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4. Myotonic dystrophy

Author

Hamshere, Marion, primary, Newman, Emma, additional, Alwazzan, Madawi, additional, and Brook, J. David, additional

Published
2020
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10. 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 J.M., 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.

Published
2019
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12. Erratum: Integrative analysis of genomic variants reveals new associations of candidate haploinsufficient genes with congenital heart disease (PLoS Genetics (2021) 17:7 (e1009679) DOI: 10.1371/journal.pgen.1009679)

Author

Audain, Enrique, Wilsdon, Anna, Breckpot, Jeroen, Izarzugaza, Jose M. G., Fitzgerald, Tomas W., Kahlert, Anne-Karin, Sifrim, Alejandro, Wunnemann, Florian, Perez-Riverol, Yasset, Abdul-Khaliq, Hashim, Bak, Mads, Bassett, Anne S., Benson, D. Woodrow, Berger, Felix, Daehnert, Ingo, Devriendt, Koenraad, Dittrich, Sven, Daubeney, Piers Ef, 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, Human Genetics, Medical Biology, ACS - Heart failure & arrhythmias, ACS - Pulmonary hypertension & thrombosis, Amsterdam Cardiovascular Sciences, and Amsterdam Reproduction & Development (AR&D)

Abstract

The thirteenth author's name is spelled incorrectly. The correct name is: D. Woodrow Benson.

Published
2021

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

Author

Audain, Enrique, primary, Wilsdon, Anna, additional, Breckpot, Jeroen, additional, Izarzugaza, Jose M. G., additional, Fitzgerald, Tomas W., additional, Kahlert, Anne-Karin, additional, Sifrim, Alejandro, additional, Wünnemann, Florian, additional, Perez-Riverol, Yasset, additional, Abdul-Khaliq, Hashim, additional, Bak, Mads, additional, Bassett, Anne S., additional, Benson, D. Woodrow, additional, Berger, Felix, additional, Daehnert, Ingo, additional, Devriendt, Koenraad, additional, Dittrich, Sven, additional, Daubeney, Piers EF, additional, Garg, Vidu, additional, Hackmann, Karl, additional, Hoff, Kirstin, additional, Hofmann, Philipp, additional, Dombrowsky, Gregor, additional, Pickardt, Thomas, additional, Bauer, Ulrike, additional, Keavney, Bernard D., additional, Klaassen, Sabine, additional, Kramer, Hans-Heiner, additional, Marshall, Christian R., additional, Milewicz, Dianna M., additional, Lemaire, Scott, additional, Coselli, Joseph S., additional, Mitchell, Michael E., additional, Tomita-Mitchell, Aoy, additional, Prakash, Siddharth K., additional, Stamm, Karl, additional, Stewart, Alexandre F. R., additional, Silversides, Candice K., additional, Siebert, Reiner, additional, Stiller, Brigitte, additional, Rosenfeld, Jill A., additional, Vater, Inga, additional, Postma, Alex V., additional, Caliebe, Almuth, additional, Brook, J. David, additional, Andelfinger, Gregor, additional, Hurles, Matthew E., additional, Thienpont, Bernard, additional, Larsen, Lars Allan, additional, and Hitz, Marc-Phillip, additional

Published
2021
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15. Integrative analysis of genomic variants reveals new associations of candidate haploinsufficient genes with congenital heart disease

