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47 results on '"Postma, Alex V."'

1. Biallelic variants in POPDC2 cause a novel autosomal recessive syndrome presenting with cardiac conduction defects and variable hypertrophic cardiomyopathy

Author: Genetica Groep Van Tintelen, Cancer, Child Health, Circulatory Health, Nicastro, Michele, Vermeer, Alexa M C, Postema, Pieter G, Tadros, Rafik, Bowling, Forrest Z, Aegisdottir, Hildur M, Tragante, Vinicius, Mach, Lukas, Postma, Alex V, Lodder, Elisabeth M, van Duijvenboden, Karel, Zwart, Rob, Beekman, Leander, Wu, Lingshuang, van der Zwaag, Paul A, Alders, Mariëlle, Allouba, Mona, Aguib, Yasmine, Santomel, J Luis, de Una, David, Monserrat, Lorenzo, Miranda, Antonio M A, Kanemaru, Kazumasa, Cranley, James, van Zeggeren, Ingeborg E, Aronica, Eleonora M A, Ripolone, Michela, Zanotti, Simona, Sveinbjornsson, Gardar, Ivarsdottir, Erna V, Hólm, Hilma, Guðbjartsson, Daníel F, Skúladóttir, Ástrós Th, Stefánsson, Kári, Nadauld, Lincoln, Knowlton, Kirk U, Ostrowski, Sisse Rye, Sørensen, Erik, Vesterager Pedersen, Ole Birger, Ghouse, Jonas, Rand, Søren, Bundgaard, Henning, Ullum, Henrik, Erikstrup, Christian, Aagaard, Bitten, Bruun, Mie Topholm, Christiansen, Mette, Jensen, Henrik K, Carere, Deanna Alexis, Cummings, Christopher T, Fishler, Kristen, Tøring, Pernille Mathiesen, Brusgaard, Klaus, Juul, Trine Maxel, Saaby, Lotte, Winkel, Bo Gregers, Mogensen, Jens, Fortunato, Francesco, Comi, Giacomo Pietro, Ronchi, Dario, van Tintelen, J Peter, Noseda, Michela, Airola, Michael V, Christiaans, Imke, Wilde, Arthur A M, Wilders, Ronald, Clur, Sally-Ann, Verkerk, Arie O, Bezzina, Connie R, Lahrouchi, Najim, Genetica Groep Van Tintelen, Cancer, Child Health, Circulatory Health, Nicastro, Michele, Vermeer, Alexa M C, Postema, Pieter G, Tadros, Rafik, Bowling, Forrest Z, Aegisdottir, Hildur M, Tragante, Vinicius, Mach, Lukas, Postma, Alex V, Lodder, Elisabeth M, van Duijvenboden, Karel, Zwart, Rob, Beekman, Leander, Wu, Lingshuang, van der Zwaag, Paul A, Alders, Mariëlle, Allouba, Mona, Aguib, Yasmine, Santomel, J Luis, de Una, David, Monserrat, Lorenzo, Miranda, Antonio M A, Kanemaru, Kazumasa, Cranley, James, van Zeggeren, Ingeborg E, Aronica, Eleonora M A, Ripolone, Michela, Zanotti, Simona, Sveinbjornsson, Gardar, Ivarsdottir, Erna V, Hólm, Hilma, Guðbjartsson, Daníel F, Skúladóttir, Ástrós Th, Stefánsson, Kári, Nadauld, Lincoln, Knowlton, Kirk U, Ostrowski, Sisse Rye, Sørensen, Erik, Vesterager Pedersen, Ole Birger, Ghouse, Jonas, Rand, Søren, Bundgaard, Henning, Ullum, Henrik, Erikstrup, Christian, Aagaard, Bitten, Bruun, Mie Topholm, Christiansen, Mette, Jensen, Henrik K, Carere, Deanna Alexis, Cummings, Christopher T, Fishler, Kristen, Tøring, Pernille Mathiesen, Brusgaard, Klaus, Juul, Trine Maxel, Saaby, Lotte, Winkel, Bo Gregers, Mogensen, Jens, Fortunato, Francesco, Comi, Giacomo Pietro, Ronchi, Dario, van Tintelen, J Peter, Noseda, Michela, Airola, Michael V, Christiaans, Imke, Wilde, Arthur A M, Wilders, Ronald, Clur, Sally-Ann, Verkerk, Arie O, Bezzina, Connie R, and Lahrouchi, Najim
Published: 2024

2. Identification of novel genetic risk factors of dilated cardiomyopathy: from canine to human

Author: Niskanen, Julia E, Ohlsson, Åsa, Ljungvall, Ingrid, Drögemüller, Michaela, Ernst, Robert F, Dooijes, Dennis, van Deutekom, Hanneke W M, van Tintelen, J Peter, Snijders Blok, Christian J B, van Vugt, Marion, van Setten, Jessica, Asselbergs, Folkert W, Petrič, Aleksandra Domanjko, Salonen, Milla, Hundi, Sruthi, Hörtenhuber, Matthias, Kere, Juha, Pyle, W Glen, Donner, Jonas, Postma, Alex V, Leeb, Tosso, Andersson, Göran, Hytönen, Marjo K, Häggström, Jens, Wiberg, Maria, Friederich, Jana, Eberhard, Jenny, Harakalova, Magdalena, van Steenbeek, Frank G, Wess, Gerhard, Lohi, Hannes, Niskanen, Julia E, Ohlsson, Åsa, Ljungvall, Ingrid, Drögemüller, Michaela, Ernst, Robert F, Dooijes, Dennis, van Deutekom, Hanneke W M, van Tintelen, J Peter, Snijders Blok, Christian J B, van Vugt, Marion, van Setten, Jessica, Asselbergs, Folkert W, Petrič, Aleksandra Domanjko, Salonen, Milla, Hundi, Sruthi, Hörtenhuber, Matthias, Kere, Juha, Pyle, W Glen, Donner, Jonas, Postma, Alex V, Leeb, Tosso, Andersson, Göran, Hytönen, Marjo K, Häggström, Jens, Wiberg, Maria, Friederich, Jana, Eberhard, Jenny, Harakalova, Magdalena, van Steenbeek, Frank G, Wess, Gerhard, and Lohi, Hannes
Abstract: BACKGROUND: Dilated cardiomyopathy (DCM) is a life-threatening heart disease and a common cause of heart failure due to systolic dysfunction and subsequent left or biventricular dilatation. A significant number of cases have a genetic etiology; however, as a complex disease, the exact genetic risk factors are largely unknown, and many patients remain without a molecular diagnosis.METHODS: We performed GWAS followed by whole-genome, transcriptome, and immunohistochemical analyses in a spontaneously occurring canine model of DCM. Canine gene discovery was followed up in three human DCM cohorts.RESULTS: Our results revealed two independent additive loci associated with the typical DCM phenotype comprising left ventricular systolic dysfunction and dilatation. We highlight two novel candidate genes, RNF207 and PRKAA2, known for their involvement in cardiac action potentials, energy homeostasis, and morphology. We further illustrate the distinct genetic etiologies underlying the typical DCM phenotype and ventricular premature contractions. Finally, we followed up on the canine discoveries in human DCM patients and discovered candidate variants in our two novel genes.CONCLUSIONS: Collectively, our study yields insight into the molecular pathophysiology of DCM and provides a large animal model for preclinical studies.
Published: 2023

3. Familial multiple discoid fibromas is linked to a locus on chromosome 5 including the FNIP1 gene

Author: Genetica Klinische Genetica, van de Beek, Irma, Glykofridis, Iris E., Tanck, Michael W.T., Luijten, Monique N.H., Starink, Theo M., Balk, Jesper A., Johannesma, Paul C., Hennekam, Eric, van den Hoff, Maurice J.B., Gunst, Quinn D., Gille, Johan J.P., Polstra, Abeltje M., Postmus, Pieter E., van Steensel, Maurice A.M., Postma, Alex V., Wolthuis, Rob M.F., Menko, Fred H., Houweling, Arjan C., Waisfisz, Quinten, Genetica Klinische Genetica, van de Beek, Irma, Glykofridis, Iris E., Tanck, Michael W.T., Luijten, Monique N.H., Starink, Theo M., Balk, Jesper A., Johannesma, Paul C., Hennekam, Eric, van den Hoff, Maurice J.B., Gunst, Quinn D., Gille, Johan J.P., Polstra, Abeltje M., Postmus, Pieter E., van Steensel, Maurice A.M., Postma, Alex V., Wolthuis, Rob M.F., Menko, Fred H., Houweling, Arjan C., and Waisfisz, Quinten
Published: 2023

4. Identification of novel genetic risk factors of dilated cardiomyopathy: from canine to human

Author: Interne geneeskunde GD, CS_Genetics, Genetics, Niskanen, Julia E, Ohlsson, Åsa, Ljungvall, Ingrid, Drögemüller, Michaela, Ernst, Robert F, Dooijes, Dennis, van Deutekom, Hanneke W M, van Tintelen, J Peter, Snijders Blok, Christian J B, van Vugt, Marion, van Setten, Jessica, Asselbergs, Folkert W, Petrič, Aleksandra Domanjko, Salonen, Milla, Hundi, Sruthi, Hörtenhuber, Matthias, Kere, Juha, Pyle, W Glen, Donner, Jonas, Postma, Alex V, Leeb, Tosso, Andersson, Göran, Hytönen, Marjo K, Häggström, Jens, Wiberg, Maria, Friederich, Jana, Eberhard, Jenny, Harakalova, Magdalena, van Steenbeek, Frank G, Wess, Gerhard, Lohi, Hannes, Interne geneeskunde GD, CS_Genetics, Genetics, Niskanen, Julia E, Ohlsson, Åsa, Ljungvall, Ingrid, Drögemüller, Michaela, Ernst, Robert F, Dooijes, Dennis, van Deutekom, Hanneke W M, van Tintelen, J Peter, Snijders Blok, Christian J B, van Vugt, Marion, van Setten, Jessica, Asselbergs, Folkert W, Petrič, Aleksandra Domanjko, Salonen, Milla, Hundi, Sruthi, Hörtenhuber, Matthias, Kere, Juha, Pyle, W Glen, Donner, Jonas, Postma, Alex V, Leeb, Tosso, Andersson, Göran, Hytönen, Marjo K, Häggström, Jens, Wiberg, Maria, Friederich, Jana, Eberhard, Jenny, Harakalova, Magdalena, van Steenbeek, Frank G, Wess, Gerhard, and Lohi, Hannes
Published: 2023

5. TGFBR1 Variants Can Associate with Non-Syndromic Congenital Heart Disease without Aortopathy

Author: Genetica Groep Van Tintelen, Child Health, Circulatory Health, Alaamery, Manal, Albesher, Nour, Alhabshan, Fahad, Barnett, Phil, Salim Kabbani, Mohamed, Chaikhouni, Farah, Ilgun, Aho, Mook, Olaf R F, Alsaif, Hessa, Christoffels, Vincent M, van Tintelen, Peter, Wilde, Arthur A M, Houweling, Arjan C, Massadeh, Salam, Postma, Alex V, Genetica Groep Van Tintelen, Child Health, Circulatory Health, Alaamery, Manal, Albesher, Nour, Alhabshan, Fahad, Barnett, Phil, Salim Kabbani, Mohamed, Chaikhouni, Farah, Ilgun, Aho, Mook, Olaf R F, Alsaif, Hessa, Christoffels, Vincent M, van Tintelen, Peter, Wilde, Arthur A M, Houweling, Arjan C, Massadeh, Salam, and Postma, Alex V
Published: 2023

6. Common genetic variants improve risk stratification after the atrial switch operation for transposition of the great arteries

Author: Cardiologie, Team Medisch, Circulatory Health, Woudstra, Odilia I., Skoric-Milosavljevic, Doris, Mulder, Barbara J.M., Meijboom, Folkert J., Post, Marco C., Jongbloed, Monique R.M., van Dijk, Arie P.J., van Melle, Joost P., Konings, Thelma C., Postma, Alex V., Bezzina, Connie R., Bouma, Berto J., Tanck, Michael W.T., Cardiologie, Team Medisch, Circulatory Health, Woudstra, Odilia I., Skoric-Milosavljevic, Doris, Mulder, Barbara J.M., Meijboom, Folkert J., Post, Marco C., Jongbloed, Monique R.M., van Dijk, Arie P.J., van Melle, Joost P., Konings, Thelma C., Postma, Alex V., Bezzina, Connie R., Bouma, Berto J., and Tanck, Michael W.T.
Published: 2023

