park, Soo-Mi, additional, Canham, Natalie, additional, Holder, Susan E., additional, Wilson, Meredith, additional, Hackett, Anna, additional, Field, Michael, additional, Floyd, James A.B., additional, Hurles, Matthew, additional, and Raymond, F. Lucy, additional

Published
2014
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127. Genotype–phenotype study in type V osteogenesis imperfecta

Author

Balasubramanian, Meena, primary, Parker, Michael J., additional, Dalton, Ann, additional, Giunta, Cecilia, additional, Lindert, Uschi, additional, Peres, Luiz C., additional, Wagner, Bart E., additional, Arundel, Paul, additional, Offiah, Amaka, additional, and Bishop, Nicholas J., additional

Published
2013
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129. Distinct genetic architectures for syndromic and nonsyndromic congenital heart defects identified by exome sequencing

Author

Sifrim, Alejandro, Hitz, Marc-Phillip, Wilsdon, Anna, Breckpot, Jeroen, Al Turki, Saeed H., Thienpont, Bernard, McRae, Jeremy, Fitzgerald, Tomas W, Singh, Tarjinder, Swaminathan, Ganesh Jawahar, Prigmore, Elena, Rajan, Diana, Abdul-Khaliq, Hashim, Banka, Siddharth, Bauer, Ulrike M. M., Bentham, Jamie, Berger, Felix, Bhattacharya, Shoumo, Bu'Lock, Frances, Canham, Natalie, Colgiu, Irina-Gabriela, Cosgrove, Catherine, Cox, Helen, Daehnert, Ingo, Daly, Allan, Danesh, John, Fryer, Alan, Gewillig, Marc, Hobson, Emma, Hoff, Kirstin, Homfray, Tessa, Kahlert, Anne-Karin, Ketley, Ami, Kramer, Hans-Heiner, Lachlan, Katherine, Lampe, Anne Katrin, Louw, Jacoba J., Manickara, Ashok Kumar, Manase, Dorin, McCarthy, Karen P., Metcalfe, Kay, Moore, Carmel, Newbury-Ecob, Ruth, Omer, Seham Osman, Ouwehand, Willem H., Park, Soo-Mi, Parker, Michael J., Pickardt, Thomas, Pollard, Martin O., Robert, Leema, Roberts, David J., Sambrook, Jennifer, Setchfield, Kerry, Stiller, Brigitte, Thornborough, Chris, Toka, Okan, Watkins, Hugh, Williams, Denise, Wright, Michael, Mital, Seema, Daubeney, Piers E. F., Keavney, Bernard, Goodship, Judith, Abu-Sulaiman, Riyadh Mahdi, Klaassen, Sabine, Wright, Caroline F., Firth, Helen V., Barrett, Jeffrey C., Devriendt, Koenraad, FitzPatrick, David R., Brook, J. David, and Hurles, Matthew

Abstract

Congenital Heart Defects (CHD) have a neonatal incidence of 0.8-1%1,2. Despite abundant examples of monogenic CHD in humans and mice, CHD has a low absolute sibling recurrence risk (~2.7%)3, suggesting a considerable role for de novo mutations (DNM), and/or incomplete penetrance4,5. De novo protein-truncating variants (PTVs) have been shown to be enriched among the 10% of ‘syndromic’ patients with extra-cardiac manifestations6,7. We exome sequenced 1,891 probands, including both syndromic (S-CHD, n=610) and non-syndromic cases (NS-CHD, n=1,281). In S-CHD, we confirmed a significant enrichment of de novo PTVs, but not inherited PTVs, in known CHD-associated genes, consistent with recent findings8. Conversely, in NS-CHD we observed significant enrichment of PTVs inherited from unaffected parents in CHD-associated genes. We identified three novel genome-wide significant S-CHD disorders caused by DNMs in CHD4, CDK13 and PRKD1. Our study reveals distinct genetic architectures underlying the low sibling recurrence risk in S-CHD and NS-CHD.

