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1. Author Correction: CHD3 helicase domain mutations cause a neurodevelopmental syndrome with macrocephaly and impaired speech and language

Author

Snijders Blok, Lot, Rousseau, Justine, Twist, Joanna, Ehresmann, Sophie, Takaku, Motoki, Venselaar, Hanka, Rodan, Lance H., Nowak, Catherine B., Douglas, Jessica, Swoboda, Kathryn J., Steeves, Marcie A., Sahai, Inderneel, Stumpel, Connie T. R. M., Stegmann, Alexander P. A., Wheeler, Patricia, Willing, Marcia, Fiala, Elise, Kochhar, Aaina, Gibson, William T., Cohen, Ana S. A., Agbahovbe, Ruky, Innes, A. Micheil, Au, P. Y. Billie, Rankin, Julia, Anderson, Ilse J., Skinner, Steven A., Louie, Raymond J., Warren, Hannah E., Afenjar, Alexandra, Keren, Boris, Nava, Caroline, Buratti, Julien, Isapof, Arnaud, Rodriguez, Diana, Lewandowski, Raymond, Propst, Jennifer, van Essen, Ton, Choi, Murim, Lee, Sangmoon, Chae, Jong H., Price, Susan, Schnur, Rhonda E., Douglas, Ganka, Wentzensen, Ingrid M., Zweier, Christiane, Reis, André, Bialer, Martin G., Moore, Christine, Koopmans, Marije, Brilstra, Eva H., Monroe, Glen R., van Gassen, Koen L. I., van Binsbergen, Ellen, Newbury-Ecob, Ruth, Bownass, Lucy, Bader, Ingrid, Mayr, Johannes A., Wortmann, Saskia B., Jakielski, Kathy J., Strand, Edythe A., Kloth, Katja, Bierhals, Tatjana, McRae, Jeremy F., Clayton, Stephen, Fitzgerald, Tomas W., Kaplanis, Joanna, Prigmore, Elena, Rajan, Diana, Sifrim, Alejandro, Aitken, Stuart, Akawi, Nadia, Alvi, Mohsan, Ambridge, Kirsty, Barrett, Daniel M., Bayzetinova, Tanya, Jones, Philip, Jones, Wendy D., King, Daniel, Krishnappa, Netravathi, Mason, Laura E., Singh, Tarjinder, Tivey, Adrian R., Ahmed, Munaza, Anjum, Uruj, Archer, Hayley, Armstrong, Ruth, Awada, Jana, Balasubramanian, Meena, Banka, Siddharth, Baralle, Diana, Barnicoat, Angela, Batstone, Paul, Baty, David, Bennett, Chris, Berg, Jonathan, Bernhard, Birgitta, Bevan, A. Paul, Bitner-Glindzicz, Maria, Blair, Edward, Blyth, Moira, Bohanna, David, Bourdon, Louise, Bourn, David, Bradley, Lisa, Brady, Angela, Brent, Simon, Brewer, Carole, Brunstrom, Kate, Bunyan, David J., Burn, John, Canham, Natalie, Castle, Bruce, Chandler, Kate, Chatzimichali, Elena, Cilliers, Deirdre, Clarke, Angus, Clasper, Susan, Clayton-Smith, Jill, Clowes, Virginia, Coates, Andrea, Cole, Trevor, Colgiu, Irina, Collins, Amanda, Collinson, Morag N., Connell, Fiona, Cooper, Nicola, Cox, Helen, Cresswell, Lara, Cross, Gareth, Crow, Yanick, D’Alessandro, Mariella, Dabir, Tabib, Davidson, Rosemarie, Davies, Sally, de Vries, Dylan, Dean, John, Deshpande, Charu, Devlin, Gemma, Dixit, Abhijit, Dobbie, Angus, Donaldson, Alan, Donnai, Dian, Donnelly, Deirdre, Donnelly, Carina, Douglas, Angela, Douzgou, Sofia, Duncan, Alexis, Eason, Jacqueline, Ellard, Sian, Ellis, Ian, Elmslie, Frances, Evans, Karenza, Everest, Sarah, Fendick, Tina, Fisher, Richard, Flinter, Frances, Foulds, Nicola, Fry, Andrew, Fryer, Alan, Gardiner, Carol, Gaunt, Lorraine, Ghali, Neeti, Gibbons, Richard, Gill, Harinder, Goodship, Judith, Goudie, David, Gray, Emma, Green, Andrew, Greene, Philip, Greenhalgh, Lynn, Gribble, Susan, Harrison, Rachel, Harrison, Lucy, Harrison, Victoria, Hawkins, Rose, He, Liu, Hellens, Stephen, Henderson, Alex, Hewitt, Sarah, Hildyard, Lucy, Hobson, Emma, Holden, Simon, Holder, Muriel, Holder, Susan, Hollingsworth, Georgina, Homfray, Tessa, Humphreys, Mervyn, Hurst, Jane, Hutton, Ben, Ingram, Stuart, Irving, Melita, Islam, Lily, Jackson, Andrew, Jarvis, Joanna, Jenkins, Lucy, Johnson, Diana, Jones, Elizabeth, Josifova, Dragana, Joss, Shelagh, Kaemba, Beckie, Kazembe, Sandra, Kelsell, Rosemary, Kerr, Bronwyn, Kingston, Helen, Kini, Usha, Kinning, Esther, Kirby, Gail, Kirk, Claire, Kivuva, Emma, Kraus, Alison, Kumar, Dhavendra, Kumar, V. K. Ajith, Lachlan, Katherine, Lam, Wayne, Lampe, Anne, Langman, Caroline, Lees, Melissa, Lim, Derek, Longman, Cheryl, Lowther, Gordon, Lynch, Sally A., Magee, Alex, Maher, Eddy, Male, Alison, Mansour, Sahar, Marks, Karen, Martin, Katherine, Maye, Una, McCann, Emma, McConnell, Vivienne, McEntagart, Meriel, McGowan, Ruth, McKay, Kirsten, McKee, Shane, McMullan, Dominic J., McNerlan, Susan, McWilliam, Catherine, Mehta, Sarju, Metcalfe, Kay, Middleton, Anna, Miedzybrodzka, Zosia, Miles, Emma, Mohammed, Shehla, Montgomery, Tara, Moore, David, Morgan, Sian, Morton, Jenny, Mugalaasi, Hood, Murday, Victoria, Murphy, Helen, Naik, Swati, Nemeth, Andrea, Nevitt, Louise, Norman, Andrew, O’Shea, Rosie, Ogilvie, Caroline, Ong, Kai-Ren, Park, Soo-Mi, Parker, Michael J., Patel, Chirag, Paterson, Joan, Payne, Stewart, Perrett, Daniel, Phipps, Julie, Pilz, Daniela T., Pollard, Martin, Pottinger, Caroline, Poulton, Joanna, Pratt, Norman, Prescott, Katrina, Pridham, Abigail, Procter, Annie, Purnell, Hellen, Quarrell, Oliver, Ragge, Nicola, Rahbari, Raheleh, Randall, Josh, Raymond, Lucy, Rice, Debbie, Robert, Leema, Roberts, Eileen, Roberts, Jonathan, Roberts, Paul, Roberts, Gillian, Ross, Alison, Rosser, Elisabeth, Saggar, Anand, Samant, Shalaka, Sampson, Julian, Sandford, Richard, Sarkar, Ajoy, Schweiger, Susann, Scott, Richard, Scurr, Ingrid, Selby, Ann, Seller, Anneke, Sequeira, Cheryl, Shannon, Nora, Sharif, Saba, Shaw-Smith, Charles, Shearing, Emma, Shears, Debbie, Sheridan, Eamonn, Simonic, Ingrid, Singzon, Roldan, Skitt, Zara, Smith, Audrey, Smith, Kath, Smithson, Sarah, Sneddon, Linda, Splitt, Miranda, Squires, Miranda, Stewart, Fiona, Stewart, Helen, Straub, Volker, Suri, Mohnish, Sutton, Vivienne, Swaminathan, Ganesh Jawahar, Sweeney, Elizabeth, Tatton-Brown, Kate, Taylor, Cat, Taylor, Rohan, Tein, Mark, Temple, I. Karen, Thomson, Jenny, Tischkowitz, Marc, Tomkins, Susan, Torokwa, Audrey, Treacy, Becky, Turner, Claire, Turnpenny, Peter, Tysoe, Carolyn, Vandersteen, Anthony, Varghese, Vinod, Vasudevan, Pradeep, Vijayarangakannan, Parthiban, Vogt, Julie, Wakeling, Emma, Wallwark, Sarah, Waters, Jonathon, Weber, Astrid, Wellesley, Diana, Whiteford, Margo, Widaa, Sara, Wilcox, Sarah, Wilkinson, Emily, Williams, Denise, Williams, Nicola, Wilson, Louise, Woods, Geoff, Wragg, Christopher, Wright, Michael, Yates, Laura, Yau, Michael, Nellåker, Chris, Parker, Michael, Firth, Helen V., Wright, Caroline F., FitzPatrick, David R., Barrett, Jeffrey C., Hurles, Matthew E., Roberts, John D., Petrovich, Robert M., Machida, Shinichi, Kurumizaka, Hitoshi, Lelieveld, Stefan, Pfundt, Rolph, Jansen, Sandra, Deriziotis, Pelagia, Faivre, Laurence, Thevenon, Julien, Assoum, Mirna, Shriberg, Lawrence, Kleefstra, Tjitske, Brunner, Han G., Wade, Paul A., Fisher, Simon E., and Campeau, Philippe M.