7. Germline variants in HEY2 functional domains lead to congenital heart defects and thoracic aortic aneurysms

Author: van Walree, Eva S, Dombrowsky, Gregor, Jansen, Iris E, Umićević Mirkov, Maša, Zwart, Rob, Ilgun, Aho, Guo, Dongchuan, Clur, Sally-Ann B, Amin, Ahmed S, Savage, Jeanne E, van der Wal, Allard C, Waisfisz, Quinten, Maugeri, Alessandra, Wilsdon, Anna, Bu'Lock, Frances A, Hurles, Matthew E, Dittrich, Sven, Berger, Felix, Audain Martinez, Enrique, Christoffels, Vincent M, Hitz, Marc-Philip, Milewicz, Dianna M, Posthuma, Daniëlle, Meijers-Heijboer, Hanne, Postma, Alex V, Mathijssen, Inge B, van Walree, Eva S, Dombrowsky, Gregor, Jansen, Iris E, Umićević Mirkov, Maša, Zwart, Rob, Ilgun, Aho, Guo, Dongchuan, Clur, Sally-Ann B, Amin, Ahmed S, Savage, Jeanne E, van der Wal, Allard C, Waisfisz, Quinten, Maugeri, Alessandra, Wilsdon, Anna, Bu'Lock, Frances A, Hurles, Matthew E, Dittrich, Sven, Berger, Felix, Audain Martinez, Enrique, Christoffels, Vincent M, Hitz, Marc-Philip, Milewicz, Dianna M, Posthuma, Daniëlle, Meijers-Heijboer, Hanne, Postma, Alex V, and Mathijssen, Inge B
Published: 2022
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8. Common Genetic Variants Contribute to Risk of Transposition of the Great Arteries

Author: Skoric-Milosavljevic, Doris, Tadros, Rafik, Bosada, Fernanda M, Tessadori, Federico, van Weerd, Jan Hendrik, Woudstra, Odilia Ilse, Tjong, Fleur V Y, Lahrouchi, Najim, Bajolle, Fanny, Cordell, Heather J, Agopian, A J, Blue, Gillian M, Barge-Schaapveld, Daniela Qcm, Gewillig, Marc H, Preuss, Christoph, Lodder, Elisabeth M, Barnett, Phil, Ilgun, Aho, Beekman, Leander, van Duijvenboden, Karel, Bokenkamp, Regina, Müller-Nurasyid, Martina, Vliegen, Hubert W, Konings, Thelma C, van Melle, Joost P, van Dijk, Arie, van Kimmenade, Roland Rj, Roos-Hesselink, Jolien W, Sieswerda, Gertjan, Meijboom, Folkert, Abdul-Khaliq, Hashim, Berger, Felix, Dittrich, Sven, Hitz, Marc-Phillip, Moosmann, Julia, Riede, Frank-Thomas, Schubert, Stephan, Galan, Pilar, Lathrop, G Mark, Munter, Hans Markus, Al-Chalabi, Ammar, Shaw, Christopher E, Shaw, Pamela J, Morrison, Karen E, Veldink, Jan H, van den Berg, Leonard H, Evans, Sylvia M, Nobrega, Marcelo A, Aneas, Ivy, Radivojkov-Blagojevic, Milena, Meitinger, Thomas, Oechslin, Erwin, Mondal, Tapas, Bergin, M Lynn, Smythe, John F, Altamirano-Diaz, Luis, Lougheed, Jane, Bouma, Berto J, Chaix, Marie A, Kline, Jennie, Bassett, Anne Susan, Andelfinger, Gregor, van der Palen, Roel Lf, Bouvagnet, Patrice, Clur, Sally-Ann B, Breckpot, Jeroen, Kerstjens-Frederikse, Wilhelmina S, Winlaw, David S, Bauer, Ulrike, Mital, Seema, Goldmuntz, Elizabeth, Keavney, Bernard D, Bonnet, Damien, Mulder, Barbara J, Tanck, Michael, Bakkers, Jeroen, Christoffels, Vincent M, Boogerd, Cornelis J, Postma, Alex V, Bezzina, Connie R, Skoric-Milosavljevic, Doris, Tadros, Rafik, Bosada, Fernanda M, Tessadori, Federico, van Weerd, Jan Hendrik, Woudstra, Odilia Ilse, Tjong, Fleur V Y, Lahrouchi, Najim, Bajolle, Fanny, Cordell, Heather J, Agopian, A J, Blue, Gillian M, Barge-Schaapveld, Daniela Qcm, Gewillig, Marc H, Preuss, Christoph, Lodder, Elisabeth M, Barnett, Phil, Ilgun, Aho, Beekman, Leander, van Duijvenboden, Karel, Bokenkamp, Regina, Müller-Nurasyid, Martina, Vliegen, Hubert W, Konings, Thelma C, van Melle, Joost P, van Dijk, Arie, van Kimmenade, Roland Rj, Roos-Hesselink, Jolien W, Sieswerda, Gertjan, Meijboom, Folkert, Abdul-Khaliq, Hashim, Berger, Felix, Dittrich, Sven, Hitz, Marc-Phillip, Moosmann, Julia, Riede, Frank-Thomas, Schubert, Stephan, Galan, Pilar, Lathrop, G Mark, Munter, Hans Markus, Al-Chalabi, Ammar, Shaw, Christopher E, Shaw, Pamela J, Morrison, Karen E, Veldink, Jan H, van den Berg, Leonard H, Evans, Sylvia M, Nobrega, Marcelo A, Aneas, Ivy, Radivojkov-Blagojevic, Milena, Meitinger, Thomas, Oechslin, Erwin, Mondal, Tapas, Bergin, M Lynn, Smythe, John F, Altamirano-Diaz, Luis, Lougheed, Jane, Bouma, Berto J, Chaix, Marie A, Kline, Jennie, Bassett, Anne Susan, Andelfinger, Gregor, van der Palen, Roel Lf, Bouvagnet, Patrice, Clur, Sally-Ann B, Breckpot, Jeroen, Kerstjens-Frederikse, Wilhelmina S, Winlaw, David S, Bauer, Ulrike, Mital, Seema, Goldmuntz, Elizabeth, Keavney, Bernard D, Bonnet, Damien, Mulder, Barbara J, Tanck, Michael, Bakkers, Jeroen, Christoffels, Vincent M, Boogerd, Cornelis J, Postma, Alex V, and Bezzina, Connie R
Abstract: Background: Dextro-transposition of the great arteries (D-TGA) is a severe congenital heart defect which affects approximately 1 in 4,000 live births. While there are several reports of D-TGA patients with rare variants in individual genes, the majority of D-TGA cases remain genetically elusive. Familial recurrence patterns and the observation that most cases with D-TGA are sporadic suggest a polygenic inheritance for the disorder, yet this remains unexplored. Methods: We sought to study the role of common single nucleotide polymorphisms (SNPs) in risk for D-TGA. We conducted a genome-wide association study in an international set of 1,237 patients with D-TGA and identified a genome-wide significant susceptibility locus on chromosome 3p14.3, which was subsequently replicated in an independent case-control set (rs56219800, meta-analysis P=8.6x10-10, OR=0.69 per C allele). Results: SNP-based heritability analysis showed that 25% of variance in susceptibility to D-TGA may be explained by common variants. A genome-wide polygenic risk score derived from the discovery set was significantly associated to D-TGA in the replication set (P=4x10-5). The genome-wide significant locus (3p14.3) co-localizes with a putative regulatory element that interacts with the promoter of WNT5A, which encodes the Wnt Family Member 5A protein known for its role in cardiac development in mice. We show that this element drives reporter gene activity in the developing heart of mice and zebrafish and is bound by the developmental transcription factor TBX20. We further demonstrate that TBX20 attenuates Wnt5a expression levels in the developing mouse heart. Conclusions: This work provides support for a polygenic architecture in D-TGA and identifies a susceptibility locus on chromosome 3p14.3 near WNT5A. Genomic and functional data support a causal role of WNT5A at the locus.
Published: 2022

9. Germline variants in HEY2 functional domains lead to congenital heart defects and thoracic aortic aneurysms

Author: van Walree, Eva S., Dombrowsky, Gregor, Jansen, Iris E., Mirkov, Maša Umićević, Zwart, Rob, Ilgun, Aho, Guo, Dongchuan, Clur, Sally Ann B., Amin, Ahmed S., Savage, Jeanne E., van der Wal, Allard C., Waisfisz, Quinten, Maugeri, Alessandra, Wilsdon, Anna, Bu’Lock, Frances A., Hurles, Matthew E., Dittrich, Sven, Berger, Felix, Audain Martinez, Enrique, Christoffels, Vincent M., Hitz, Marc Philip, Milewicz, Dianna M., Posthuma, Daniëlle, Meijers-Heijboer, Hanne, Postma, Alex V., Mathijssen, Inge B., van Walree, Eva S., Dombrowsky, Gregor, Jansen, Iris E., Mirkov, Maša Umićević, Zwart, Rob, Ilgun, Aho, Guo, Dongchuan, Clur, Sally Ann B., Amin, Ahmed S., Savage, Jeanne E., van der Wal, Allard C., Waisfisz, Quinten, Maugeri, Alessandra, Wilsdon, Anna, Bu’Lock, Frances A., Hurles, Matthew E., Dittrich, Sven, Berger, Felix, Audain Martinez, Enrique, Christoffels, Vincent M., Hitz, Marc Philip, Milewicz, Dianna M., Posthuma, Daniëlle, Meijers-Heijboer, Hanne, Postma, Alex V., and Mathijssen, Inge B.
Abstract: Purpose: In this study we aimed to establish the genetic cause of a myriad of cardiovascular defects prevalent in individuals from a genetically isolated population, who were found to share a common ancestor in 1728. Methods: Trio genome sequencing was carried out in an index patient with critical congenital heart disease (CHD); family members had either exome or Sanger sequencing. To confirm enrichment, we performed a gene-based association test and meta-analysis in two independent validation cohorts: one with 2685 CHD cases versus 4370. These controls were also ancestry-matched (same as FTAA controls), and the other with 326 cases with familial thoracic aortic aneurysms (FTAA) and dissections versus 570 ancestry-matched controls. Functional consequences of identified variants were evaluated using expression studies. Results: We identified a loss-of-function variant in the Notch target transcription factor-encoding gene HEY2. The homozygous state (n = 3) causes life-threatening congenital heart defects, while 80% of heterozygous carriers (n = 20) had cardiovascular defects, mainly CHD and FTAA of the ascending aorta. We confirm enrichment of rare risk variants in HEY2 functional domains after meta-analysis (MetaSKAT p = 0.018). Furthermore, we show that several identified variants lead to dysregulation of repression by HEY2. Conclusion: A homozygous germline loss-of-function variant in HEY2 leads to critical CHD. The majority of heterozygotes show a myriad of cardiovascular defects.
Published: 2021
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10. Common Genetic Variants Contribute to Risk of Transposition of the Great Arteries