Author

Audain, Enrique, primary, Wilsdon, Anna, additional, Breckpot, Jeroen, additional, Izarzugaza, Jose M. G., additional, Fitzgerald, Tomas W., additional, Kahlert, Anne-Karin, additional, Sifrim, Alejandro, additional, Wünnemann, Florian, additional, Perez-Riverol, Yasset, additional, Abdul-Khaliq, Hashim, additional, Bak, Mads, additional, Bassett, Anne S., additional, Benson, Woodrow D., additional, Berger, Felix, additional, Daehnert, Ingo, additional, Devriendt, Koenraad, additional, Dittrich, Sven, additional, Daubeney, Piers EF, additional, Garg, Vidu, additional, Hackmann, Karl, additional, Hoff, Kirstin, additional, Hofmann, Philipp, additional, Dombrowsky, Gregor, additional, Pickardt, Thomas, additional, Bauer, Ulrike, additional, Keavney, Bernard D., additional, Klaassen, Sabine, additional, Kramer, Hans-Heiner, additional, Marshall, Christian R., additional, Milewicz, Dianna M., additional, Lemaire, Scott, additional, Coselli, Joseph S., additional, Mitchell, Michael E., additional, Tomita-Mitchell, Aoy, additional, Prakash, Siddharth K., additional, Stamm, Karl, additional, Stewart, Alexandre F. R., additional, Silversides, Candice K., additional, Siebert, Reiner, additional, Stiller, Brigitte, additional, Rosenfeld, Jill A., additional, Vater, Inga, additional, Postma, Alex V., additional, Caliebe, Almuth, additional, Brook, J. David, additional, Andelfinger, Gregor, additional, Hurles, Matthew E., additional, Thienpont, Bernard, additional, Larsen, Lars Allan, additional, and Hitz, Marc-Phillip, additional

Published
2021
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16. 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

18. Systems genetics analysis identifies calcium-signaling defects as novel cause of congenital heart disease

Author

Izarzugaza, Jose M.G., Ellesøe, Sabrina G., Doganli, Canan, Ehlers, Natasja Spring, Dalgaard, Marlene D., Audain, Enrique, Dombrowsky, Gregor, Banasik, Karina, Sifrim, Alejandro, Wilsdon, Anna, Thienpont, Bernard, Breckpot, Jeroen, Gewillig, Marc, Brook, J. David, Hitz, Marc Phillip, Larsen, Lars A., Brunak, Søren, Izarzugaza, Jose M.G., Ellesøe, Sabrina G., Doganli, Canan, Ehlers, Natasja Spring, Dalgaard, Marlene D., Audain, Enrique, Dombrowsky, Gregor, Banasik, Karina, Sifrim, Alejandro, Wilsdon, Anna, Thienpont, Bernard, Breckpot, Jeroen, Gewillig, Marc, Brook, J. David, Hitz, Marc Phillip, Larsen, Lars A., and Brunak, Søren

Abstract

Background: Congenital heart disease (CHD) occurs in almost 1% of newborn children and is considered a multifactorial disorder. CHD may segregate in families due to significant contribution of genetic factors in the disease etiology. The aim of the study was to identify pathophysiological mechanisms in families segregating CHD. Methods: We used whole exome sequencing to identify rare genetic variants in ninety consenting participants from 32 Danish families with recurrent CHD. We applied a systems biology approach to identify developmental mechanisms influenced by accumulation of rare variants. We used an independent cohort of 714 CHD cases and 4922 controls for replication and performed functional investigations using zebrafish as in vivo model. Results: We identified 1785 genes, in which rare alleles were shared between affected individuals within a family. These genes were enriched for known cardiac developmental genes, and 218 of these genes were mutated in more than one family. Our analysis revealed a functional cluster, enriched for proteins with a known participation in calcium signaling. Replication in an independent cohort confirmed increased mutation burden of calcium-signaling genes in CHD patients. Functional investigation of zebrafish orthologues of ITPR1, PLCB2, and ADCY2 verified a role in cardiac development and suggests a combinatorial effect of inactivation of these genes. Conclusions: The study identifies abnormal calcium signaling as a novel pathophysiological mechanism in human CHD and confirms the complex genetic architecture underlying CHD.

Published
2020

19. 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, BuʼLock, Frances A., Thornborough, Chris, OʼSullivan, 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.

Published
2013
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20. Phenotype-specific effect of chromosome 1q21.1 rearrangements and GJA5 duplications in 2436 congenital heart disease patients and 6760 controls

Author

Soemedi, Rachel, Topf, Ana, Wilson, Ian J., Darlay, Rebecca, Rahman, Thahira, Glen, Elise, Hall, Darroch, Huang, Ni, Bentham, Jamie, Bhattacharya, Shoumo, Cosgrove, Catherine, Brook, J. David, Granados-Riveron, Javier, Setchfield, Kerry, BuʼLock, Frances, Thornborough, Chris, Devriendt, Koenraad, Breckpot, Jeroen, Hofbeck, Michael, Lathrop, Mark, Rauch, Anita, Blue, Gillian M., Winlaw, David S., Hurles, Matthew, Santibanez-Koref, Mauro, Cordell, Heather J., Goodship, Judith A., and Keavney, Bernard D.

Published
2012
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21. CDK12 inhibition reduces abnormalities in cells from patients with myotonic dystrophy and in a mouse model

Author

Ketley, Ami, primary, Wojciechowska, Marzena, additional, Ghidelli-Disse, Sonja, additional, Bamborough, Paul, additional, Ghosh, Tushar K., additional, Morato, Marta Lopez, additional, Sedehizadeh, Saam, additional, Malik, Naveed Altaf, additional, Tang, Zhenzhi, additional, Powalowska, Paulina, additional, Tanner, Matthew, additional, Billeter-Clark, Rudolf, additional, Trueman, Rebecca C., additional, Geiszler, Philippine C., additional, Agostini, Alessandra, additional, Othman, Othman, additional, Bösche, Markus, additional, Bantscheff, Marcus, additional, Rüdiger, Martin, additional, Mossakowska, Danuta E., additional, Drewry, David H., additional, Zuercher, William J., additional, Thornton, Charles A., additional, Drewes, Gerard, additional, Uings, Iain, additional, Hayes, Christopher J., additional, and Brook, J. David, additional

Published
2020
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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

26. Campomelic dysplasia and autosomal sex reversal caused by mutations in an SRY-related gene

Author

Foster, Jamie W., Dominguez-Steglich, Marina A., Guioli, Silvana, Kowk, Cheni, Weller, Polly A., Stevanovic, Milena, Weissenbach, Jean, Mansour, Sahar, Young, Ian D., Goodfellow, Peter N., Brook, J. David, and Schafer, Alan J.

Subjects
Mutation (Biology) -- Analysis, Sex determination, Genetic -- Analysis, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Translocation chromosome breakpoint cloning in a sex-reversed patient suffering from campomelic dysplasia and analysis of mutations in SOX9, which is an SRY-related gene, shows that SOX9 takes part in both testis development and bone formation. The results support the view that campomelic dysplasia is an autosomal dominant disease. There might also be a close relationship between SOX9 and SRY gene because of their sequence similarities and the dosage sensitivity exhibited by SOX9 in sex determination.

Published
1994

32. Unstable DNA sequence in myotonic dystrophy

Author

Harley, Helen G., Rundle, Shelley A., Reardon, William, Myring, Jenny, Crow, Stephen, Brook, J. David, Harper, Peter S., and Shaw, Duncan J.

Subjects
Myotonic dystrophy -- Genetic aspects, DNA -- Analysis
Published
1992

33. The mutation spectrum in Holt-Oram syndrome

Author

CROSS, STEPHEN J, CHING, YUNG-HAO, LI, QUAN YI, ARMSTRONG-BUISSERET, LINDSAY, SPRANGER, STEPHANIE, LYONNET, STANISLAW, BONNET, DAMIEN, PENTTINEN, MAILA, JONVEAUX, PHILIPPE, LEHEUP, BRUNO, MORTIER, GEERT, VAN RAVENSWAAIJ, CONNY, GARDINER, CAROL-ANNE, BROOK, J DAVID, and NEWBURY-ECOB, RUTH

Published
2000

37. Small molecules which improve pathogenesis of myotonic dystrophy type 1

Author

Brook, J. David and Wojciechowska, Marzena

Subjects
congenital, hereditary, and neonatal diseases and abnormalities, myotonic dystrophy type 1, myotonic dystrophy type 1 pathogenesis, sequestration of muscleblind-like 1, antisense oligonucleotides, aberrant alternative splicing, small molecule compounds
Abstract

Myotonic dystrophy type 1 (DM1) is the most common muscular dystrophy in adults for which there is currently no treatment. The pathogenesis of this autosomal dominant disorder is associated with the expansion of CTG repeats in the 3?-UTR of the DMPK gene. DMPK transcripts with expanded CUG repeats (CUGexpDMPK) are retained in the nucleus forming multiple discrete foci, and their presence triggers a cascade of toxic events. Thus far, most research emphasis has been on interactions of CUGexpDMPK with the muscleblind-like (MBNL) family of splicing factors. These proteins are sequestered by the expanded CUG repeats of DMPK RNA leading to their functional depletion. As a consequence, abnormalities in many pathways of RNA metabolism, including alternative splicing, are detected in DM1. To date, in vitro and in vivo efforts to develop therapeutic strategies for DM1 have mostly been focused on targeting CUGexpDMPK via reducing their expression and/or preventing interactions with MBNL1. Antisense oligonucleotides targeted to the CUG repeats in the DMPK transcripts are of particular interest due to their potential capacity to discriminate between mutant and normal transcripts. However, a growing number of reports describe alternative strategies using small molecule chemicals acting independently of a direct interaction with CUGexpDMPK. In this review, we summarize current knowledge about these chemicals and we describe the beneficial effects they caused in different DM1 experimental models. We also present potential mechanisms of action of these compounds and pathways they affect which could be considered for future therapeutic interventions in DM1.

Published
2018

38. Global Increase in Circular RNA Levels in Myotonic Dystrophy

Author

Czubak, Karol, primary, Taylor, Katarzyna, additional, Piasecka, Agnieszka, additional, Sobczak, Krzysztof, additional, Kozlowska, Katarzyna, additional, Philips, Anna, additional, Sedehizadeh, Saam, additional, Brook, J. David, additional, Wojciechowska, Marzena, additional, and Kozlowski, Piotr, additional

Published
2019
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39. Global increase in circRNA levels in myotonic dystrophy

Author

Czubak, Karol, primary, Taylor, Katarzyna, additional, Piasecka, Agnieszka, additional, Sobczak, Krzysztof, additional, Kozlowska, Katarzyna, additional, Philips, Anna, additional, Sedehizadeh, Saam, additional, Brook, J. David, additional, Wojciechowska, Marzena, additional, and Kozlowski, Piotr, additional

Published
2018
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40. 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., 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

41. Quantitative Methods to Monitor RNA Biomarkers in Myotonic Dystrophy

Author

Wojciechowska, Marzena, primary, Sobczak, Krzysztof, additional, Kozlowski, Piotr, additional, Sedehizadeh, Saam, additional, Wojtkowiak-Szlachcic, Agnieszka, additional, Czubak, Karol, additional, Markus, Robert, additional, Lusakowska, Anna, additional, Kaminska, Anna, additional, and Brook, J. David, additional

Published
2018
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42. Phenotype-specific effect of chromosome 1q21.1 rearrangements and GJA5 duplications in 2436 congenital heart disease patients and 6760 controls

Author

Soemedi, Rachel, Topf, Ana, Wilson, Ian J., Darlay, Rebecca, Rahman, Thahira, Glen, Elise, Hall, Darroch, Huang, Ni, Bentham, Jamie, Bhattacharya, Shoumo, Cosgrove, Catherine, Brook, J. David, Granados-Riveron, Javier, Setchfield, Kerry, Bu'Lock, Frances, Thornborough, Chris, Devriendt, Koenraad, Breckpot, Jeroen, Hofbeck, Michael, Lathrop, Mark, Rauch, Anita, Blue, Gillian M., Winlaw, David S., Hurles, Matthew, Santibanez-Koref, Mauro, Cordell, Heather J., Goodship, Judith A., Keavney, Bernard D., Soemedi, Rachel, Topf, Ana, Wilson, Ian J., Darlay, Rebecca, Rahman, Thahira, Glen, Elise, Hall, Darroch, Huang, Ni, Bentham, Jamie, Bhattacharya, Shoumo, Cosgrove, Catherine, Brook, J. David, Granados-Riveron, Javier, Setchfield, Kerry, Bu'Lock, