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1. New GJA8 variants and phenotypes highlight its critical role in a broad spectrum of eye anomalies

Author

Ceroni, Fabiola, Aguilera-Garcia, Domingo, Chassaing, Nicolas, Bax, Dorine Arjanne, Blanco-Kelly, Fiona, Ramos, Patricia, Tarilonte, Maria, Villaverde, Cristina, Rodrigues Jacy da Silva, Luciana, Ballesta-Martinez, Maria Juliana, Sanchez-Soler, Maria Jose, Holt, Richard James, Cooper-Charles, Lisa, Bruty, Jonathan, Wallis, Yvonne, McMullan, Dominic, Hoffman, Jonathan, Bunyan, David, Stewart, Alison, Stewart, Helen, Lachlan, Katherine, Fryer, Alan, McKay, Victoria, Roume, Joëlle, Dureau, Pascal, Saggar, Anand, Griffiths, Michael, Calvas, Patrick, Ayuso, Carmen, Corton, Marta, Ragge, Nicola K., Ceroni, Fabiola, Aguilera-Garcia, Domingo, Chassaing, Nicolas, Bax, Dorine Arjanne, Blanco-Kelly, Fiona, Ramos, Patricia, Tarilonte, Maria, Villaverde, Cristina, Rodrigues Jacy da Silva, Luciana, Ballesta-Martinez, Maria Juliana, Sanchez-Soler, Maria Jose, Holt, Richard James, Cooper-Charles, Lisa, Bruty, Jonathan, Wallis, Yvonne, McMullan, Dominic, Hoffman, Jonathan, Bunyan, David, Stewart, Alison, Stewart, Helen, Lachlan, Katherine, Fryer, Alan, McKay, Victoria, Roume, Joëlle, Dureau, Pascal, Saggar, Anand, Griffiths, Michael, Calvas, Patrick, Ayuso, Carmen, Corton, Marta, and Ragge, Nicola K.

Abstract

GJA8 encodes connexin 50 (Cx50), a transmembrane protein involved in the formation of lens gap junctions. GJA8 mutations have been linked to early onset cataracts in humans and animal models. In mice, missense mutations and homozygous Gja8 deletions lead to smaller lenses and microphthalmia in addition to cataract, suggesting that Gja8 may play a role in both lens development and ocular growth. Following screening of GJA8 in a cohort of 426 individuals with severe congenital eye anomalies, primarily anophthalmia, microphthalmia and coloboma, we identified four known [p.(Thr39Arg), p.(Trp45Leu), p.(Asp51Asn), and p.(Gly94Arg)] and two novel [p.(Phe70Leu) and p.(Val97Gly)] likely pathogenic variants in seven families. Five of these co-segregated with cataracts and microphthalmia, whereas the variant p.(Gly94Arg) was identified in an individual with congenital aphakia, sclerocornea, microphthalmia and coloboma. Four missense variants of unknown or unlikely clinical significance were also identified. Furthermore, the screening of GJA8 structural variants in a subgroup of 188 individuals identified heterozygous 1q21 microdeletions in five families with coloboma and other ocular and/or extraocular findings. However, the exact genotype–phenotype correlation of these structural variants remains to be established. Our data expand the spectrum of GJA8 variants and associated phenotypes, confirming the importance of this gene in early eye development.

Published
2018

2. De novo mutations in MSL3 cause an X-linked syndrome marked by impaired histone H4 lysine 16 acetylation

Author

Basilicata, M. Felicia, Bruel, Ange Line, Semplicio, Giuseppe, Valsecchi, Claudia Isabelle Keller, Aktaş, Tuğçe, Duffourd, Yannis, Rumpf, Tobias, Morton, Jenny, Bache, Iben, Szymanski, Witold G., Gilissen, Christian, Vanakker, Olivier, Õunap, Katrin, Mittler, Gerhard, van der Burgt, Ineke, El Chehadeh, Salima, Cho, Megan T., Pfundt, Rolph, Tan, Tiong Yang, Kirchhoff, Maria, Menten, Björn, Vergult, Sarah, Lindstrom, Kristin, Reis, André, Johnson, Diana S., Fryer, Alan, McKay, Victoria, Fisher, Richard B., Thauvin-Robinet, Christel, Francis, David, Roscioli, Tony, Pajusalu, Sander, Radtke, Kelly, Ganesh, Jaya, Brunner, Han G., Wilson, Meredith, Faivre, Laurence, Kalscheuer, Vera M., Thevenon, Julien, Akhtar, Asifa, Basilicata, M. Felicia, Bruel, Ange Line, Semplicio, Giuseppe, Valsecchi, Claudia Isabelle Keller, Aktaş, Tuğçe, Duffourd, Yannis, Rumpf, Tobias, Morton, Jenny, Bache, Iben, Szymanski, Witold G., Gilissen, Christian, Vanakker, Olivier, Õunap, Katrin, Mittler, Gerhard, van der Burgt, Ineke, El Chehadeh, Salima, Cho, Megan T., Pfundt, Rolph, Tan, Tiong Yang, Kirchhoff, Maria, Menten, Björn, Vergult, Sarah, Lindstrom, Kristin, Reis, André, Johnson, Diana S., Fryer, Alan, McKay, Victoria, Fisher, Richard B., Thauvin-Robinet, Christel, Francis, David, Roscioli, Tony, Pajusalu, Sander, Radtke, Kelly, Ganesh, Jaya, Brunner, Han G., Wilson, Meredith, Faivre, Laurence, Kalscheuer, Vera M., Thevenon, Julien, and Akhtar, Asifa

Abstract

The etiological spectrum of ultra-rare developmental disorders remains to be fully defined. Chromatin regulatory mechanisms maintain cellular identity and function, where misregulation may lead to developmental defects. Here, we report pathogenic variations in MSL3, which encodes a member of the chromatin-associated male-specific lethal (MSL) complex responsible for bulk histone H4 lysine 16 acetylation (H4K16ac) in flies and mammals. These variants cause an X-linked syndrome affecting both sexes. Clinical features of the syndrome include global developmental delay, progressive gait disturbance, and recognizable facial dysmorphism. MSL3 mutations affect MSL complex assembly and activity, accompanied by a pronounced loss of H4K16ac levels in vivo. Patient-derived cells display global transcriptome alterations of pathways involved in morphogenesis and cell migration. Finally, we use histone deacetylase inhibitors to rebalance acetylation levels, alleviating some of the molecular and cellular phenotypes of patient cells. Taken together, we characterize a syndrome that allowed us to decipher the developmental importance of MSL3 in humans.