Author: Skoric-Milosavljevic, Doris, Tadros, Rafik, Bosada, Fernanda M, Tessadori, Federico, van Weerd, Jan Hendrik, Woudstra, Odilia Ilse, Tjong, Fleur V Y, Lahrouchi, Najim, Bajolle, Fanny, Cordell, Heather J, Agopian, A J, Blue, Gillian M, Barge-Schaapveld, Daniela Qcm, Gewillig, Marc H, Preuss, Christoph, Lodder, Elisabeth M, Barnett, Phil, Ilgun, Aho, Beekman, Leander, van Duijvenboden, Karel, Bokenkamp, Regina, Müller-Nurasyid, Martina, Vliegen, Hubert W, Konings, Thelma C, van Melle, Joost P, van Dijk, Arie, van Kimmenade, Roland Rj, Roos-Hesselink, Jolien W, Sieswerda, Gertjan, Meijboom, Folkert, Abdul-Khaliq, Hashim, Berger, Felix, Dittrich, Sven, Hitz, Marc-Phillip, Moosmann, Julia, Riede, Frank-Thomas, Schubert, Stephan, Galan, Pilar, Lathrop, G Mark, Munter, Hans Markus, Al-Chalabi, Ammar, Shaw, Christopher E, Shaw, Pamela J, Morrison, Karen E, Veldink, Jan H, van den Berg, Leonard H, Evans, Sylvia M, Nobrega, Marcelo A, Aneas, Ivy, Radivojkov-Blagojevic, Milena, Meitinger, Thomas, Oechslin, Erwin, Mondal, Tapas, Bergin, M Lynn, Smythe, John F, Altamirano-Diaz, Luis, Lougheed, Jane, Bouma, Berto J, Chaix, Marie A, Kline, Jennie, Bassett, Anne Susan, Andelfinger, Gregor, van der Palen, Roel Lf, Bouvagnet, Patrice, Clur, Sally-Ann B, Breckpot, Jeroen, Kerstjens-Frederikse, Wilhelmina S, Winlaw, David S, Bauer, Ulrike, Mital, Seema, Goldmuntz, Elizabeth, Keavney, Bernard D, Bonnet, Damien, Mulder, Barbara J, Tanck, Michael, Bakkers, Jeroen, Christoffels, Vincent M, Boogerd, Cornelis J, Postma, Alex V, Bezzina, Connie R, Skoric-Milosavljevic, Doris, Tadros, Rafik, Bosada, Fernanda M, Tessadori, Federico, van Weerd, Jan Hendrik, Woudstra, Odilia Ilse, Tjong, Fleur V Y, Lahrouchi, Najim, Bajolle, Fanny, Cordell, Heather J, Agopian, A J, Blue, Gillian M, Barge-Schaapveld, Daniela Qcm, Gewillig, Marc H, Preuss, Christoph, Lodder, Elisabeth M, Barnett, Phil, Ilgun, Aho, Beekman, Leander, van Duijvenboden, Karel, Bokenkamp, Regina, Müller-Nurasyid, Martina, Vliegen, Hubert W, Konings, Thelma C, van Melle, Joost P, van Dijk, Arie, van Kimmenade, Roland Rj, Roos-Hesselink, Jolien W, Sieswerda, Gertjan, Meijboom, Folkert, Abdul-Khaliq, Hashim, Berger, Felix, Dittrich, Sven, Hitz, Marc-Phillip, Moosmann, Julia, Riede, Frank-Thomas, Schubert, Stephan, Galan, Pilar, Lathrop, G Mark, Munter, Hans Markus, Al-Chalabi, Ammar, Shaw, Christopher E, Shaw, Pamela J, Morrison, Karen E, Veldink, Jan H, van den Berg, Leonard H, Evans, Sylvia M, Nobrega, Marcelo A, Aneas, Ivy, Radivojkov-Blagojevic, Milena, Meitinger, Thomas, Oechslin, Erwin, Mondal, Tapas, Bergin, M Lynn, Smythe, John F, Altamirano-Diaz, Luis, Lougheed, Jane, Bouma, Berto J, Chaix, Marie A, Kline, Jennie, Bassett, Anne Susan, Andelfinger, Gregor, van der Palen, Roel Lf, Bouvagnet, Patrice, Clur, Sally-Ann B, Breckpot, Jeroen, Kerstjens-Frederikse, Wilhelmina S, Winlaw, David S, Bauer, Ulrike, Mital, Seema, Goldmuntz, Elizabeth, Keavney, Bernard D, Bonnet, Damien, Mulder, Barbara J, Tanck, Michael, Bakkers, Jeroen, Christoffels, Vincent M, Boogerd, Cornelis J, Postma, Alex V, and Bezzina, Connie R
Abstract: Background: Dextro-transposition of the great arteries (D-TGA) is a severe congenital heart defect which affects approximately 1 in 4,000 live births. While there are several reports of D-TGA patients with rare variants in individual genes, the majority of D-TGA cases remain genetically elusive. Familial recurrence patterns and the observation that most cases with D-TGA are sporadic suggest a polygenic inheritance for the disorder, yet this remains unexplored. Methods: We sought to study the role of common single nucleotide polymorphisms (SNPs) in risk for D-TGA. We conducted a genome-wide association study in an international set of 1,237 patients with D-TGA and identified a genome-wide significant susceptibility locus on chromosome 3p14.3, which was subsequently replicated in an independent case-control set (rs56219800, meta-analysis P=8.6x10-10, OR=0.69 per C allele). Results: SNP-based heritability analysis showed that 25% of variance in susceptibility to D-TGA may be explained by common variants. A genome-wide polygenic risk score derived from the discovery set was significantly associated to D-TGA in the replication set (P=4x10-5). The genome-wide significant locus (3p14.3) co-localizes with a putative regulatory element that interacts with the promoter of WNT5A, which encodes the Wnt Family Member 5A protein known for its role in cardiac development in mice. We show that this element drives reporter gene activity in the developing heart of mice and zebrafish and is bound by the developmental transcription factor TBX20. We further demonstrate that TBX20 attenuates Wnt5a expression levels in the developing mouse heart. Conclusions: This work provides support for a polygenic architecture in D-TGA and identifies a susceptibility locus on chromosome 3p14.3 near WNT5A. Genomic and functional data support a causal role of WNT5A at the locus.
Published: 2021

11. Germline variants in HEY2 functional domains lead to congenital heart defects and thoracic aortic aneurysms

Author: van Walree, Eva S., Dombrowsky, Gregor, Jansen, Iris E., Mirkov, Maša Umićević, Zwart, Rob, Ilgun, Aho, Guo, Dongchuan, Clur, Sally Ann B., Amin, Ahmed S., Savage, Jeanne E., van der Wal, Allard C., Waisfisz, Quinten, Maugeri, Alessandra, Wilsdon, Anna, Bu’Lock, Frances A., Hurles, Matthew E., Dittrich, Sven, Berger, Felix, Audain Martinez, Enrique, Christoffels, Vincent M., Hitz, Marc Philip, Milewicz, Dianna M., Posthuma, Daniëlle, Meijers-Heijboer, Hanne, Postma, Alex V., Mathijssen, Inge B., van Walree, Eva S., Dombrowsky, Gregor, Jansen, Iris E., Mirkov, Maša Umićević, Zwart, Rob, Ilgun, Aho, Guo, Dongchuan, Clur, Sally Ann B., Amin, Ahmed S., Savage, Jeanne E., van der Wal, Allard C., Waisfisz, Quinten, Maugeri, Alessandra, Wilsdon, Anna, Bu’Lock, Frances A., Hurles, Matthew E., Dittrich, Sven, Berger, Felix, Audain Martinez, Enrique, Christoffels, Vincent M., Hitz, Marc Philip, Milewicz, Dianna M., Posthuma, Daniëlle, Meijers-Heijboer, Hanne, Postma, Alex V., and Mathijssen, Inge B.
Abstract: Purpose: In this study we aimed to establish the genetic cause of a myriad of cardiovascular defects prevalent in individuals from a genetically isolated population, who were found to share a common ancestor in 1728. Methods: Trio genome sequencing was carried out in an index patient with critical congenital heart disease (CHD); family members had either exome or Sanger sequencing. To confirm enrichment, we performed a gene-based association test and meta-analysis in two independent validation cohorts: one with 2685 CHD cases versus 4370. These controls were also ancestry-matched (same as FTAA controls), and the other with 326 cases with familial thoracic aortic aneurysms (FTAA) and dissections versus 570 ancestry-matched controls. Functional consequences of identified variants were evaluated using expression studies. Results: We identified a loss-of-function variant in the Notch target transcription factor-encoding gene HEY2. The homozygous state (n = 3) causes life-threatening congenital heart defects, while 80% of heterozygous carriers (n = 20) had cardiovascular defects, mainly CHD and FTAA of the ascending aorta. We confirm enrichment of rare risk variants in HEY2 functional domains after meta-analysis (MetaSKAT p = 0.018). Furthermore, we show that several identified variants lead to dysregulation of repression by HEY2. Conclusion: A homozygous germline loss-of-function variant in HEY2 leads to critical CHD. The majority of heterozygotes show a myriad of cardiovascular defects.
Published: 2021
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12. Integrative analysis of genomic variants reveals new associations of candidate haploinsufficient genes with congenital heart disease

Author: Audain, Enrique, Wilsdon, Anna, Breckpot, Jeroen, Izarzugaza, Jose M.G., Fitzgerald, Tomas W., Kahlert, Anne Karin, Sifrim, Alejandro, Wünnemann, Florian, Perez-Riverol, Yasset, Abdul-Khaliq, Hashim, Bak, Mads, Bassett, Anne S., Benson, Woodrow D., Berger, Felix, Daehnert, Ingo, Devriendt, Koenraad, Dittrich, Sven, Daubeney, Piers E.F., Garg, Vidu, Hackmann, Karl, Hoff, Kirstin, Hofmann, Philipp, Dombrowsky, Gregor, Pickardt, Thomas, Bauer, Ulrike, Keavney, Bernard D., Klaassen, Sabine, Kramer, Hans Heiner, Marshall, Christian R., Milewicz, Dianna M., Lemaire, Scott, Coselli, Joseph S., Mitchell, Michael E., Tomita-Mitchell, Aoy, Prakash, Siddharth K., Stamm, Karl, Stewart, Alexandre F.R., Silversides, Candice K., Siebert, Reiner, Stiller, Brigitte, Rosenfeld, Jill A., Vater, Inga, Postma, Alex V., Caliebe, Almuth, Brook, J. David, Andelfinger, Gregor, Hurles, Matthew E., Thienpont, Bernard, Larsen, Lars Allan, Hitz, Marc Phillip, Audain, Enrique, Wilsdon, Anna, Breckpot, Jeroen, Izarzugaza, Jose M.G., Fitzgerald, Tomas W., Kahlert, Anne Karin, Sifrim, Alejandro, Wünnemann, Florian, Perez-Riverol, Yasset, Abdul-Khaliq, Hashim, Bak, Mads, Bassett, Anne S., Benson, Woodrow D., Berger, Felix, Daehnert, Ingo, Devriendt, Koenraad, Dittrich, Sven, Daubeney, Piers E.F., Garg, Vidu, Hackmann, Karl, Hoff, Kirstin, Hofmann, Philipp, Dombrowsky, Gregor, Pickardt, Thomas, Bauer, Ulrike, Keavney, Bernard D., Klaassen, Sabine, Kramer, Hans Heiner, Marshall, Christian R., Milewicz, Dianna M., Lemaire, Scott, Coselli, Joseph S., Mitchell, Michael E., Tomita-Mitchell, Aoy, Prakash, Siddharth K., Stamm, Karl, Stewart, Alexandre F.R., Silversides, Candice K., Siebert, Reiner, Stiller, Brigitte, Rosenfeld, Jill A., Vater, Inga, Postma, Alex V., Caliebe, Almuth, Brook, J. David, Andelfinger, Gregor, Hurles, Matthew E., Thienpont, Bernard, Larsen, Lars Allan, and Hitz, Marc Phillip
Abstract: Numerous genetic studies have established a role for rare genomic variants in Congenital Heart Disease (CHD) at the copy number variation (CNV) and de novo variant (DNV) level. To identify novel haploinsufficient CHD disease genes, we performed an integrative analysis of CNVs and DNVs identified in probands with CHD including cases with sporadic thoracic aortic aneurysm. We assembled CNV data from 7,958 cases and 14,082 controls and performed a gene-wise analysis of the burden of rare genomic deletions in cases versus controls. In addition, we performed variation rate testing for DNVs identified in 2,489 parentoffspring trios. Our analysis revealed 21 genes which were significantly affected by rare CNVs and/or DNVs in probands. Fourteen of these genes have previously been associated with CHD while the remaining genes (FEZ1, MYO16, ARID1B, NALCN, WAC, KDM5B and WHSC1) have only been associated in small cases series or show new associations with CHD. In addition, a systems level analysis revealed affected protein-protein interaction networks involved in Notch signaling pathway, heart morphogenesis, DNA repair and cilia/centrosome function. Taken together, this approach highlights the importance of re-analyzing existing datasets to strengthen disease association and identify novel disease genes and pathways. This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
Published: 2021

13. Integrative analysis of genomic variants reveals new associations of candidate haploinsufficient genes with congenital heart disease