Published
2018
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131. Two families with sibling recurrence of the 17q21.31 microdeletion syndrome due to low-grade mosaicism

Author

Koolen, David A, primary, Dupont, Juliette, additional, de Leeuw, Nicole, additional, Vissers, Lisenka ELM, additional, van den Heuvel, Simone PA, additional, Bradbury, Alyson, additional, Steer, James, additional, de Brouwer, Arjan PM, additional, ten Kate, Leo P, additional, Nillesen, Willy M, additional, de Vries, Bert BA, additional, and Parker, Michael J, additional

Published
2012
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134. How genetically heterogeneous is Kabuki syndrome?: MLL2 testing in 116 patients, review and analyses of mutation and phenotypic spectrum

Author

Banka, Siddharth, primary, Veeramachaneni, Ratna, additional, Reardon, William, additional, Howard, Emma, additional, Bunstone, Sancha, additional, Ragge, Nicola, additional, Parker, Michael J, additional, Crow, Yanick J, additional, Kerr, Bronwyn, additional, Kingston, Helen, additional, Metcalfe, Kay, additional, Chandler, Kate, additional, Magee, Alex, additional, Stewart, Fiona, additional, McConnell, Vivienne P M, additional, Donnelly, Deirdre E, additional, Berland, Siren, additional, Houge, Gunnar, additional, Morton, Jenny E, additional, Oley, Christine, additional, Revencu, Nicole, additional, Park, Soo-Mi, additional, Davies, Sally J, additional, Fry, Andrew E, additional, Lynch, Sally Ann, additional, Gill, Harinder, additional, Schweiger, Susann, additional, Lam, Wayne W K, additional, Tolmie, John, additional, Mohammed, Shehla N, additional, Hobson, Emma, additional, Smith, Audrey, additional, Blyth, Moira, additional, Bennett, Christopher, additional, Vasudevan, Pradeep C, additional, García-Miñaúr, Sixto, additional, Henderson, Alex, additional, Goodship, Judith, additional, Wright, Michael J, additional, Fisher, Richard, additional, Gibbons, Richard, additional, Price, Susan M, additional, C de Silva, Deepthi, additional, Temple, I Karen, additional, Collins, Amanda L, additional, Lachlan, Katherine, additional, Elmslie, Frances, additional, McEntagart, Meriel, additional, Castle, Bruce, additional, Clayton-Smith, Jill, additional, Black, Graeme C, additional, and Donnai, Dian, additional

Published
2011
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137. Effective business structures

Author

Drum, Paul and Parker, Michael J.

Subjects
Capital gains tax -- Management, Small business -- Australia, Taxation -- Australia, Banking, finance and accounting industries
Abstract

Suggestions are presented on how small businesses in Australia can best access capital gains tax (CGT) concessions through relevant business planning. Various risk factors in capital gains tax, such as a magnified effect on even the most straightforward transactions, make it important to keep up to date with CGT and effective business structures to make the best use of small business CGT concessions.

Published
2001

142. Genetic and phenotypic dissection of 1q43q44 microdeletion syndrome and neurodevelopmental phenotypes associated with mutations in ZBTB18 and HNRNPU

Author

Depienne, Christel, Nava, Caroline, Keren, Boris, Heide, Solveig, Rastetter, Agnès, Passemard, Sandrine, Chantot-Bastaraud, Sandra, Moutard, Marie-Laure, Agrawal, Pankaj B., VanNoy, Grace, Stoler, Joan M., Amor, David J., Billette de Villemeur, Thierry, Doummar, Diane, Alby, Caroline, Cormier-Daire, Valérie, Garel, Catherine, Marzin, Pauline, Scheidecker, Sophie, de Saint-Martin, Anne, Hirsch, Edouard, Korff, Christian, Bottani, Armand, Faivre, Laurence, Verloes, Alain, Orzechowski, Christine, Burglen, Lydie, Leheup, Bruno, Roume, Joelle, Andrieux, Joris, Sheth, Frenny, Datar, Chaitanya, Parker, Michael J., Pasquier, Laurent, Odent, Sylvie, Naudion, Sophie, Delrue, Marie-Ange, Le Caignec, Cédric, Vincent, Marie, Isidor, Bertrand, Renaldo, Florence, Stewart, Fiona, Toutain, Annick, Koehler, Udo, Häckl, Birgit, von Stülpnagel, Celina, Kluger, Gerhard, Møller, Rikke S., Pal, Deb, Jonson, Tord, Soller, Maria, Verbeek, Nienke E., van Haelst, Mieke M., de Kovel, Carolien, Koeleman, Bobby, Monroe, Glen, van Haaften, Gijs, Attié-Bitach, Tania, Boutaud, Lucile, Héron, Delphine, and Mignot, Cyril

Abstract

Subtelomeric 1q43q44 microdeletions cause a syndrome associating intellectual disability, microcephaly, seizures and anomalies of the corpus callosum. Despite several previous studies assessing genotype-phenotype correlations, the contribution of genes located in this region to the specific features of this syndrome remains uncertain. Among those, three genes, AKT3, HNRNPU and ZBTB18 are highly expressed in the brain and point mutations in these genes have been recently identified in children with neurodevelopmental phenotypes. In this study, we report the clinical and molecular data from 17 patients with 1q43q44 microdeletions, four with ZBTB18 mutations and seven with HNRNPU mutations, and review additional data from 37 previously published patients with 1q43q44 microdeletions. We compare clinical data of patients with 1q43q44 microdeletions with those of patients with point mutations in HNRNPU and ZBTB18 to assess the contribution of each gene as well as the possibility of epistasis between genes. Our study demonstrates that AKT3 haploinsufficiency is the main driver for microcephaly, whereas HNRNPU alteration mostly drives epilepsy and determines the degree of intellectual disability. ZBTB18 deletions or mutations are associated with variable corpus callosum anomalies with an incomplete penetrance. ZBTB18 may also contribute to microcephaly and HNRNPU to thin corpus callosum, but with a lower penetrance. Co-deletion of contiguous genes has additive effects. Our results confirm and refine the complex genotype-phenotype correlations existing in the 1qter microdeletion syndrome and define more precisely the neurodevelopmental phenotypes associated with genetic alterations of AKT3, ZBTB18 and HNRNPU in humans. Electronic supplementary material The online version of this article (doi:10.1007/s00439-017-1772-0) contains supplementary material, which is available to authorized users.

Published
2017
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147. Discovering misattributed paternity in genetic counselling: different ethical perspectives in two countries.

Author

Tozzo, Pamela, Caenazzo, Luciana, and Parker, Michael J

Subjects
PATERNITY, GENETIC testing, MEDICAL informatics, MEDICAL personnel, GENETIC counseling, DEONTOLOGICAL ethics
Abstract

Misattributed paternity or 'false' paternity is when a man is wrongly thought, by himself and possibly by others, to be the biological father of a child. Nowadays, because of the progression of genetics and genomics the possibility of finding misattributed paternity during familial genetic testing has increased. In contrast to other medical information, which pertains primarily to individuals, information obtained by genetic testing and/or pedigree analysis necessarily has implications for other biologically related members in the family. Disclosing or not a misattributed paternity has a number of different biological and social consequences for the people involved. Such an issue presents important ethical and deontological challenges. The debate centres on whether or not to inform the family and, particularly, whom in the family, about the possibility that misattributed paternity might be discovered incidentally, and whether or not it is the duty of the healthcare professional (HCP) to disclose the results and to whom. In this paper, we consider the different perspectives and reported problems, and analyse their cultural, ethical and legal dimensions. We compare the position of HCPs from an Italian and British point of view, particularly their role in genetic counselling. We discuss whether the Oviedo Convention of the Council of Europe (1997) can be seen as a basis for enriching the debate. [ABSTRACT FROM AUTHOR]

Published
2014
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