Published
2018

3. De Novo Heterozygous Mutations in SMC3 Cause a Range of Cornelia de Lange Syndrome-Overlapping Phenotypes

Author

Concepcion Gil-Rodriguez, Maria, Deardorff, Matthew A., Ansari, Morad, Tan, Christopher A., Parenti, Ilaria, Baquero-Montoya, Carolina, Ousager, Lilian B., Puisac, Beatriz, Hernandez-Marcos, Maria, Esperanza Teresa-Rodrigo, Maria, Marcos-Alcalde, Inigo, Wesselink, Jan-Jaap, Lusa-Bernal, Silvia, Bijlsma, Emilia K., Braunholz, Diana, Bueno-Martinez, Ines, Clark, Dinah, Cooper, Nicola S., Curry, Cynthia J., Fisher, Richard, Fryer, Alan, Ganesh, Jaya, Gervasini, Cristina, Gillessen-Kaesbach, Gabriele, Guo, Yiran, Hakonarson, Hakon, Hopkin, Robert J., Kaur, Maninder, Keating, Brendan J., Kibaek, Maria, Kinning, Esther, Kleefstra, Tjitske, Kline, Antonie D., Kuchinskaya, Ekaterina, Larizza, Lidia, Li, Yun R., Liu, Xuanzhu, Mariani, Milena, Picker, Jonathan D., Pie, Angeles, Pozojevic, Jelena, Queralt, Ethel, Richer, Julie, Roeder, Elizabeth, Sinha, Anubha, Scott, Richard H., So, Joyce, Wusik, Katherine A., Wilson, Louise, Zhang, Jianguo, Gomez-Puertas, Paulino, Casale, Cesar H., Stroem, Lena, Selicorni, Angelo, Ramos, Feliciano J., Jackson, Laird G., Krantz, Ian D., Das, Soma, Hennekam, Raoul C. M., Kaiser, Frank J., FitzPatrick, David R., Pie, Juan, Concepcion Gil-Rodriguez, Maria, Deardorff, Matthew A., Ansari, Morad, Tan, Christopher A., Parenti, Ilaria, Baquero-Montoya, Carolina, Ousager, Lilian B., Puisac, Beatriz, Hernandez-Marcos, Maria, Esperanza Teresa-Rodrigo, Maria, Marcos-Alcalde, Inigo, Wesselink, Jan-Jaap, Lusa-Bernal, Silvia, Bijlsma, Emilia K., Braunholz, Diana, Bueno-Martinez, Ines, Clark, Dinah, Cooper, Nicola S., Curry, Cynthia J., Fisher, Richard, Fryer, Alan, Ganesh, Jaya, Gervasini, Cristina, Gillessen-Kaesbach, Gabriele, Guo, Yiran, Hakonarson, Hakon, Hopkin, Robert J., Kaur, Maninder, Keating, Brendan J., Kibaek, Maria, Kinning, Esther, Kleefstra, Tjitske, Kline, Antonie D., Kuchinskaya, Ekaterina, Larizza, Lidia, Li, Yun R., Liu, Xuanzhu, Mariani, Milena, Picker, Jonathan D., Pie, Angeles, Pozojevic, Jelena, Queralt, Ethel, Richer, Julie, Roeder, Elizabeth, Sinha, Anubha, Scott, Richard H., So, Joyce, Wusik, Katherine A., Wilson, Louise, Zhang, Jianguo, Gomez-Puertas, Paulino, Casale, Cesar H., Stroem, Lena, Selicorni, Angelo, Ramos, Feliciano J., Jackson, Laird G., Krantz, Ian D., Das, Soma, Hennekam, Raoul C. M., Kaiser, Frank J., FitzPatrick, David R., and Pie, Juan

Abstract

Cornelia de Lange syndrome (CdLS) is characterized by facial dysmorphism, growth failure, intellectual disability, limb malformations, and multiple organ involvement. Mutations in five genes, encoding subunits of the cohesin complex (SMC1A, SMC3, RAD21) and its regulators (NIPBL, HDAC8), account for at least 70% of patients with CdLS or CdLS-like phenotypes. To date, only the clinical features from a single CdLS patient with SMC3 mutation has been published. Here, we report the efforts of an international research and clinical collaboration to provide clinical comparison of 16 patients with CdLS-like features caused by mutations in SMC3. Modeling of the mutation effects on protein structure suggests a dominant-negative effect on the multimeric cohesin complex. When compared with typical CdLS, many SMC3-associated phenotypes are also characterized by postnatal microcephaly but with a less distinctive craniofacial appearance, a milder prenatal growth retardation that worsens in childhood, few congenital heart defects, and an absence of limb deficiencies. While most mutations are unique, two unrelated affected individuals shared the same mutation but presented with different phenotypes. This work confirms that de novo SMC3 mutations account for approximate to 1%-2% of CdLS-like phenotypes., Funding Agencies|Spanish Ministry of Health - Fondo de Investigacion Sanitaria (FIS) [PI12/01318]; Diputacion General de Aragon (Grupo Consolidado) [B20]; European Social Fund ("Construyendo Europa desde Aragon"); Spanish Ministerio de Economia y Competitividad [IPT2011-0964-900000, SAF2011-13156-E]; University of Zaragoza [PIF-UZ_2009-BIO-02]; Fundacio La Marato de TV3 [1013EXPFMTV3]; University of Lubeck (Schwerpunktprogramm, Medizinische Genetik: Von seltenen Varianten zur Krankheitsentstehung); German Federal Ministry of Education and Research; Medical Research Council (UK); National Institutes of Health Grants (NICHD) [K08HD055488, P01 HD052860]; USA CdLS Foundation; Doris Duke Charitable Foundation [2012059]; Fundacion Severo Ochoa; European Social Fund