Author: Audain, Enrique, Wilsdon, Anna, Breckpot, Jeroen, Izarzugaza, Jose M.G., Fitzgerald, Tomas W., Kahlert, Anne Karin, Sifrim, Alejandro, Wünnemann, Florian, Perez-Riverol, Yasset, Abdul-Khaliq, Hashim, Bak, Mads, Bassett, Anne S., Benson, Woodrow D., Berger, Felix, Daehnert, Ingo, Devriendt, Koenraad, Dittrich, Sven, Daubeney, Piers E.F., Garg, Vidu, Hackmann, Karl, Hoff, Kirstin, Hofmann, Philipp, Dombrowsky, Gregor, Pickardt, Thomas, Bauer, Ulrike, Keavney, Bernard D., Klaassen, Sabine, Kramer, Hans Heiner, Marshall, Christian R., Milewicz, Dianna M., Lemaire, Scott, Coselli, Joseph S., Mitchell, Michael E., Tomita-Mitchell, Aoy, Prakash, Siddharth K., Stamm, Karl, Stewart, Alexandre F.R., Silversides, Candice K., Siebert, Reiner, Stiller, Brigitte, Rosenfeld, Jill A., Vater, Inga, Postma, Alex V., Caliebe, Almuth, Brook, J. David, Andelfinger, Gregor, Hurles, Matthew E., Thienpont, Bernard, Larsen, Lars Allan, Hitz, Marc Phillip, Audain, Enrique, Wilsdon, Anna, Breckpot, Jeroen, Izarzugaza, Jose M.G., Fitzgerald, Tomas W., Kahlert, Anne Karin, Sifrim, Alejandro, Wünnemann, Florian, Perez-Riverol, Yasset, Abdul-Khaliq, Hashim, Bak, Mads, Bassett, Anne S., Benson, Woodrow D., Berger, Felix, Daehnert, Ingo, Devriendt, Koenraad, Dittrich, Sven, Daubeney, Piers E.F., Garg, Vidu, Hackmann, Karl, Hoff, Kirstin, Hofmann, Philipp, Dombrowsky, Gregor, Pickardt, Thomas, Bauer, Ulrike, Keavney, Bernard D., Klaassen, Sabine, Kramer, Hans Heiner, Marshall, Christian R., Milewicz, Dianna M., Lemaire, Scott, Coselli, Joseph S., Mitchell, Michael E., Tomita-Mitchell, Aoy, Prakash, Siddharth K., Stamm, Karl, Stewart, Alexandre F.R., Silversides, Candice K., Siebert, Reiner, Stiller, Brigitte, Rosenfeld, Jill A., Vater, Inga, Postma, Alex V., Caliebe, Almuth, Brook, J. David, Andelfinger, Gregor, Hurles, Matthew E., Thienpont, Bernard, Larsen, Lars Allan, and Hitz, Marc Phillip
Abstract: Numerous genetic studies have established a role for rare genomic variants in Congenital Heart Disease (CHD) at the copy number variation (CNV) and de novo variant (DNV) level. To identify novel haploinsufficient CHD disease genes, we performed an integrative analysis of CNVs and DNVs identified in probands with CHD including cases with sporadic thoracic aortic aneurysm. We assembled CNV data from 7,958 cases and 14,082 controls and performed a gene-wise analysis of the burden of rare genomic deletions in cases versus controls. In addition, we performed variation rate testing for DNVs identified in 2,489 parentoffspring trios. Our analysis revealed 21 genes which were significantly affected by rare CNVs and/or DNVs in probands. Fourteen of these genes have previously been associated with CHD while the remaining genes (FEZ1, MYO16, ARID1B, NALCN, WAC, KDM5B and WHSC1) have only been associated in small cases series or show new associations with CHD. In addition, a systems level analysis revealed affected protein-protein interaction networks involved in Notch signaling pathway, heart morphogenesis, DNA repair and cilia/centrosome function. Taken together, this approach highlights the importance of re-analyzing existing datasets to strengthen disease association and identify novel disease genes and pathways. This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
Published: 2021

14. Integrative analysis of genomic variants reveals new associations of candidate haploinsufficient genes with congenital heart disease

Author: Audain, Enrique, Wilsdon, Anna, Breckpot, Jeroen, Izarzugaza, Jose M.G., Fitzgerald, Tomas W., Kahlert, Anne Karin, Sifrim, Alejandro, Wünnemann, Florian, Perez-Riverol, Yasset, Abdul-Khaliq, Hashim, Bak, Mads, Bassett, Anne S., Benson, Woodrow D., Berger, Felix, Daehnert, Ingo, Devriendt, Koenraad, Dittrich, Sven, Daubeney, Piers E.F., Garg, Vidu, Hackmann, Karl, Hoff, Kirstin, Hofmann, Philipp, Dombrowsky, Gregor, Pickardt, Thomas, Bauer, Ulrike, Keavney, Bernard D., Klaassen, Sabine, Kramer, Hans Heiner, Marshall, Christian R., Milewicz, Dianna M., Lemaire, Scott, Coselli, Joseph S., Mitchell, Michael E., Tomita-Mitchell, Aoy, Prakash, Siddharth K., Stamm, Karl, Stewart, Alexandre F.R., Silversides, Candice K., Siebert, Reiner, Stiller, Brigitte, Rosenfeld, Jill A., Vater, Inga, Postma, Alex V., Caliebe, Almuth, Brook, J. David, Andelfinger, Gregor, Hurles, Matthew E., Thienpont, Bernard, Larsen, Lars Allan, Hitz, Marc Phillip, Audain, Enrique, Wilsdon, Anna, Breckpot, Jeroen, Izarzugaza, Jose M.G., Fitzgerald, Tomas W., Kahlert, Anne Karin, Sifrim, Alejandro, Wünnemann, Florian, Perez-Riverol, Yasset, Abdul-Khaliq, Hashim, Bak, Mads, Bassett, Anne S., Benson, Woodrow D., Berger, Felix, Daehnert, Ingo, Devriendt, Koenraad, Dittrich, Sven, Daubeney, Piers E.F., Garg, Vidu, Hackmann, Karl, Hoff, Kirstin, Hofmann, Philipp, Dombrowsky, Gregor, Pickardt, Thomas, Bauer, Ulrike, Keavney, Bernard D., Klaassen, Sabine, Kramer, Hans Heiner, Marshall, Christian R., Milewicz, Dianna M., Lemaire, Scott, Coselli, Joseph S., Mitchell, Michael E., Tomita-Mitchell, Aoy, Prakash, Siddharth K., Stamm, Karl, Stewart, Alexandre F.R., Silversides, Candice K., Siebert, Reiner, Stiller, Brigitte, Rosenfeld, Jill A., Vater, Inga, Postma, Alex V., Caliebe, Almuth, Brook, J. David, Andelfinger, Gregor, Hurles, Matthew E., Thienpont, Bernard, Larsen, Lars Allan, and Hitz, Marc Phillip
Abstract: Numerous genetic studies have established a role for rare genomic variants in Congenital Heart Disease (CHD) at the copy number variation (CNV) and de novo variant (DNV) level. To identify novel haploinsufficient CHD disease genes, we performed an integrative analysis of CNVs and DNVs identified in probands with CHD including cases with sporadic thoracic aortic aneurysm. We assembled CNV data from 7,958 cases and 14,082 controls and performed a gene-wise analysis of the burden of rare genomic deletions in cases versus controls. In addition, we performed variation rate testing for DNVs identified in 2,489 parentoffspring trios. Our analysis revealed 21 genes which were significantly affected by rare CNVs and/or DNVs in probands. Fourteen of these genes have previously been associated with CHD while the remaining genes (FEZ1, MYO16, ARID1B, NALCN, WAC, KDM5B and WHSC1) have only been associated in small cases series or show new associations with CHD. In addition, a systems level analysis revealed affected protein-protein interaction networks involved in Notch signaling pathway, heart morphogenesis, DNA repair and cilia/centrosome function. Taken together, this approach highlights the importance of re-analyzing existing datasets to strengthen disease association and identify novel disease genes and pathways. This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
Published: 2021

15. Terminal osseous dysplasia with pigmentary defects and cardiomyopathy caused by a novel FLNA variant

Author: Rumping, Lynne, Wessels, Marja W., Postma, Alex V., van Schuppen, Joost, van Slegtenhorst, Marjon A., Saris, Jasper J., van Tintelen, J. Peter, Robertson, Stephen P., Alders, Mariëlle, Maas, Saskia M., Deprez, Ronald H.Lekanne, Rumping, Lynne, Wessels, Marja W., Postma, Alex V., van Schuppen, Joost, van Slegtenhorst, Marjon A., Saris, Jasper J., van Tintelen, J. Peter, Robertson, Stephen P., Alders, Mariëlle, Maas, Saskia M., and Deprez, Ronald H.Lekanne
Abstract: Terminal osseous dysplasia with pigmentary defects (TODPD), also known as digitocutaneous dysplasia, is one of the X-linked filaminopathies caused by a variety of FLNA-variants. TODPD is characterized by skeletal defects, skin fibromata and dysmorphic facial features. So far, only a single recurrent variant (c.5217G>A;p.Val1724_Thr1739del) in FLNA has found to be responsible for TODPD. We identified a novel c.5217+5G>C variant in FLNA in a female proband with skeletal defects, skin fibromata, interstitial lung disease, epilepsy, and restrictive cardiomyopathy. This variant causes mis-splicing of exon 31 predicting the production of a FLNA-protein with an in-frame-deletion of 16 residues identical to the miss-splicing-effect of the recurrent TODPD c.5217G>A variant. This mis-spliced transcript was explicitly detected in heart tissue, but was absent from blood, skin, and lung. X-inactivation analyses showed extreme skewing with almost complete inactivation of the mutated allele (>90%) in these tissues, except for heart. The mother of the proband, who also has fibromata and skeletal abnormalities, is also carrier of the FLNA-variant and was diagnosed with noncompaction cardiomyopathy after cardiac screening. No other relevant variants in cardiomyopathy-related genes were found. Here we describe a novel variant in FLNA (c.5217+5G>C) as the second pathogenic variant responsible for TODPD. Cardiomyopathy has not been described as a phenotypic feature of TODPD before.
Published: 2021

16. Terminal osseous dysplasia with pigmentary defects and cardiomyopathy caused by a novel FLNA variant

Author: Genetica Sectie Metabole Diagnostiek, Genetica, Child Health, Circulatory Health, Rumping, Lynne, Wessels, Marja W, Postma, Alex V, van Schuppen, Joost, van Slegtenhorst, Marjon A, Saris, Jasper J, van Tintelen, J Peter, Robertson, Stephen P, Alders, Mariëlle, Maas, Saskia M, Deprez, Ronald H Lekanne, Genetica Sectie Metabole Diagnostiek, Genetica, Child Health, Circulatory Health, Rumping, Lynne, Wessels, Marja W, Postma, Alex V, van Schuppen, Joost, van Slegtenhorst, Marjon A, Saris, Jasper J, van Tintelen, J Peter, Robertson, Stephen P, Alders, Mariëlle, Maas, Saskia M, and Deprez, Ronald H Lekanne
Published: 2021

17. Flotillins in the intercalated disc are potential modulators of cardiac excitability

Author: Kessler, Elise L., van Stuijvenberg, Leonie, van Bavel, Joanne J.A., van Bennekom, Joëlle, Zwartsen, Anne, Rivaud, Mathilde R., Vink, Aryan, Efimov, Igor R., Postma, Alex V., van Tintelen, J. Peter, Remme, Carol A., Vos, Marc A., Banning, Antje, de Boer, Teun P., Tikkanen, Ritva, van Veen, Toon A.B., Kessler, Elise L., van Stuijvenberg, Leonie, van Bavel, Joanne J.A., van Bennekom, Joëlle, Zwartsen, Anne, Rivaud, Mathilde R., Vink, Aryan, Efimov, Igor R., Postma, Alex V., van Tintelen, J. Peter, Remme, Carol A., Vos, Marc A., Banning, Antje, de Boer, Teun P., Tikkanen, Ritva, and van Veen, Toon A.B.
Published: 2019

18. Flotillins in the intercalated disc are potential modulators of cardiac excitability

Author: Kessler, Elise L., van Stuijvenberg, Leonie, van Bavel, Joanne J.A., van Bennekom, Joëlle, Zwartsen, Anne, Rivaud, Mathilde R., Vink, Aryan, Efimov, Igor R., Postma, Alex V., van Tintelen, J. Peter, Remme, Carol A., Vos, Marc A., Banning, Antje, de Boer, Teun P., Tikkanen, Ritva, van Veen, Toon A.B., Kessler, Elise L., van Stuijvenberg, Leonie, van Bavel, Joanne J.A., van Bennekom, Joëlle, Zwartsen, Anne, Rivaud, Mathilde R., Vink, Aryan, Efimov, Igor R., Postma, Alex V., van Tintelen, J. Peter, Remme, Carol A., Vos, Marc A., Banning, Antje, de Boer, Teun P., Tikkanen, Ritva, and van Veen, Toon A.B.
Published: 2019

19. Whole Exome Sequencing Reveals the Major Genetic Contributors to Nonsyndromic Tetralogy of Fallot

Author: Page, Donna J, Miossec, Matthieu J, Williams, Simon G, Monaghan, Richard M, Fotiou, Elisavet, Cordell, Heather J, Sutcliffe, Louise, Topf, Ana, Bourgey, Mathieu, Bourque, Guillaume, Eveleigh, Robert, Dunwoodie, Sally L, Winlaw, David S, Bhattacharya, Shoumo, Breckpot, Jeroen, Devriendt, Koenraad, Gewillig, Marc, Brook, J David, Setchfield, Kerry J, Bu’Lock, Frances A, O’Sullivan, John, Stuart, Graham, Bezzina, Connie R, Mulder, Barbara JM, Postma, Alex V, Bentham, James R, Baron, Martin, Bhaskar, Sanjeev S, Black, Graeme C, Newman, William G, Hentges, Kathryn E, Lathrop, G Mark, Santibanez-Koref, Mauro, Keavney, Bernard D, Page, Donna J, Miossec, Matthieu J, Williams, Simon G, Monaghan, Richard M, Fotiou, Elisavet, Cordell, Heather J, Sutcliffe, Louise, Topf, Ana, Bourgey, Mathieu, Bourque, Guillaume, Eveleigh, Robert, Dunwoodie, Sally L, Winlaw, David S, Bhattacharya, Shoumo, Breckpot, Jeroen, Devriendt, Koenraad, Gewillig, Marc, Brook, J David, Setchfield, Kerry J, Bu’Lock, Frances A, O’Sullivan, John, Stuart, Graham, Bezzina, Connie R, Mulder, Barbara JM, Postma, Alex V, Bentham, James R, Baron, Martin, Bhaskar, Sanjeev S, Black, Graeme C, Newman, William G, Hentges, Kathryn E, Lathrop, G Mark, Santibanez-Koref, Mauro, and Keavney, Bernard D
Abstract: Rationale: Familial recurrence studies provide strong evidence for a genetic component to the predisposition to sporadic, nonsyndromic Tetralogy of Fallot (TOF), the most common cyanotic congenital heart disease phenotype. Rare genetic variants have been identified as important contributors to the risk of congenital heart disease, but relatively small numbers of TOF cases have been studied to date. Objective: We used whole exome sequencing to assess the prevalence of unique, deleterious variants in the largest cohort of nonsyndromic TOF patients reported to date. Methods and Results: Eight hundred twenty-nine TOF patients underwent whole exome sequencing. The presence of unique, deleterious variants was determined; defined by their absence in the Genome Aggregation Database and a scaled combined annotation-dependent depletion score of ≥20. The clustering of variants in 2 genes, NOTCH1 and FLT4, surpassed thresholds for genome-wide significance (assigned as P<5×10−8) after correction for multiple comparisons. NOTCH1 was most frequently found to harbor unique, deleterious variants. Thirty-one changes were observed in 37 probands (4.5%; 95% CI, 3.2%–6.1%) and included 7 loss-of-function variants 22 missense variants and 2 in-frame indels. Sanger sequencing of the unaffected parents of 7 cases identified 5 de novo variants. Three NOTCH1 variants (p.G200R, p.C607Y, and p.N1875S) were subjected to functional evaluation, and 2 showed a reduction in Jagged1-induced NOTCH signaling. FLT4 variants were found in 2.4% (95% CI, 1.6%–3.8%) of TOF patients, with 21 patients harboring 22 unique, deleterious variants. The variants identified were distinct to those that cause the congenital lymphoedema syndrome Milroy disease. In addition to NOTCH1, FLT4 and the well-established TOF gene, TBX1, we identified potential association with variants in several other candidates, including RYR1, ZFPM1, CAMTA2, DLX6, and PCM1. Conclusions: The NOTCH1 locus is the most frequent site of genetic
Published: 2019

20. Homozygous frameshift mutations in FAT1 cause a syndrome characterized by colobomatous-microphthalmia, ptosis, nephropathy and syndactyly

Author: Lahrouchi, Najim, George, Aman, Ratbi, Ilham, Schneider, Ronen, Elalaoui, Siham C., Moosa, Shahida, Bharti, Sanita, Sharma, Ruchi, Abu-Asab, Mones, Onojafe, Felix, Adadi, Najlae, Lodder, Elisabeth M., Laarabi, Fatima-Zahra, Lamsyah, Yassine, Elorch, Hamza, Chebbar, Imane, Postma, Alex, V, Lougaris, Vassilios, Plebani, Alessandro, Altmueller, Janine, Kyrieleis, Henriette, Meiner, Vardiella, McNeill, Helen, Bharti, Kapil, Lyonnet, Stanislas, Wollnik, Bernd, Henrion-Caude, Alexandra, Berraho, Amina, Hildebrandt, Friedhelm, Bezzina, Connie R., Brooks, Brian P., Sefiani, Abdelaziz, Lahrouchi, Najim, George, Aman, Ratbi, Ilham, Schneider, Ronen, Elalaoui, Siham C., Moosa, Shahida, Bharti, Sanita, Sharma, Ruchi, Abu-Asab, Mones, Onojafe, Felix, Adadi, Najlae, Lodder, Elisabeth M., Laarabi, Fatima-Zahra, Lamsyah, Yassine, Elorch, Hamza, Chebbar, Imane, Postma, Alex, V, Lougaris, Vassilios, Plebani, Alessandro, Altmueller, Janine, Kyrieleis, Henriette, Meiner, Vardiella, McNeill, Helen, Bharti, Kapil, Lyonnet, Stanislas, Wollnik, Bernd, Henrion-Caude, Alexandra, Berraho, Amina, Hildebrandt, Friedhelm, Bezzina, Connie R., Brooks, Brian P., and Sefiani, Abdelaziz
Abstract: A failure in optic fissure fusion during development can lead to blinding malformations of the eye. Here, we report a syndrome characterized by facial dysmorphism, colobomatous microphthalmia, ptosis and syndactyly with or without nephropathy, associated with homozygous frameshift mutations in FAT1. We show that Fat1 knockout mice and zebrafish embryos homozygous for truncating fatla mutations exhibit completely penetrant coloboma, recapitulating the most consistent developmental defect observed in affected individuals. In human retinal pigment epithelium (RPE) cells, the primary site for the fusion of optic fissure margins, FAT1 is localized at earliest cell-cell junctions, consistent with a role in facilitating optic fissure fusion during vertebrate eye development. Our findings establish FAT1 as a gene with pleiotropic effects in human, in that frameshift mutations cause a severe multi-system disorder whereas recessive missense mutations had been previously associated with isolated glomerulotubular nephropathy.
Published: 2019

21. Flotillins in the intercalated disc are potential modulators of cardiac excitability

Author: Kessler, Elise L., van Stuijvenberg, Leonie, van Bavel, Joanne J.A., van Bennekom, Joëlle, Zwartsen, Anne, Rivaud, Mathilde R., Vink, Aryan, Efimov, Igor R., Postma, Alex V., van Tintelen, J. Peter, Remme, Carol A., Vos, Marc A., Banning, Antje, de Boer, Teun P., Tikkanen, Ritva, van Veen, Toon A.B., Kessler, Elise L., van Stuijvenberg, Leonie, van Bavel, Joanne J.A., van Bennekom, Joëlle, Zwartsen, Anne, Rivaud, Mathilde R., Vink, Aryan, Efimov, Igor R., Postma, Alex V., van Tintelen, J. Peter, Remme, Carol A., Vos, Marc A., Banning, Antje, de Boer, Teun P., Tikkanen, Ritva, and van Veen, Toon A.B.
Published: 2019

22. Flotillins in the intercalated disc are potential modulators of cardiac excitability

Author: Experimentele Afd. Cardiologie 1, Circulatory Health, Medische Fysiologie, Pathologie Secretariaat, Pathologie Pathologen staf, Genetica, Conductiegroep, Kessler, Elise L., van Stuijvenberg, Leonie, van Bavel, Joanne J.A., van Bennekom, Joëlle, Zwartsen, Anne, Rivaud, Mathilde R., Vink, Aryan, Efimov, Igor R., Postma, Alex V., van Tintelen, J. Peter, Remme, Carol A., Vos, Marc A., Banning, Antje, de Boer, Teun P., Tikkanen, Ritva, van Veen, Toon A.B., Experimentele Afd. Cardiologie 1, Circulatory Health, Medische Fysiologie, Pathologie Secretariaat, Pathologie Pathologen staf, Genetica, Conductiegroep, Kessler, Elise L., van Stuijvenberg, Leonie, van Bavel, Joanne J.A., van Bennekom, Joëlle, Zwartsen, Anne, Rivaud, Mathilde R., Vink, Aryan, Efimov, Igor R., Postma, Alex V., van Tintelen, J. Peter, Remme, Carol A., Vos, Marc A., Banning, Antje, de Boer, Teun P., Tikkanen, Ritva, and van Veen, Toon A.B.
Published: 2019

23. Whole Exome Sequencing Reveals the Major Genetic Contributors to Nonsyndromic Tetralogy of Fallot

Author: Page, Donna J, Miossec, Matthieu J, Williams, Simon G, Monaghan, Richard M, Fotiou, Elisavet, Cordell, Heather J, Sutcliffe, Louise, Topf, Ana, Bourgey, Mathieu, Bourque, Guillaume, Eveleigh, Robert, Dunwoodie, Sally L, Winlaw, David S, Bhattacharya, Shoumo, Breckpot, Jeroen, Devriendt, Koenraad, Gewillig, Marc, Brook, J David, Setchfield, Kerry J, Bu’Lock, Frances A, O’Sullivan, John, Stuart, Graham, Bezzina, Connie R, Mulder, Barbara JM, Postma, Alex V, Bentham, James R, Baron, Martin, Bhaskar, Sanjeev S, Black, Graeme C, Newman, William G, Hentges, Kathryn E, Lathrop, G Mark, Santibanez-Koref, Mauro, Keavney, Bernard D, Page, Donna J, Miossec, Matthieu J, Williams, Simon G, Monaghan, Richard M, Fotiou, Elisavet, Cordell, Heather J, Sutcliffe, Louise, Topf, Ana, Bourgey, Mathieu, Bourque, Guillaume, Eveleigh, Robert, Dunwoodie, Sally L, Winlaw, David S, Bhattacharya, Shoumo, Breckpot, Jeroen, Devriendt, Koenraad, Gewillig, Marc, Brook, J David, Setchfield, Kerry J, Bu’Lock, Frances A, O’Sullivan, John, Stuart, Graham, Bezzina, Connie R, Mulder, Barbara JM, Postma, Alex V, Bentham, James R, Baron, Martin, Bhaskar, Sanjeev S, Black, Graeme C, Newman, William G, Hentges, Kathryn E, Lathrop, G Mark, Santibanez-Koref, Mauro, and Keavney, Bernard D
Abstract: Rationale: Familial recurrence studies provide strong evidence for a genetic component to the predisposition to sporadic, nonsyndromic Tetralogy of Fallot (TOF), the most common cyanotic congenital heart disease phenotype. Rare genetic variants have been identified as important contributors to the risk of congenital heart disease, but relatively small numbers of TOF cases have been studied to date. Objective: We used whole exome sequencing to assess the prevalence of unique, deleterious variants in the largest cohort of nonsyndromic TOF patients reported to date. Methods and Results: Eight hundred twenty-nine TOF patients underwent whole exome sequencing. The presence of unique, deleterious variants was determined; defined by their absence in the Genome Aggregation Database and a scaled combined annotation-dependent depletion score of ≥20. The clustering of variants in 2 genes, NOTCH1 and FLT4, surpassed thresholds for genome-wide significance (assigned as P<5×10−8) after correction for multiple comparisons. NOTCH1 was most frequently found to harbor unique, deleterious variants. Thirty-one changes were observed in 37 probands (4.5%; 95% CI, 3.2%–6.1%) and included 7 loss-of-function variants 22 missense variants and 2 in-frame indels. Sanger sequencing of the unaffected parents of 7 cases identified 5 de novo variants. Three NOTCH1 variants (p.G200R, p.C607Y, and p.N1875S) were subjected to functional evaluation, and 2 showed a reduction in Jagged1-induced NOTCH signaling. FLT4 variants were found in 2.4% (95% CI, 1.6%–3.8%) of TOF patients, with 21 patients harboring 22 unique, deleterious variants. The variants identified were distinct to those that cause the congenital lymphoedema syndrome Milroy disease. In addition to NOTCH1, FLT4 and the well-established TOF gene, TBX1, we identified potential association with variants in several other candidates, including RYR1, ZFPM1, CAMTA2, DLX6, and PCM1. Conclusions: The NOTCH1 locus is the most frequent site of genetic
Published: 2019

24. Homozygous frameshift mutations in FAT1 cause a syndrome characterized by colobomatous-microphthalmia, ptosis, nephropathy and syndactyly

Author: Lahrouchi, Najim, George, Aman, Ratbi, Ilham, Schneider, Ronen, Elalaoui, Siham C., Moosa, Shahida, Bharti, Sanita, Sharma, Ruchi, Abu-Asab, Mones, Onojafe, Felix, Adadi, Najlae, Lodder, Elisabeth M., Laarabi, Fatima-Zahra, Lamsyah, Yassine, Elorch, Hamza, Chebbar, Imane, Postma, Alex, V, Lougaris, Vassilios, Plebani, Alessandro, Altmueller, Janine, Kyrieleis, Henriette, Meiner, Vardiella, McNeill, Helen, Bharti, Kapil, Lyonnet, Stanislas, Wollnik, Bernd, Henrion-Caude, Alexandra, Berraho, Amina, Hildebrandt, Friedhelm, Bezzina, Connie R., Brooks, Brian P., Sefiani, Abdelaziz, Lahrouchi, Najim, George, Aman, Ratbi, Ilham, Schneider, Ronen, Elalaoui, Siham C., Moosa, Shahida, Bharti, Sanita, Sharma, Ruchi, Abu-Asab, Mones, Onojafe, Felix, Adadi, Najlae, Lodder, Elisabeth M., Laarabi, Fatima-Zahra, Lamsyah, Yassine, Elorch, Hamza, Chebbar, Imane, Postma, Alex, V, Lougaris, Vassilios, Plebani, Alessandro, Altmueller, Janine, Kyrieleis, Henriette, Meiner, Vardiella, McNeill, Helen, Bharti, Kapil, Lyonnet, Stanislas, Wollnik, Bernd, Henrion-Caude, Alexandra, Berraho, Amina, Hildebrandt, Friedhelm, Bezzina, Connie R., Brooks, Brian P., and Sefiani, Abdelaziz
Abstract: A failure in optic fissure fusion during development can lead to blinding malformations of the eye. Here, we report a syndrome characterized by facial dysmorphism, colobomatous microphthalmia, ptosis and syndactyly with or without nephropathy, associated with homozygous frameshift mutations in FAT1. We show that Fat1 knockout mice and zebrafish embryos homozygous for truncating fatla mutations exhibit completely penetrant coloboma, recapitulating the most consistent developmental defect observed in affected individuals. In human retinal pigment epithelium (RPE) cells, the primary site for the fusion of optic fissure margins, FAT1 is localized at earliest cell-cell junctions, consistent with a role in facilitating optic fissure fusion during vertebrate eye development. Our findings establish FAT1 as a gene with pleiotropic effects in human, in that frameshift mutations cause a severe multi-system disorder whereas recessive missense mutations had been previously associated with isolated glomerulotubular nephropathy.
Published: 2019

25. Loss-of-function variants in myocardin cause congenital megabladder in humans and mice

Author: Genetica Klinische Genetica, Child Health, Houweling, Arjan C, Beaman, Glenda M, Postma, Alex V, Gainous, T Blair, Lichtenbelt, Klaske D, Brancati, Francesco, Lopes, Filipa M, van der Made, Ingeborg, Polstra, Abeltje M, Robinson, Michael L, Wright, Kevin D, Ellingford, Jamie M, Jackson, Ashley R, Overwater, Eline, Genesio, Rita, Romano, Silvio, Camerota, Letizia, D'Angelo, Emanuela, Meijers-Heijboer, Elizabeth J, Christoffels, Vincent M, McHugh, Kirk M, Black, Brian L, Newman, William G, Woolf, Adrian S, Creemers, Esther E, Genetica Klinische Genetica, Child Health, Houweling, Arjan C, Beaman, Glenda M, Postma, Alex V, Gainous, T Blair, Lichtenbelt, Klaske D, Brancati, Francesco, Lopes, Filipa M, van der Made, Ingeborg, Polstra, Abeltje M, Robinson, Michael L, Wright, Kevin D, Ellingford, Jamie M, Jackson, Ashley R, Overwater, Eline, Genesio, Rita, Romano, Silvio, Camerota, Letizia, D'Angelo, Emanuela, Meijers-Heijboer, Elizabeth J, Christoffels, Vincent M, McHugh, Kirk M, Black, Brian L, Newman, William G, Woolf, Adrian S, and Creemers, Esther E
Published: 2019

26. Whole-Exome Sequencing Identifies Pathogenic Variants in TJP1 Gene Associated With Arrhythmogenic Cardiomyopathy

Author: De Bortoli, Marzia, Postma, Alex V, Poloni, Giulia, Calore, Martina, Minervini, Giovanni, Mazzotti, Elisa, Rigato, Ilaria, Ebert, Micaela, Lorenzon, Alessandra, Vazza, Giovanni, Cipriani, Alberto, Bariani, Riccardo, Perazzolo Marra, Martina, Husser, Daniela, Thiene, Gaetano, Daliento, Luciano, Corrado, Domenico, Basso, Cristina, Tosatto, Silvio C E, Bauce, Barbara, van Tintelen, J Peter, Rampazzo, Alessandra, De Bortoli, Marzia, Postma, Alex V, Poloni, Giulia, Calore, Martina, Minervini, Giovanni, Mazzotti, Elisa, Rigato, Ilaria, Ebert, Micaela, Lorenzon, Alessandra, Vazza, Giovanni, Cipriani, Alberto, Bariani, Riccardo, Perazzolo Marra, Martina, Husser, Daniela, Thiene, Gaetano, Daliento, Luciano, Corrado, Domenico, Basso, Cristina, Tosatto, Silvio C E, Bauce, Barbara, van Tintelen, J Peter, and Rampazzo, Alessandra
Published: 2018

27. Familial co-occurrence of congenital heart defects follows distinct patterns

Author: Ellesøe, Sabrina G., Workman, Christopher T., Bouvagnet, Patrice, Loffredo, Christopher A., McBride, Kim L., Hinton, Robert B., Van Engelen, Klaartje, Gertsen, Emma C., Mulder, Barbara J.M., Postma, Alex V., Anderson, Robert H., Hjortdal, Vibeke E., Brunak, Søren, Larsen, Lars A., Ellesøe, Sabrina G., Workman, Christopher T., Bouvagnet, Patrice, Loffredo, Christopher A., McBride, Kim L., Hinton, Robert B., Van Engelen, Klaartje, Gertsen, Emma C., Mulder, Barbara J.M., Postma, Alex V., Anderson, Robert H., Hjortdal, Vibeke E., Brunak, Søren, and Larsen, Lars A.
Published: 2018

28. Whole-Exome Sequencing Identifies Pathogenic Variants in TJP1 Gene Associated With Arrhythmogenic Cardiomyopathy

Author: De Bortoli, Marzia, Postma, Alex V, Poloni, Giulia, Calore, Martina, Minervini, Giovanni, Mazzotti, Elisa, Rigato, Ilaria, Ebert, Micaela, Lorenzon, Alessandra, Vazza, Giovanni, Cipriani, Alberto, Bariani, Riccardo, Perazzolo Marra, Martina, Husser, Daniela, Thiene, Gaetano, Daliento, Luciano, Corrado, Domenico, Basso, Cristina, Tosatto, Silvio C E, Bauce, Barbara, van Tintelen, J Peter, Rampazzo, Alessandra, De Bortoli, Marzia, Postma, Alex V, Poloni, Giulia, Calore, Martina, Minervini, Giovanni, Mazzotti, Elisa, Rigato, Ilaria, Ebert, Micaela, Lorenzon, Alessandra, Vazza, Giovanni, Cipriani, Alberto, Bariani, Riccardo, Perazzolo Marra, Martina, Husser, Daniela, Thiene, Gaetano, Daliento, Luciano, Corrado, Domenico, Basso, Cristina, Tosatto, Silvio C E, Bauce, Barbara, van Tintelen, J Peter, and Rampazzo, Alessandra
Published: 2018

29. Familial co-occurrence of congenital heart defects follows distinct patterns

Author: Ellesøe, Sabrina G., Workman, Christopher T., Bouvagnet, Patrice, Loffredo, Christopher A., McBride, Kim L., Hinton, Robert B., Van Engelen, Klaartje, Gertsen, Emma C., Mulder, Barbara J.M., Postma, Alex V., Anderson, Robert H., Hjortdal, Vibeke E., Brunak, Søren, Larsen, Lars A., Ellesøe, Sabrina G., Workman, Christopher T., Bouvagnet, Patrice, Loffredo, Christopher A., McBride, Kim L., Hinton, Robert B., Van Engelen, Klaartje, Gertsen, Emma C., Mulder, Barbara J.M., Postma, Alex V., Anderson, Robert H., Hjortdal, Vibeke E., Brunak, Søren, and Larsen, Lars A.
Published: 2018

30. Whole-Exome Sequencing Identifies Pathogenic Variants in TJP1 Gene Associated With Arrhythmogenic Cardiomyopathy

Author: De Bortoli, Marzia, Postma, Alex V, Poloni, Giulia, Calore, Martina, Minervini, Giovanni, Mazzotti, Elisa, Rigato, Ilaria, Ebert, Micaela, Lorenzon, Alessandra, Vazza, Giovanni, Cipriani, Alberto, Bariani, Riccardo, Perazzolo Marra, Martina, Husser, Daniela, Thiene, Gaetano, Daliento, Luciano, Corrado, Domenico, Basso, Cristina, Tosatto, Silvio C E, Bauce, Barbara, van Tintelen, J Peter, Rampazzo, Alessandra, De Bortoli, Marzia, Postma, Alex V, Poloni, Giulia, Calore, Martina, Minervini, Giovanni, Mazzotti, Elisa, Rigato, Ilaria, Ebert, Micaela, Lorenzon, Alessandra, Vazza, Giovanni, Cipriani, Alberto, Bariani, Riccardo, Perazzolo Marra, Martina, Husser, Daniela, Thiene, Gaetano, Daliento, Luciano, Corrado, Domenico, Basso, Cristina, Tosatto, Silvio C E, Bauce, Barbara, van Tintelen, J Peter, and Rampazzo, Alessandra
Published: 2018

31. Familial co-occurrence of congenital heart defects follows distinct patterns

Author: Ellesøe, Sabrina G., Workman, Christopher T., Bouvagnet, Patrice, Loffredo, Christopher A., McBride, Kim L., Hinton, Robert B., Van Engelen, Klaartje, Gertsen, Emma C., Mulder, Barbara J.M., Postma, Alex V., Anderson, Robert H., Hjortdal, Vibeke E., Brunak, Søren, Larsen, Lars A., Ellesøe, Sabrina G., Workman, Christopher T., Bouvagnet, Patrice, Loffredo, Christopher A., McBride, Kim L., Hinton, Robert B., Van Engelen, Klaartje, Gertsen, Emma C., Mulder, Barbara J.M., Postma, Alex V., Anderson, Robert H., Hjortdal, Vibeke E., Brunak, Søren, and Larsen, Lars A.
Published: 2018

32. Whole-Exome Sequencing Identifies Pathogenic Variants in TJP1 Gene Associated With Arrhythmogenic Cardiomyopathy

Author: Genetica, De Bortoli, Marzia, Postma, Alex V, Poloni, Giulia, Calore, Martina, Minervini, Giovanni, Mazzotti, Elisa, Rigato, Ilaria, Ebert, Micaela, Lorenzon, Alessandra, Vazza, Giovanni, Cipriani, Alberto, Bariani, Riccardo, Perazzolo Marra, Martina, Husser, Daniela, Thiene, Gaetano, Daliento, Luciano, Corrado, Domenico, Basso, Cristina, Tosatto, Silvio C E, Bauce, Barbara, van Tintelen, J Peter, Rampazzo, Alessandra, Genetica, De Bortoli, Marzia, Postma, Alex V, Poloni, Giulia, Calore, Martina, Minervini, Giovanni, Mazzotti, Elisa, Rigato, Ilaria, Ebert, Micaela, Lorenzon, Alessandra, Vazza, Giovanni, Cipriani, Alberto, Bariani, Riccardo, Perazzolo Marra, Martina, Husser, Daniela, Thiene, Gaetano, Daliento, Luciano, Corrado, Domenico, Basso, Cristina, Tosatto, Silvio C E, Bauce, Barbara, van Tintelen, J Peter, and Rampazzo, Alessandra
Published: 2018

33. Familial co-occurrence of congenital heart defects follows distinct patterns

Author: Ellesøe, Sabrina G., Workman, Christopher T., Bouvagnet, Patrice, Loffredo, Christopher A., McBride, Kim L., Hinton, Robert B., Van Engelen, Klaartje, Gertsen, Emma C., Mulder, Barbara J.M., Postma, Alex V., Anderson, Robert H., Hjortdal, Vibeke E., Brunak, Søren, Larsen, Lars A., Ellesøe, Sabrina G., Workman, Christopher T., Bouvagnet, Patrice, Loffredo, Christopher A., McBride, Kim L., Hinton, Robert B., Van Engelen, Klaartje, Gertsen, Emma C., Mulder, Barbara J.M., Postma, Alex V., Anderson, Robert H., Hjortdal, Vibeke E., Brunak, Søren, and Larsen, Lars A.
Published: 2018

34. Familial co-occurrence of congenital heart defects follows distinct patterns

Author: Ellesøe, Sabrina G, Workman, Christopher T, Bouvagnet, Patrice, Loffredo, Christopher A, McBride, Kim L, Hinton, Robert B, van Engelen, Klaartje, Gertsen, Emma C, Mulder, Barbara J M, Postma, Alex V, Anderson, Robert H, Hjortdal, Vibeke E, Brunak, Søren, Larsen, Lars A, Ellesøe, Sabrina G, Workman, Christopher T, Bouvagnet, Patrice, Loffredo, Christopher A, McBride, Kim L, Hinton, Robert B, van Engelen, Klaartje, Gertsen, Emma C, Mulder, Barbara J M, Postma, Alex V, Anderson, Robert H, Hjortdal, Vibeke E, Brunak, Søren, and Larsen, Lars A
Abstract: Aims: Congenital heart defects (CHD) affect almost 1% of all live born children and the number of adults with CHD is increasing. In families where CHD has occurred previously, estimates of recurrence risk, and the type of recurring malformation are important for counselling and clinical decision-making, but the recurrence patterns in families are poorly understood. We aimed to determine recurrence patterns, by investigating the co-occurrences of CHD in 1163 families with known malformations, comprising 3080 individuals with clinically confirmed diagnosis.Methods and results: We calculated rates of concordance and discordance for 41 specific types of malformations, observing a high variability in the rates of concordance and discordance. By calculating odds ratios for each of 1640 pairs of discordant lesions observed between affected family members, we were able to identify 178 pairs of malformations that co-occurred significantly more or less often than expected in families. The data show that distinct groups of cardiac malformations co-occur in families, suggesting influence from underlying developmental mechanisms. Analysis of human and mouse susceptibility genes showed that they were shared in 19% and 20% of pairs of co-occurring discordant malformations, respectively, but none of malformations that rarely co-occur, suggesting that a significant proportion of co-occurring lesions in families is caused by overlapping susceptibility genes.Conclusion: Familial CHD follow specific patterns of recurrence, suggesting a strong influence from genetically regulated developmental mechanisms. Co-occurrence of malformations in families is caused by shared susceptibility genes.
Published: 2018