Subjects
Male, Models, Molecular, Developmental Disabilities, Gene Expression, General Physics and Astronomy, 02 engineering and technology, Chromatin remodelling, Sociology, lcsh:Science, Independent research, Adenosine Triphosphatases, 0303 health sciences, Multidisciplinary, biology, Health innovation, Disease genetics, Published Erratum, Neurodevelopmental disorders, 021001 nanoscience & nanotechnology, Spelling, 3. Good health, Phenotype, General partnership, Child, Preschool, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, Female, medicine.symptom, Construct (philosophy), 0210 nano-technology, Psychology, Mi-2 Nucleosome Remodeling and Deacetylase Complex, Clinical epigenetics, Genotype, Science, Mutation, Missense, Library science, Child health, Speech Disorders, General Biochemistry, Genetics and Molecular Biology, Domain (software engineering), 03 medical and health sciences, Protein Domains, Intellectual Disability, medicine, Humans, Author Correction, 030304 developmental biology, Research ethics, Language Disorders, Whole Genome Sequencing, Core Grant, Macrocephaly, DNA Helicases, Helicase, General Chemistry, Chromatin Assembly and Disassembly, Megalencephaly, HEK293 Cells, biology.protein, lcsh:Q, Neuroscience, Impaired speech
Abstract

An Author Correction to this article was published on 15 February 2019 An Author Correction to this article was published on 02 May 2019 We thank all individuals and families for their contribution. We thank Amaia Carrion Castillo and Else Eising for assistance with the WGS analysis of the index individual, and Sarah Graham and Elliot Sollis for cloning the wild-type CHD3 construct for immunofluorescence. This work was supported by the Netherlands Organization for Scientific Research (NWO) Gravitation Grant 24.001.006 to the Language in Interaction Consortium (L.S.B., S.E.F., and H.G.B.), the Max Planck Society (S.E.F.), the National Institute on Deafness and Other Communication Disorders Grant DC000496 (L.Sh.) and a core grant to the Waisman Center from the National Institute of Child Health and Human Development (Grant U54 HD090256) to L.Sh., the Canadian Institutes of Health Research Grants MOP-119595 and PJT-148830 to W.T.G. Individuals 11, 16, 24, and 28 were part of The DDD Study cohort. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund [Grant number HICF-1009-003], a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute [Grant number WT098051]. The views expressed in this publication are those of the author(s) and not necessarily those of the Wellcome Trust or the Department of Health. The DDD study has UK Research Ethics Committee approval (10/H0305/83, granted by the Cambridge South REC, and GEN/284/12, granted by the Republic of Ireland REC). The research team acknowledges the support of the National Institute for Health Research, through the Comprehensive Clinical Research Network.

Published
2019
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2. Prevalence and architecture of de novo mutations in developmental disorders

Author

McRae, Jeremy F., Clayton, Stephen, Fitzgerald, Tomas W., Kaplanis, Joanna, Prigmore, Elena, Rajan, Diana, Sifrim, Alejandro, Aitken, Stuart, Akawi, Nadia, Alvi, Mohsan, Ambridge, Kirsty, Barrett, Daniel M., Bayzetinova, Tanya, Jones, Philip, Jones, Wendy D., King, Daniel, Krishnappa, Netravathi, Mason, Laura E., Singh, Tarjinder, Tivey, Adrian R., Ahmed, Munaza, Anjum, Uruj, Archer, Hayley, Armstrong, Ruth, Awada, Jana, Balasubramanian, Meena, Banka, Siddharth, Baralle, Diana, Barnicoat, Angela, Batstone, Paul, Baty, David, Bennett, Chris, Berg, Jonathan, Bernhard, Birgitta, Bevan, A. Paul, Bitner-Glindzicz, Maria, Blair, Edward, Blyth, Moira, Bohanna, David, Bourdon, Louise, Bourn, David, Bradley, Lisa, Brady, Angela, Brent, Simon, Brewer, Carole, Brunstrom, Kate, Bunyan, David J., Burn, John, Canham, Natalie, Castle, Bruce, Chandler, Kate, Chatzimichali, Elena, Cilliers, Deirdre, Clarke, Angus, Clasper, Susan, Clayton-Smith, Jill, Clowes, Virginia, Coates, Andrea, Cole, Trevor, Colgiu, Irina, Collins, Amanda, Collinson, Morag N., Connell, Fiona, Cooper, Nicola, Cox, Helen, Cresswell, Lara, Cross, Gareth, Crow, Yanick, DAlessandro, Mariella, Dabir, Tabib, Davidson, Rosemarie, Davies, Sally, de Vries, Dylan, Dean, John, Deshpande, Charu, Devlin, Gemma, Dixit, Abhijit, Dobbie, Angus, Donaldson, Alan, Donnai, Dian, Donnelly, Deirdre, Donnelly, Carina, Douglas, Angela, Douzgou, Sofia, Duncan, Alexis, Eason, Jacqueline, Ellard, Sian, Ellis, Ian, Elmslie, Frances, Evans, Karenza, Everest, Sarah, Fendick, Tina, Fisher, Richard, Flinter, Frances, Foulds, Nicola, Fry, Andrew, Fryer, Alan, Gardiner, Carol, Gaunt, Lorraine, Ghali, Neeti, Gibbons, Richard, Gill, Harinder, Goodship, Judith, Goudie, David, Gray, Emma, Green, Andrew, Greene, Philip, Greenhalgh, Lynn, Gribble, Susan, Harrison, Rachel, Harrison, Lucy, Harrison, Victoria, Hawkins, Rose, He, Liu, Hellens, Stephen, Henderson, Alex, Hewitt, Sarah, Hildyard, Lucy, Hobson, Emma, Holden, Simon, Holder, Muriel, Holder, Susan, Hollingsworth, Georgina, Homfray, Tessa, Humphreys, Mervyn, Hurst, Jane, Hutton, Ben, Ingram, Stuart, Irving, Melita, Islam, Lily, Jackson, Andrew, Jarvis, Joanna, Jenkins, Lucy, Johnson, Diana, Jones, Elizabeth, Josifova, Dragana, Joss, Shelagh, Kaemba, Beckie, Kazembe, Sandra, Kelsell, Rosemary, Kerr, Bronwyn, Kingston, Helen, Kini, Usha, Kinning, Esther, Kirby, Gail, Kirk, Claire, Kivuva, Emma, Kraus, Alison, Kumar, Dhavendra, Kumar, V. K. Ajith, Lachlan, Katherine, Lam, Wayne, Lampe, Anne, Langman, Caroline, Lees, Melissa, Lim, Derek, Longman, Cheryl, Lowther, Gordon, Lynch, Sally A., Magee, Alex, Maher, Eddy, Male, Alison, Mansour, Sahar, Marks, Karen, Martin, Katherine, Maye, Una, McCann, Emma, McConnell, Vivienne, McEntagart, Meriel, McGowan, Ruth, McKay, Kirsten, McKee, Shane, McMullan, Dominic J., McNerlan, Susan, McWilliam, Catherine, Mehta, Sarju, Metcalfe, Kay, Middleton, Anna, Miedzybrodzka, Zosia, Miles, Emma, Mohammed, Shehla, Montgomery, Tara, Moore, David, Morgan, Sian, Morton, Jenny, Mugalaasi, Hood, Murday, Victoria, Murphy, Helen, Naik, Swati, Nemeth, Andrea, Nevitt, Louise, Newbury-Ecob, Ruth, Norman, Andrew, OShea, Rosie, Ogilvie, Caroline, Ong, Kai-Ren, Park, Soo-Mi, Parker, Michael J., Patel, Chirag, Paterson, Joan, Payne, Stewart, Perrett, Daniel, Phipps, Julie, Pilz, Daniela T., Pollard, Martin, Pottinger, Caroline, Poulton, Joanna, Pratt, Norman, Prescott, Katrina, Price, Sue, Pridham, Abigail, Procter, Annie, Purnell, Hellen, Quarrell, Oliver, Ragge, Nicola, Rahbari, Raheleh, Randall, Josh, Rankin, Julia, Raymond, Lucy, Rice, Debbie, Robert, Leema, Roberts, Eileen, Roberts, Jonathan, Roberts, Paul, Roberts, Gillian, Ross, Alison, Rosser, Elisabeth, Saggar, Anand, Samant, Shalaka, Sampson, Julian, Sandford, Richard, Sarkar, Ajoy, Schweiger, Susann, Scott, Richard, Scurr, Ingrid, Selby, Ann, Seller, Anneke, Sequeira, Cheryl, Shannon, Nora, Sharif, Saba, Shaw-Smith, Charles, Shearing, Emma, Shears, Debbie, Sheridan, Eamonn, Simonic, Ingrid, Singzon, Roldan, Skitt, Zara, Smith, Audrey, Smith, Kath, Smithson, Sarah, Sneddon, Linda, Splitt, Miranda, Squires, Miranda, Stewart, Fiona, Stewart, Helen, Straub, Volker, Suri, Mohnish, Sutton, Vivienne, Swaminathan, Ganesh Jawahar, Sweeney, Elizabeth, Tatton-Brown, Kate, Taylor, Cat, Taylor, Rohan, Tein, Mark, Temple, I. Karen, Thomson, Jenny, Tischkowitz, Marc, Tomkins, Susan, Torokwa, Audrey, Treacy, Becky, Turner, Claire, Turnpenny, Peter, Tysoe, Carolyn, Vandersteen, Anthony, Varghese, Vinod, Vasudevan, Pradeep, Vijayarangakannan, Parthiban, Vogt, Julie, Wakeling, Emma, Wallwark, Sarah, Waters, Jonathon, Weber, Astrid, Wellesley, Diana, Whiteford, Margo, Widaa, Sara, Wilcox, Sarah, Wilkinson, Emily, Williams, Denise, Williams, Nicola, Wilson, Louise, Woods, Geoff, Wragg, Christopher, Wright, Michael, Yates, Laura, Yau, Michael, Nellker, Chris, Parker, Michael, Firth, Helen V., Wright, Caroline F., FitzPatrick, David R., Barrett, Jeffrey C., and Hurles, Matthew E.

Subjects
Distribution, Genetic aspects, Company distribution practices, Developmental disabilities -- Genetic aspects, Genetic disorders -- Distribution
Abstract

Author(s): Deciphering Developmental Disorders Study; Jeremy F. McRae [1]; Stephen Clayton [1]; Tomas W. Fitzgerald [1]; Joanna Kaplanis [1]; Elena Prigmore [1]; Diana Rajan [1]; Alejandro Sifrim [1]; Stuart Aitken [...], The genomes of individuals with severe, undiagnosed developmental disorders are enriched in damaging de novo mutations (DNMs) in developmentally important genes. Here we have sequenced the exomes of 4,293 families containing individuals with developmental disorders, and meta-analysed these data with data from another 3,287 individuals with similar disorders. We show that the most important factors influencing the diagnostic yield of DNMs are the sex of the affected individual, the relatedness of their parents, whether close relatives are affected and the parental ages. We identified 94 genes enriched in damaging DNMs, including 14 that previously lacked compelling evidence of involvement in developmental disorders. We have also characterized the phenotypic diversity among these disorders. We estimate that 42% of our cohort carry pathogenic DNMs in coding sequences; approximately half of these DNMs disrupt gene function and the remainder result in altered protein function. We estimate that developmental disorders caused by DNMs have an average prevalence of 1 in 213 to 1 in 448 births, depending on parental age. Given current global demographics, this equates to almost 400,000 children born per year.

Published
2017
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3. How genetically heterogeneous is Kabuki syndrome?: MLL2 testing in 116 patients, review and analyses of mutation and phenotypic spectrum

Author

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

Abstract

MLL2 mutations are detected in 55 to 80% of patients with Kabuki syndrome (KS). In 20 to 45% patients with KS, the genetic basis remains unknown, suggesting possible genetic heterogeneity. Here, we present the largest yet reported cohort of 116 patients with KS. We identified MLL2 variants in 74 patients, of which 47 are novel and a majority are truncating. We show that pathogenic missense mutations were commonly located in exon 48. We undertook a systematic facial KS morphology study of patients with KS at our regional dysmorphology meeting. Our data suggest that nearly all patients with typical KS facial features have pathogenic MLL2 mutations, although KS can be phenotypically variable. Furthermore, we show that MLL2 mutation-positive KS patients are more likely to have feeding problems, kidney anomalies, early breast bud development, joint dislocations and palatal malformations in comparison with MLL2 mutation-negative patients. Our work expands the mutation spectrum of MLL2 that may help in better understanding of this molecule, which is important in gene expression, epigenetic control of active chromatin states, embryonic development and cancer. Our analyses of the phenotype indicates that MLL2 mutation-positive and -negative patients differ systematically, and genetic heterogeneity of KS is not as extensive as previously suggested. Moreover, phenotypic variability of KS suggests that MLL2 testing should be considered even in atypical patients.

Published
2012

4. Distinct genetic architectures for syndromic and nonsyndromic congenital heart defects identified by exome sequencing

Author

Sifrim, Alejandro, Hitz, Marc-Phillip, Wilsdon, Anna, Breckpot, Jeroen, Turki, Saeed H Al, 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 A., 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, Christopher, 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, Hurles, Matthew E., Sifrim, Alejandro, Hitz, Marc-Phillip, Wilsdon, Anna, Breckpot, Jeroen, Turki, Saeed H Al, 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 A., 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, Christopher, 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 E.

Abstract

Congenital heart defects (CHDs) have a neonatal incidence of 0.8–1%. Despite abundant examples of monogenic CHD in humans and mice, CHD has a low absolute sibling recurrence risk (~2.7%), suggesting a considerable role for de novo mutations (DNMs) and/or incomplete penetrance. De novo protein-truncating variants (PTVs) have been shown to be enriched among the 10% of 'syndromic' patients with extra-cardiac manifestations. We exome sequenced 1,891 probands, including both syndromic CHD (S-CHD, n = 610) and nonsyndromic CHD (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 findings. Conversely, in NS-CHD we observed significant enrichment of PTVs inherited from unaffected parents in CHD-associated genes. We identified three genome-wide significant S-CHD disorders caused by DNMs in CHD4, CDK13 and PRKD1. Our study finds evidence for distinct genetic architectures underlying the low sibling recurrence risk in S-CHD and NS-CHD.

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5. SDHC epi-mutation testing in gastrointestinal stromal tumours and related tumours in clinical practice.

Author

Casey RT, Ten Hoopen R, Ochoa E, Challis BG, Whitworth J, Smith PS, Martin JE, Clark GR, Rodger F, Maranian M, Allinson K, Madhu B, Roberts T, Campos L, Anstee J, Park SM, Marker A, Watts C, Bulusu VR, Giger OT, and Maher ER

Subjects
Adolescent, Adrenal Gland Neoplasms genetics, Adult, Aged, DNA Methylation genetics, Epigenomics methods, Female, Gastrointestinal Stromal Tumors metabolism, Genes, Regulator genetics, Germ-Line Mutation, High-Throughput Nucleotide Sequencing methods, Humans, Male, Membrane Proteins genetics, Membrane Proteins metabolism, Middle Aged, Mutation, Paraganglioma genetics, Pheochromocytoma genetics, Promoter Regions, Genetic genetics, Succinate Dehydrogenase metabolism, Transcriptome genetics, Epigenesis, Genetic genetics, Gastrointestinal Stromal Tumors genetics, Succinate Dehydrogenase genetics
Abstract

The enzyme succinate dehydrogenase (SDH) functions in the citric acid cycle and loss of function predisposes to the development of phaeochromocytoma/paraganglioma (PPGL), wild type gastrointestinal stromal tumour (wtGIST) and renal cell carcinoma. SDH-deficient tumours are most commonly associated with a germline SDH subunit gene (SDHA/B/C/D) mutation but can also be associated with epigenetic silencing of the SDHC gene. However, clinical diagnostic testing for an SDHC epimutation is not widely available. The objective of this study was to investigate the indications for and the optimum diagnostic pathways for the detection of SDHC epimutations in clinical practice. SDHC promoter methylation analysis of 32 paraffin embedded tumours (including 15 GIST and 17 PPGL) was performed using a pyrosequencing technique and correlated with SDHC gene expression. SDHC promoter methylation was identified in 6 (18.7%) tumours. All 6 SDHC epimutation cases presented with SDH deficient wtGIST and 3/6 cases had multiple primary tumours. No case of constitutional SDHC promoter hypermethylation was detected. Whole genome sequencing of germline DNA from three wtGIST cases with an SDHC epimutation, did not reveal any causative sequence anomalies. Herein, we recommend a diagnostic workflow for the detection of an SDHC epimutation in a service setting.

Published
2019
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6. How genetically heterogeneous is Kabuki syndrome?: MLL2 testing in 116 patients, review and analyses of mutation and phenotypic spectrum.

Author

Banka S, Veeramachaneni R, Reardon W, Howard E, Bunstone S, Ragge N, Parker MJ, Crow YJ, Kerr B, Kingston H, Metcalfe K, Chandler K, Magee A, Stewart F, McConnell VP, Donnelly DE, Berland S, Houge G, Morton JE, Oley C, Revencu N, Park SM, Davies SJ, Fry AE, Lynch SA, Gill H, Schweiger S, Lam WW, Tolmie J, Mohammed SN, Hobson E, Smith A, Blyth M, Bennett C, Vasudevan PC, García-Miñaúr S, Henderson A, Goodship J, Wright MJ, Fisher R, Gibbons R, Price SM, C de Silva D, Temple IK, Collins AL, Lachlan K, Elmslie F, McEntagart M, Castle B, Clayton-Smith J, Black GC, and Donnai D

Subjects
Cohort Studies, Face abnormalities, Female, Humans, Sequence Analysis, DNA, Abnormalities, Multiple genetics, DNA-Binding Proteins genetics, Genetic Heterogeneity, Hematologic Diseases genetics, Mutation, Neoplasm Proteins genetics, Phenotype, Vestibular Diseases genetics
Abstract

MLL2 mutations are detected in 55 to 80% of patients with Kabuki syndrome (KS). In 20 to 45% patients with KS, the genetic basis remains unknown, suggesting possible genetic heterogeneity. Here, we present the largest yet reported cohort of 116 patients with KS. We identified MLL2 variants in 74 patients, of which 47 are novel and a majority are truncating. We show that pathogenic missense mutations were commonly located in exon 48. We undertook a systematic facial KS morphology study of patients with KS at our regional dysmorphology meeting. Our data suggest that nearly all patients with typical KS facial features have pathogenic MLL2 mutations, although KS can be phenotypically variable. Furthermore, we show that MLL2 mutation-positive KS patients are more likely to have feeding problems, kidney anomalies, early breast bud development, joint dislocations and palatal malformations in comparison with MLL2 mutation-negative patients. Our work expands the mutation spectrum of MLL2 that may help in better understanding of this molecule, which is important in gene expression, epigenetic control of active chromatin states, embryonic development and cancer. Our analyses of the phenotype indicates that MLL2 mutation-positive and -negative patients differ systematically, and genetic heterogeneity of KS is not as extensive as previously suggested. Moreover, phenotypic variability of KS suggests that MLL2 testing should be considered even in atypical patients.

Published
2012
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7. Assembly of a Ca2+-dependent BK channel signaling complex by binding to beta2 adrenergic receptor.

Author

Liu G, Shi J, Yang L, Cao L, Park SM, Cui J, and Marx SO

Subjects
Animals, Aorta metabolism, Brain metabolism, Cell Line, Cloning, Molecular, Dimerization, Electrophysiology, Female, Gene Expression Regulation, Glutathione Transferase metabolism, Humans, Immunohistochemistry, Large-Conductance Calcium-Activated Potassium Channel alpha Subunits, Lung metabolism, Models, Biological, Muscle, Smooth metabolism, Oocytes physiology, Patch-Clamp Techniques, Phosphorylation, Potassium Channels genetics, Precipitin Tests, RNA, Messenger genetics, Rats, Receptors, Adrenergic, beta-2 chemistry, Receptors, Adrenergic, beta-2 genetics, Recombinant Fusion Proteins chemistry, Recombinant Fusion Proteins metabolism, Signal Transduction, Up-Regulation, Urinary Bladder metabolism, Xenopus, Calcium metabolism, Potassium Channels metabolism, Potassium Channels, Calcium-Activated metabolism, Receptors, Adrenergic, beta-2 metabolism
Abstract

Large-conductance voltage and Ca2+-activated potassium channels (BKCa) play a critical role in modulating contractile tone of smooth muscle, and neuronal processes. In most mammalian tissues, activation of beta-adrenergic receptors and protein kinase A (PKAc) increases BKCa channel activity, contributing to sympathetic nervous system/hormonal regulation of membrane excitability. Here we report the requirement of an association of the beta2-adrenergic receptor (beta2AR) with the pore forming alpha subunit of BKCa and an A-kinase-anchoring protein (AKAP79/150) for beta2 agonist regulation. beta2AR can simultaneously interact with both BKCa and L-type Ca2+ channels (Cav1.2) in vivo, which enables the assembly of a unique, highly localized signal transduction complex to mediate Ca2+- and phosphorylation-dependent modulation of BKCa current. Our findings reveal a novel function for G protein-coupled receptors as a scaffold to couple two families of ion channels into a physical and functional signaling complex to modulate beta-adrenergic regulation of membrane excitability.

Published
2004
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