Published
2015
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4. Mutations in DDX3X Are a Common Cause of Unexplained Intellectual Disability with Gender-Specific Effects on Wnt Signaling

Author

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

Published
2015

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

Author

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

Published
2015

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

Author

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

Published
2015

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

Author

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

Abstract

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

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

Author

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

Published
2015

9. De Novo Heterozygous Mutations in SMC3 Cause a Range of Cornelia de Lange Syndrome-Overlapping Phenotypes

Author

Concepcion Gil-Rodriguez, Maria, Deardorff, Matthew A., Ansari, Morad, Tan, Christopher A., Parenti, Ilaria, Baquero-Montoya, Carolina, Ousager, Lilian B., Puisac, Beatriz, Hernandez-Marcos, Maria, Esperanza Teresa-Rodrigo, Maria, Marcos-Alcalde, Inigo, Wesselink, Jan-Jaap, Lusa-Bernal, Silvia, Bijlsma, Emilia K., Braunholz, Diana, Bueno-Martinez, Ines, Clark, Dinah, Cooper, Nicola S., Curry, Cynthia J., Fisher, Richard, Fryer, Alan, Ganesh, Jaya, Gervasini, Cristina, Gillessen-Kaesbach, Gabriele, Guo, Yiran, Hakonarson, Hakon, Hopkin, Robert J., Kaur, Maninder, Keating, Brendan J., Kibaek, Maria, Kinning, Esther, Kleefstra, Tjitske, Kline, Antonie D., Kuchinskaya, Ekaterina, Larizza, Lidia, Li, Yun R., Liu, Xuanzhu, Mariani, Milena, Picker, Jonathan D., Pie, Angeles, Pozojevic, Jelena, Queralt, Ethel, Richer, Julie, Roeder, Elizabeth, Sinha, Anubha, Scott, Richard H., So, Joyce, Wusik, Katherine A., Wilson, Louise, Zhang, Jianguo, Gomez-Puertas, Paulino, Casale, Cesar H., Stroem, Lena, Selicorni, Angelo, Ramos, Feliciano J., Jackson, Laird G., Krantz, Ian D., Das, Soma, Hennekam, Raoul C. M., Kaiser, Frank J., FitzPatrick, David R., Pie, Juan, Concepcion Gil-Rodriguez, Maria, Deardorff, Matthew A., Ansari, Morad, Tan, Christopher A., Parenti, Ilaria, Baquero-Montoya, Carolina, Ousager, Lilian B., Puisac, Beatriz, Hernandez-Marcos, Maria, Esperanza Teresa-Rodrigo, Maria, Marcos-Alcalde, Inigo, Wesselink, Jan-Jaap, Lusa-Bernal, Silvia, Bijlsma, Emilia K., Braunholz, Diana, Bueno-Martinez, Ines, Clark, Dinah, Cooper, Nicola S., Curry, Cynthia J., Fisher, Richard, Fryer, Alan, Ganesh, Jaya, Gervasini, Cristina, Gillessen-Kaesbach, Gabriele, Guo, Yiran, Hakonarson, Hakon, Hopkin, Robert J., Kaur, Maninder, Keating, Brendan J., Kibaek, Maria, Kinning, Esther, Kleefstra, Tjitske, Kline, Antonie D., Kuchinskaya, Ekaterina, Larizza, Lidia, Li, Yun R., Liu, Xuanzhu, Mariani, Milena, Picker, Jonathan D., Pie, Angeles, Pozojevic, Jelena, Queralt, Ethel, Richer, Julie, Roeder, Elizabeth, Sinha, Anubha, Scott, Richard H., So, Joyce, Wusik, Katherine A., Wilson, Louise, Zhang, Jianguo, Gomez-Puertas, Paulino, Casale, Cesar H., Stroem, Lena, Selicorni, Angelo, Ramos, Feliciano J., Jackson, Laird G., Krantz, Ian D., Das, Soma, Hennekam, Raoul C. M., Kaiser, Frank J., FitzPatrick, David R., and Pie, Juan