35. Familial co-occurrence of congenital heart defects follows distinct patterns

Author: Ellesøe, Sabrina G., Workman, Christopher T., Bouvagnet, Patrice, Loffredo, Christopher A., McBride, Kim L., Hinton, Robert B., van Engelen, Klaartje, Gertsen, Emma C., Mulder, Barbara J. M., Postma, Alex V, Anderson, Robert H, Hjortdal, Vibeke E, Brunak, Søren, Larsen, Lars A, Ellesøe, Sabrina G., Workman, Christopher T., Bouvagnet, Patrice, Loffredo, Christopher A., McBride, Kim L., Hinton, Robert B., van Engelen, Klaartje, Gertsen, Emma C., Mulder, Barbara J. M., Postma, Alex V, Anderson, Robert H, Hjortdal, Vibeke E, Brunak, Søren, and Larsen, Lars A
Abstract: Congenital heart defects (CHD) affect almost 1% of all live born children and the number of adults with CHD is increasing. In families where CHD has occurred previously, estimates of recurrence risk, and the type of recurring malformation are important for counselling and clinical decision-making, but the recurrence patterns in families are poorly understood. We aimed to determine recurrence patterns, by investigating the co-occurrences of CHD in 1163 families with known malformations, comprising 3080 individuals with clinically confirmed diagnosis. We calculated rates of concordance and discordance for 41 specific types of malformations, observing a high variability in the rates of concordance and discordance. By calculating odds ratios for each of 1640 pairs of discordant lesions observed between affected family members, we were able to identify 178 pairs of malformations that co-occurred significantly more or less often than expected in families. The data show that distinct groups of cardiac malformations co-occur in families, suggesting influence from underlying developmental mechanisms. Analysis of human and mouse susceptibility genes showed that they were shared in 19% and 20% of pairs of co-occurring discordant malformations, respectively, but none of malformations that rarely co-occur, suggesting that a significant proportion of co-occurring lesions in families is caused by overlapping susceptibility genes. Familial CHD follow specific patterns of recurrence, suggesting a strong influence from genetically regulated developmental mechanisms. Co-occurrence of malformations in families is caused by shared susceptibility genes.
Published: 2018

36. Familial co-occurrence of congenital heart defects follows distinct patterns

Author: Ellesøe, Sabrina G, Workman, Christopher T, Bouvagnet, Patrice, Loffredo, Christopher A, McBride, Kim L, Hinton, Robert B, van Engelen, Klaartje, Gertsen, Emma C, Mulder, Barbara J M, Postma, Alex V, Anderson, Robert H, Hjortdal, Vibeke E, Brunak, Søren, Larsen, Lars A, Ellesøe, Sabrina G, Workman, Christopher T, Bouvagnet, Patrice, Loffredo, Christopher A, McBride, Kim L, Hinton, Robert B, van Engelen, Klaartje, Gertsen, Emma C, Mulder, Barbara J M, Postma, Alex V, Anderson, Robert H, Hjortdal, Vibeke E, Brunak, Søren, and Larsen, Lars A
Abstract: Aims: Congenital heart defects (CHD) affect almost 1% of all live born children and the number of adults with CHD is increasing. In families where CHD has occurred previously, estimates of recurrence risk, and the type of recurring malformation are important for counselling and clinical decision-making, but the recurrence patterns in families are poorly understood. We aimed to determine recurrence patterns, by investigating the co-occurrences of CHD in 1163 families with known malformations, comprising 3080 individuals with clinically confirmed diagnosis.Methods and results: We calculated rates of concordance and discordance for 41 specific types of malformations, observing a high variability in the rates of concordance and discordance. By calculating odds ratios for each of 1640 pairs of discordant lesions observed between affected family members, we were able to identify 178 pairs of malformations that co-occurred significantly more or less often than expected in families. The data show that distinct groups of cardiac malformations co-occur in families, suggesting influence from underlying developmental mechanisms. Analysis of human and mouse susceptibility genes showed that they were shared in 19% and 20% of pairs of co-occurring discordant malformations, respectively, but none of malformations that rarely co-occur, suggesting that a significant proportion of co-occurring lesions in families is caused by overlapping susceptibility genes.Conclusion: Familial CHD follow specific patterns of recurrence, suggesting a strong influence from genetically regulated developmental mechanisms. Co-occurrence of malformations in families is caused by shared susceptibility genes.
Published: 2018

37. Genome-wide association study identifies loci on 12q24 and 13q32 associated with Tetralogy of Fallot

Author: Cordell, Heather J., Töpf, Ana, Mamasoula, Chrysovalanto, Postma, Alex V., Bentham, Jamie, Zelenika, Diana, Heath, Simon, Blue, Gillian, Cosgrove, Catherine, Granados Riveron, Javier, Darlay, Rebecca, Soemedi, Rachel, Wilson, Ian J., Ayers, Kristin L., Rahman, Thahira J., Hall, Darroch, Mulder, Barbara J.M., Zwinderman, Aelko H., van Engelen, Klaartje, Brook, J. David, Setchfield, Kerry, Bu'Lock, Frances A., Thornborough, Chris, O'Sullivan, John, Stuart, A. Graham, Parsons, Jonathan, Bhattacharya, Shoumo, Winlaw, David, Mital, Seema, Gewillig, Marc, Breckpot, Jeroen, Devriendt, Koen, Moorman, Antoon F.M., Rauch, Anita, Lathrop, G. Mark, Keavney, Bernard D., Goodship, Judith A., Cordell, Heather J., Töpf, Ana, Mamasoula, Chrysovalanto, Postma, Alex V., Bentham, Jamie, Zelenika, Diana, Heath, Simon, Blue, Gillian, Cosgrove, Catherine, Granados Riveron, Javier, Darlay, Rebecca, Soemedi, Rachel, Wilson, Ian J., Ayers, Kristin L., Rahman, Thahira J., Hall, Darroch, Mulder, Barbara J.M., Zwinderman, Aelko H., van Engelen, Klaartje, Brook, J. David, Setchfield, Kerry, Bu'Lock, Frances A., Thornborough, Chris, O'Sullivan, John, Stuart, A. Graham, Parsons, Jonathan, Bhattacharya, Shoumo, Winlaw, David, Mital, Seema, Gewillig, Marc, Breckpot, Jeroen, Devriendt, Koen, Moorman, Antoon F.M., Rauch, Anita, Lathrop, G. Mark, Keavney, Bernard D., and Goodship, Judith A.
Abstract: We conducted a genome-wide association study to search for risk alleles associated with Tetralogy of Fallot (TOF), using a northern European discovery set of 835 cases and 5159 controls. A region on chromosome 12q24 was associated (P = 1.4 × 10−7) and replicated convincingly (P = 3.9 × 10−5) in 798 cases and 2931 controls [per allele odds ratio (OR) = 1.27 in replication cohort, P = 7.7 × 10−11 in combined populations]. Single nucleotide polymorphisms in the glypican 5 gene on chromosome 13q32 were also associated (P = 1.7 × 10−7) and replicated convincingly (P = 1.2 × 10−5) in 789 cases and 2927 controls (per allele OR = 1.31 in replication cohort, P = 3.03 × 10−11 in combined populations). Four additional regions on chromosomes 10, 15 and 16 showed suggestive association accompanied by nominal replication. This study, the first genome-wide association study of a congenital heart malformation phenotype, provides evidence that common genetic variation influences the risk of TOF
Published: 2017

38. A Zebrafish Loss-of-Function Model for Human CFAP53 Mutations Reveals Its Specific Role in Laterality Organ Function

Author: Noël, Emily S, Momenah, Tarek S, Al-Dagriri, Khalid, Al-Suwaid, Abdulrahman, Al-Shahrani, Safar, Jiang, Hui, Willekers, Sven, Oostveen, Yara Y, Chocron, Sonja, Postma, Alex V, Bhuiyan, Zahurul A, Bakkers, Jeroen, Noël, Emily S, Momenah, Tarek S, Al-Dagriri, Khalid, Al-Suwaid, Abdulrahman, Al-Shahrani, Safar, Jiang, Hui, Willekers, Sven, Oostveen, Yara Y, Chocron, Sonja, Postma, Alex V, Bhuiyan, Zahurul A, and Bakkers, Jeroen
Published: 2016

39. A zebrafish Loss-of-Function Model for Human CFAP53 Mutations Reveals its Specific Role in Laterality Organ Function

Author: Noël, Emily S, Momenah, Tarek S, Al-Dagriri, Khalid, Al-Suwaid, Abdulrahman, Al-Shahrani, Safar, Jiang, Hui, Willekers, Sven, Oostveen, Yara Y, Chocron, Sonja, Postma, Alex V, Bhuiyan, Zahurul A, Bakkers, Jeroen, Noël, Emily S, Momenah, Tarek S, Al-Dagriri, Khalid, Al-Suwaid, Abdulrahman, Al-Shahrani, Safar, Jiang, Hui, Willekers, Sven, Oostveen, Yara Y, Chocron, Sonja, Postma, Alex V, Bhuiyan, Zahurul A, and Bakkers, Jeroen
Abstract: Establishing correct left-right asymmetry during embryonic development is crucial for proper asymmetric positioning of the organs. Congenital heart defects such as dextrocardia, transposition of the arteries, and inflow or outflow tract malformations, comprise some of the most common birth defects and may be attributed to incorrect establishment of body laterality. Here we identify 3 new patients with dextrocardia who have mutations in CFAP53, a coiled-coil domain containing protein. To elucidate the mechanism by which CFAP53 regulates embryonic asymmetry we used genome editing to generate cfap53 zebrafish mutants. Zebrafish cfap53 mutants have specific defects in organ laterality, and randomisation of asymmetric gene expression. We show that cfap53 is required for cilia rotation specifically in Kupffer's vesicle, the zebrafish laterality organ, providing a mechanism by which patients with CFAP53 mutations develop dextrocardia and heterotaxy, and confirming previous evidence that left-right asymmetry in humans is regulated through cilia-driven fluid flow in a laterality organ. This article is protected by copyright. All rights reserved.
Published: 2016

40. A Zebrafish Loss-of-Function Model for Human CFAP53 Mutations Reveals Its Specific Role in Laterality Organ Function

Author: Noël, Emily S, Momenah, Tarek S, Al-Dagriri, Khalid, Al-Suwaid, Abdulrahman, Al-Shahrani, Safar, Jiang, Hui, Willekers, Sven, Oostveen, Yara Y, Chocron, Sonja, Postma, Alex V, Bhuiyan, Zahurul A, Bakkers, Jeroen, Noël, Emily S, Momenah, Tarek S, Al-Dagriri, Khalid, Al-Suwaid, Abdulrahman, Al-Shahrani, Safar, Jiang, Hui, Willekers, Sven, Oostveen, Yara Y, Chocron, Sonja, Postma, Alex V, Bhuiyan, Zahurul A, and Bakkers, Jeroen
Published: 2016

41. A Zebrafish Loss-of-Function Model for Human CFAP53 Mutations Reveals Its Specific Role in Laterality Organ Function

Author: Noël, Emily S, Momenah, Tarek S, Al-Dagriri, Khalid, Al-Suwaid, Abdulrahman, Al-Shahrani, Safar, Jiang, Hui, Willekers, Sven, Oostveen, Yara Y, Chocron, Sonja, Postma, Alex V, Bhuiyan, Zahurul A, Bakkers, Jeroen, Noël, Emily S, Momenah, Tarek S, Al-Dagriri, Khalid, Al-Suwaid, Abdulrahman, Al-Shahrani, Safar, Jiang, Hui, Willekers, Sven, Oostveen, Yara Y, Chocron, Sonja, Postma, Alex V, Bhuiyan, Zahurul A, and Bakkers, Jeroen
Published: 2016

42. A Zebrafish Loss-of-Function Model for Human CFAP53 Mutations Reveals Its Specific Role in Laterality Organ Function

Author: Medische Fysiologie, Hubrecht Institute with UMC, Circulatory Health, Noël, Emily S, Momenah, Tarek S, Al-Dagriri, Khalid, Al-Suwaid, Abdulrahman, Al-Shahrani, Safar, Jiang, Hui, Willekers, Sven, Oostveen, Yara Y, Chocron, Sonja, Postma, Alex V, Bhuiyan, Zahurul A, Bakkers, Jeroen, Medische Fysiologie, Hubrecht Institute with UMC, Circulatory Health, Noël, Emily S, Momenah, Tarek S, Al-Dagriri, Khalid, Al-Suwaid, Abdulrahman, Al-Shahrani, Safar, Jiang, Hui, Willekers, Sven, Oostveen, Yara Y, Chocron, Sonja, Postma, Alex V, Bhuiyan, Zahurul A, and Bakkers, Jeroen
Published: 2016

43. A zebrafish Loss-of-Function Model for Human CFAP53 Mutations Reveals its Specific Role in Laterality Organ Function

Author: Noël, Emily S, Momenah, Tarek S, Al-Dagriri, Khalid, Al-Suwaid, Abdulrahman, Al-Shahrani, Safar, Jiang, Hui, Willekers, Sven, Oostveen, Yara Y, Chocron, Sonja, Postma, Alex V, Bhuiyan, Zahurul A, Bakkers, Jeroen, Noël, Emily S, Momenah, Tarek S, Al-Dagriri, Khalid, Al-Suwaid, Abdulrahman, Al-Shahrani, Safar, Jiang, Hui, Willekers, Sven, Oostveen, Yara Y, Chocron, Sonja, Postma, Alex V, Bhuiyan, Zahurul A, and Bakkers, Jeroen
Abstract: Establishing correct left-right asymmetry during embryonic development is crucial for proper asymmetric positioning of the organs. Congenital heart defects such as dextrocardia, transposition of the arteries, and inflow or outflow tract malformations, comprise some of the most common birth defects and may be attributed to incorrect establishment of body laterality. Here we identify 3 new patients with dextrocardia who have mutations in CFAP53, a coiled-coil domain containing protein. To elucidate the mechanism by which CFAP53 regulates embryonic asymmetry we used genome editing to generate cfap53 zebrafish mutants. Zebrafish cfap53 mutants have specific defects in organ laterality, and randomisation of asymmetric gene expression. We show that cfap53 is required for cilia rotation specifically in Kupffer's vesicle, the zebrafish laterality organ, providing a mechanism by which patients with CFAP53 mutations develop dextrocardia and heterotaxy, and confirming previous evidence that left-right asymmetry in humans is regulated through cilia-driven fluid flow in a laterality organ. This article is protected by copyright. All rights reserved.
Published: 2016

44. Genome-wide association study identifies loci on 12q24 and 13q32 associated with tetralogy of Fallot

Author: Cordell, Heather J, Töpf, Ana, Mamasoula, Chrysovalanto, Postma, Alex V, Bentham, Jamie, Zelenika, Diana, Heath, Simon, Blue, Gillian, Cosgrove, Catherine, Granados Riveron, Javier, Darlay, Rebecca, Soemedi, Rachel, Wilson, Ian J, Ayers, Kristin L, Rahman, Thahira J, Hall, Darroch, Mulder, Barbara J M, Zwinderman, Aelko H, van Engelen, Klaartje, Brook, J David, Setchfield, Kerry, Bu'Lock, Frances A, Thornborough, Chris, O'Sullivan, John, Stuart, A Graham, Parsons, Jonathan, Bhattacharya, Shoumo, Winlaw, David, Mital, Seema, Gewillig, Marc, Breckpot, Jeroen, Devriendt, Koen, Moorman, Antoon F M, Rauch, Anita, Lathrop, G Mark, Keavney, Bernard D, Goodship, Judith A, Cordell, Heather J, Töpf, Ana, Mamasoula, Chrysovalanto, Postma, Alex V, Bentham, Jamie, Zelenika, Diana, Heath, Simon, Blue, Gillian, Cosgrove, Catherine, Granados Riveron, Javier, Darlay, Rebecca, Soemedi, Rachel, Wilson, Ian J, Ayers, Kristin L, Rahman, Thahira J, Hall, Darroch, Mulder, Barbara J M, Zwinderman, Aelko H, van Engelen, Klaartje, Brook, J David, Setchfield, Kerry, Bu'Lock, Frances A, Thornborough, Chris, O'Sullivan, John, Stuart, A Graham, Parsons, Jonathan, Bhattacharya, Shoumo, Winlaw, David, Mital, Seema, Gewillig, Marc, Breckpot, Jeroen, Devriendt, Koen, Moorman, Antoon F M, Rauch, Anita, Lathrop, G Mark, Keavney, Bernard D, and Goodship, Judith A
Abstract: We conducted a genome-wide association study to search for risk alleles associated with Tetralogy of Fallot (TOF), using a northern European discovery set of 835 cases and 5159 controls. A region on chromosome 12q24 was associated (P = 1.4 × 10(-7)) and replicated convincingly (P = 3.9 × 10(-5)) in 798 cases and 2931 controls [per allele odds ratio (OR) = 1.27 in replication cohort, P = 7.7 × 10(-11) in combined populations]. Single nucleotide polymorphisms in the glypican 5 gene on chromosome 13q32 were also associated (P = 1.7 × 10(-7)) and replicated convincingly (P = 1.2 × 10(-5)) in 789 cases and 2927 controls (per allele OR = 1.31 in replication cohort, P = 3.03 × 10(-11) in combined populations). Four additional regions on chromosomes 10, 15 and 16 showed suggestive association accompanied by nominal replication. This study, the first genome-wide association study of a congenital heart malformation phenotype, provides evidence that common genetic variation influences the risk of TOF.
Published: 2013

45. Haploinsufficiency of TAB2 causes congenital heart defects in humans

Author: Thienpont, Bernard, Zhang, Litu, Postma, Alex V, Breckpot, Jeroen, Tranchevent, Léon-Charles, Van Loo, Peter, Møllgård, Kjeld, Tommerup, Niels, Bache, Iben, Tümer, Zeynep, van Engelen, Klaartje, Menten, Björn, Mortier, Geert, Waggoner, Darrel, Gewillig, Marc, Moreau, Yves, Devriendt, Koen, Larsen, Lars Allan, Thienpont, Bernard, Zhang, Litu, Postma, Alex V, Breckpot, Jeroen, Tranchevent, Léon-Charles, Van Loo, Peter, Møllgård, Kjeld, Tommerup, Niels, Bache, Iben, Tümer, Zeynep, van Engelen, Klaartje, Menten, Björn, Mortier, Geert, Waggoner, Darrel, Gewillig, Marc, Moreau, Yves, Devriendt, Koen, and Larsen, Lars Allan
Abstract: Udgivelsesdato: 2010-Jun-11, Congenital heart defects (CHDs) are the most common major developmental anomalies and the most frequent cause for perinatal mortality, but their etiology remains often obscure. We identified a locus for CHDs on 6q24-q25. Genotype-phenotype correlations in 12 patients carrying a chromosomal deletion on 6q delineated a critical 850 kb region on 6q25.1 harboring five genes. Bioinformatics prioritization of candidate genes in this locus for a role in CHDs identified the TGF-beta-activated kinase 1/MAP3K7 binding protein 2 gene (TAB2) as the top-ranking candidate gene. A role for this candidate gene in cardiac development was further supported by its conserved expression in the developing human and zebrafish heart. Moreover, a critical, dosage-sensitive role during development was demonstrated by the cardiac defects observed upon titrated knockdown of tab2 expression in zebrafish embryos. To definitively confirm the role of this candidate gene in CHDs, we performed mutation analysis of TAB2 in 402 patients with a CHD, which revealed two evolutionarily conserved missense mutations. Finally, a balanced translocation was identified, cosegregating with familial CHD. Mapping of the breakpoints demonstrated that this translocation disrupts TAB2. Taken together, these data clearly demonstrate a role for TAB2 in human cardiac development.
Published: 2010

46. Haploinsufficiency of TAB2 causes congenital heart defects in humans

Author: Thienpont, Bernard, Zhang, Litu, Postma, Alex V, Breckpot, Jeroen, Tranchevent, Léon-Charles, Van Loo, Peter, Møllgård, Kjeld, Tommerup, Niels, Bache, Iben, Tümer, Zeynep, van Engelen, Klaartje, Menten, Björn, Mortier, Geert, Waggoner, Darrel, Gewillig, Marc, Moreau, Yves, Devriendt, Koen, Larsen, Lars Allan, Thienpont, Bernard, Zhang, Litu, Postma, Alex V, Breckpot, Jeroen, Tranchevent, Léon-Charles, Van Loo, Peter, Møllgård, Kjeld, Tommerup, Niels, Bache, Iben, Tümer, Zeynep, van Engelen, Klaartje, Menten, Björn, Mortier, Geert, Waggoner, Darrel, Gewillig, Marc, Moreau, Yves, Devriendt, Koen, and Larsen, Lars Allan
Abstract: Udgivelsesdato: 2010-Jun-11, Congenital heart defects (CHDs) are the most common major developmental anomalies and the most frequent cause for perinatal mortality, but their etiology remains often obscure. We identified a locus for CHDs on 6q24-q25. Genotype-phenotype correlations in 12 patients carrying a chromosomal deletion on 6q delineated a critical 850 kb region on 6q25.1 harboring five genes. Bioinformatics prioritization of candidate genes in this locus for a role in CHDs identified the TGF-beta-activated kinase 1/MAP3K7 binding protein 2 gene (TAB2) as the top-ranking candidate gene. A role for this candidate gene in cardiac development was further supported by its conserved expression in the developing human and zebrafish heart. Moreover, a critical, dosage-sensitive role during development was demonstrated by the cardiac defects observed upon titrated knockdown of tab2 expression in zebrafish embryos. To definitively confirm the role of this candidate gene in CHDs, we performed mutation analysis of TAB2 in 402 patients with a CHD, which revealed two evolutionarily conserved missense mutations. Finally, a balanced translocation was identified, cosegregating with familial CHD. Mapping of the breakpoints demonstrated that this translocation disrupts TAB2. Taken together, these data clearly demonstrate a role for TAB2 in human cardiac development.
Published: 2010

47. Genome-wide association study identifies loci on 12q24 and 13q32 associated with Tetralogy of Fallot

Author: Cordell, Heather J., Töpf, Ana, Mamasoula, Chrysovalanto, Postma, Alex V., Bentham, Jamie, Zelenika, Diana, Heath, Simon, Blue, Gillian, Cosgrove, Catherine, Granados Riveron, Javier, Darlay, Rebecca, Soemedi, Rachel, Wilson, Ian J., Ayers, Kristin L., Rahman, Thahira J., Hall, Darroch, Mulder, Barbara J.M., Zwinderman, Aelko H., van Engelen, Klaartje, Brook, J. David, Setchfield, Kerry, Bu'Lock, Frances A., Thornborough, Chris, O'Sullivan, John, Stuart, A. Graham, Parsons, Jonathan, Bhattacharya, Shoumo, Winlaw, David, Mital, Seema, Gewillig, Marc, Breckpot, Jeroen, Devriendt, Koen, Moorman, Antoon F.M., Rauch, Anita, Lathrop, G. Mark, Keavney, Bernard D., Goodship, Judith A., Cordell, Heather J., Töpf, Ana, Mamasoula, Chrysovalanto, Postma, Alex V., Bentham, Jamie, Zelenika, Diana, Heath, Simon, Blue, Gillian, Cosgrove, Catherine, Granados Riveron, Javier, Darlay, Rebecca, Soemedi, Rachel, Wilson, Ian J., Ayers, Kristin L., Rahman, Thahira J., Hall, Darroch, Mulder, Barbara J.M., Zwinderman, Aelko H., van Engelen, Klaartje, Brook, J. David, Setchfield, Kerry, Bu'Lock, Frances A., Thornborough, Chris, O'Sullivan, John, Stuart, A. Graham, Parsons, Jonathan, Bhattacharya, Shoumo, Winlaw, David, Mital, Seema, Gewillig, Marc, Breckpot, Jeroen, Devriendt, Koen, Moorman, Antoon F.M., Rauch, Anita, Lathrop, G. Mark, Keavney, Bernard D., and Goodship, Judith A.
Abstract: We conducted a genome-wide association study to search for risk alleles associated with Tetralogy of Fallot (TOF), using a northern European discovery set of 835 cases and 5159 controls. A region on chromosome 12q24 was associated (P = 1.4 × 10−7) and replicated convincingly (P = 3.9 × 10−5) in 798 cases and 2931 controls [per allele odds ratio (OR) = 1.27 in replication cohort, P = 7.7 × 10−11 in combined populations]. Single nucleotide polymorphisms in the glypican 5 gene on chromosome 13q32 were also associated (P = 1.7 × 10−7) and replicated convincingly (P = 1.2 × 10−5) in 789 cases and 2927 controls (per allele OR = 1.31 in replication cohort, P = 3.03 × 10−11 in combined populations). Four additional regions on chromosomes 10, 15 and 16 showed suggestive association accompanied by nominal replication. This study, the first genome-wide association study of a congenital heart malformation phenotype, provides evidence that common genetic variation influences the risk of TOF

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