Abstract

Cornelia de Lange syndrome (CdLS) is characterized by facial dysmorphism, growth failure, intellectual disability, limb malformations, and multiple organ involvement. Mutations in five genes, encoding subunits of the cohesin complex (SMC1A, SMC3, RAD21) and its regulators (NIPBL, HDAC8), account for at least 70% of patients with CdLS or CdLS-like phenotypes. To date, only the clinical features from a single CdLS patient with SMC3 mutation has been published. Here, we report the efforts of an international research and clinical collaboration to provide clinical comparison of 16 patients with CdLS-like features caused by mutations in SMC3. Modeling of the mutation effects on protein structure suggests a dominant-negative effect on the multimeric cohesin complex. When compared with typical CdLS, many SMC3-associated phenotypes are also characterized by postnatal microcephaly but with a less distinctive craniofacial appearance, a milder prenatal growth retardation that worsens in childhood, few congenital heart defects, and an absence of limb deficiencies. While most mutations are unique, two unrelated affected individuals shared the same mutation but presented with different phenotypes. This work confirms that de novo SMC3 mutations account for approximate to 1%-2% of CdLS-like phenotypes., Funding Agencies|Spanish Ministry of Health - Fondo de Investigacion Sanitaria (FIS) [PI12/01318]; Diputacion General de Aragon (Grupo Consolidado) [B20]; European Social Fund ("Construyendo Europa desde Aragon"); Spanish Ministerio de Economia y Competitividad [IPT2011-0964-900000, SAF2011-13156-E]; University of Zaragoza [PIF-UZ_2009-BIO-02]; Fundacio La Marato de TV3 [1013EXPFMTV3]; University of Lubeck (Schwerpunktprogramm, Medizinische Genetik: Von seltenen Varianten zur Krankheitsentstehung); German Federal Ministry of Education and Research; Medical Research Council (UK); National Institutes of Health Grants (NICHD) [K08HD055488, P01 HD052860]; USA CdLS Foundation; Doris Duke Charitable Foundation [2012059]; Fundacion Severo Ochoa; European Social Fund

Published
2015
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10. Mutations in CKAP2L, the Human Homo log of the Mouse Radmis Gene, Cause Filippi Syndrome

Author

Hussain, Muhammad Sajid, Battaglia, Agatino, Szczepanski, Sandra, Kaygusuz, Emrah, Toliat, Mohammad Reza, Sakakibara, Shin-ichi, Altmueller, Janine, Thiele, Holger, Nuernberg, Gudrun, Moosa, Shahida, Yigit, Goekhan, Beleggia, Filippo, Tinschert, Sigrid, Clayton-Smith, Jill, Vasudevan, Pradeep, Urquhart, Jill E., Donnai, Dian, Fryer, Alan, Percin, Ferda, Brancati, Francesco, Dobbie, Angus, Smigiel, Robert, Gillessen-Kaesbach, Gabriele, Wollnik, Bernd, Noegel, Angelika Anna, Newman, William G., Nuernberg, Peter, Hussain, Muhammad Sajid, Battaglia, Agatino, Szczepanski, Sandra, Kaygusuz, Emrah, Toliat, Mohammad Reza, Sakakibara, Shin-ichi, Altmueller, Janine, Thiele, Holger, Nuernberg, Gudrun, Moosa, Shahida, Yigit, Goekhan, Beleggia, Filippo, Tinschert, Sigrid, Clayton-Smith, Jill, Vasudevan, Pradeep, Urquhart, Jill E., Donnai, Dian, Fryer, Alan, Percin, Ferda, Brancati, Francesco, Dobbie, Angus, Smigiel, Robert, Gillessen-Kaesbach, Gabriele, Wollnik, Bernd, Noegel, Angelika Anna, Newman, William G., and Nuernberg, Peter

Abstract

Filippi syndrome is a rare, presumably autosomal-recessive disorder characterized by microcephaly, pre- and postnatal growth failure, syndactyly, and distinctive facial features, including a broad nasal bridge and underdeveloped alae nasi. Some affected individuals have intellectual disability, seizures, undescended testicles in males, and teeth and hair abnormalities. We performed homozygosity mapping and whole-exome sequencing in a Sardinian family with two affected children and identified a homozygous frameshift mutation, c.571dupA (p.Ile191Asnfs*6), in CKAP2L, encoding the protein cytoskeleton-associated protein 2-like (CKAP2L). The function of this protein was unknown until it was rediscovered in mice as Radmis (radial fiber and mitotic spindle) and shown to play a pivotal role in cell division of neural progenitors. Sanger sequencing of CKAP2L in a further eight unrelated individuals with clinical features consistent with Filippi syndrome revealed biallelic mutations in four subjects. In contrast to wild-type lymphoblastoid cell lines (LCLs), dividing LCLs established from the individuals homozygous for the c.571dupA mutation did not show CKAP2L at the spindle poles. Furthermore, in cells from the affected individuals, we observed an increase in the number of disorganized spindle microtubules owing to multipolar configurations and defects in chromosome segregation. The observed cellular phenotypes are in keeping with data from in vitro and in vivo knockdown studies performed in human cells and mice, respectively. Our findings show that loss-of-function mutations in CKAP2L are a major cause of Filippi syndrome.

Published
2014

11. Mutations in PIEZO2 cause Gordon syndrome, Marden-Walker syndrome, and distal arthrogryposis type 5.

Author

McMillin, Margaret J, McMillin, Margaret J, Beck, Anita E, Chong, Jessica X, Shively, Kathryn M, Buckingham, Kati J, Gildersleeve, Heidi IS, Aracena, Mariana I, Aylsworth, Arthur S, Bitoun, Pierre, Carey, John C, Clericuzio, Carol L, Crow, Yanick J, Curry, Cynthia J, Devriendt, Koenraad, Everman, David B, Fryer, Alan, Gibson, Kate, Giovannucci Uzielli, Maria Luisa, Graham, John M, Hall, Judith G, Hecht, Jacqueline T, Heidenreich, Randall A, Hurst, Jane A, Irani, Sarosh, Krapels, Ingrid PC, Leroy, Jules G, Mowat, David, Plant, Gordon T, Robertson, Stephen P, Schorry, Elizabeth K, Scott, Richard H, Seaver, Laurie H, Sherr, Elliott, Splitt, Miranda, Stewart, Helen, Stumpel, Constance, Temel, Sehime G, Weaver, David D, Whiteford, Margo, Williams, Marc S, Tabor, Holly K, Smith, Joshua D, Shendure, Jay, Nickerson, Deborah A, University of Washington Center for Mendelian Genomics, Bamshad, Michael J, McMillin, Margaret J, McMillin, Margaret J, Beck, Anita E, Chong, Jessica X, Shively, Kathryn M, Buckingham, Kati J, Gildersleeve, Heidi IS, Aracena, Mariana I, Aylsworth, Arthur S, Bitoun, Pierre, Carey, John C, Clericuzio, Carol L, Crow, Yanick J, Curry, Cynthia J, Devriendt, Koenraad, Everman, David B, Fryer, Alan, Gibson, Kate, Giovannucci Uzielli, Maria Luisa, Graham, John M, Hall, Judith G, Hecht, Jacqueline T, Heidenreich, Randall A, Hurst, Jane A, Irani, Sarosh, Krapels, Ingrid PC, Leroy, Jules G, Mowat, David, Plant, Gordon T, Robertson, Stephen P, Schorry, Elizabeth K, Scott, Richard H, Seaver, Laurie H, Sherr, Elliott, Splitt, Miranda, Stewart, Helen, Stumpel, Constance, Temel, Sehime G, Weaver, David D, Whiteford, Margo, Williams, Marc S, Tabor, Holly K, Smith, Joshua D, Shendure, Jay, Nickerson, Deborah A, University of Washington Center for Mendelian Genomics, and Bamshad, Michael J

Abstract

Gordon syndrome (GS), or distal arthrogryposis type 3, is a rare, autosomal-dominant disorder characterized by cleft palate and congenital contractures of the hands and feet. Exome sequencing of five GS-affected families identified mutations in piezo-type mechanosensitive ion channel component 2 (PIEZO2) in each family. Sanger sequencing revealed PIEZO2 mutations in five of seven additional families studied (for a total of 10/12 [83%] individuals), and nine families had an identical c.8057G>A (p.Arg2686His) mutation. The phenotype of GS overlaps with distal arthrogryposis type 5 (DA5) and Marden-Walker syndrome (MWS). Using molecular inversion probes for targeted sequencing to screen PIEZO2, we found mutations in 24/29 (82%) DA5-affected families and one of two MWS-affected families. The presence of cleft palate was significantly associated with c.8057G>A (Fisher's exact test, adjusted p value < 0.0001). Collectively, although GS, DA5, and MWS have traditionally been considered separate disorders, our findings indicate that they are etiologically related and perhaps represent variable expressivity of the same condition.

Published
2014

12. Mutations in CKAP2L, the Human Homo log of the Mouse Radmis Gene, Cause Filippi Syndrome

Author

Hussain, Muhammad Sajid, Battaglia, Agatino, Szczepanski, Sandra, Kaygusuz, Emrah, Toliat, Mohammad Reza, Sakakibara, Shin-ichi, Altmueller, Janine, Thiele, Holger, Nuernberg, Gudrun, Moosa, Shahida, Yigit, Goekhan, Beleggia, Filippo, Tinschert, Sigrid, Clayton-Smith, Jill, Vasudevan, Pradeep, Urquhart, Jill E., Donnai, Dian, Fryer, Alan, Percin, Ferda, Brancati, Francesco, Dobbie, Angus, Smigiel, Robert, Gillessen-Kaesbach, Gabriele, Wollnik, Bernd, Noegel, Angelika Anna, Newman, William G., Nuernberg, Peter, Hussain, Muhammad Sajid, Battaglia, Agatino, Szczepanski, Sandra, Kaygusuz, Emrah, Toliat, Mohammad Reza, Sakakibara, Shin-ichi, Altmueller, Janine, Thiele, Holger, Nuernberg, Gudrun, Moosa, Shahida, Yigit, Goekhan, Beleggia, Filippo, Tinschert, Sigrid, Clayton-Smith, Jill, Vasudevan, Pradeep, Urquhart, Jill E., Donnai, Dian, Fryer, Alan, Percin, Ferda, Brancati, Francesco, Dobbie, Angus, Smigiel, Robert, Gillessen-Kaesbach, Gabriele, Wollnik, Bernd, Noegel, Angelika Anna, Newman, William G., and Nuernberg, Peter

Abstract

Filippi syndrome is a rare, presumably autosomal-recessive disorder characterized by microcephaly, pre- and postnatal growth failure, syndactyly, and distinctive facial features, including a broad nasal bridge and underdeveloped alae nasi. Some affected individuals have intellectual disability, seizures, undescended testicles in males, and teeth and hair abnormalities. We performed homozygosity mapping and whole-exome sequencing in a Sardinian family with two affected children and identified a homozygous frameshift mutation, c.571dupA (p.Ile191Asnfs*6), in CKAP2L, encoding the protein cytoskeleton-associated protein 2-like (CKAP2L). The function of this protein was unknown until it was rediscovered in mice as Radmis (radial fiber and mitotic spindle) and shown to play a pivotal role in cell division of neural progenitors. Sanger sequencing of CKAP2L in a further eight unrelated individuals with clinical features consistent with Filippi syndrome revealed biallelic mutations in four subjects. In contrast to wild-type lymphoblastoid cell lines (LCLs), dividing LCLs established from the individuals homozygous for the c.571dupA mutation did not show CKAP2L at the spindle poles. Furthermore, in cells from the affected individuals, we observed an increase in the number of disorganized spindle microtubules owing to multipolar configurations and defects in chromosome segregation. The observed cellular phenotypes are in keeping with data from in vitro and in vivo knockdown studies performed in human cells and mice, respectively. Our findings show that loss-of-function mutations in CKAP2L are a major cause of Filippi syndrome.

Published
2014

13. 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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14. 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.

Full Text
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15. 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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16. 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.

Full Text
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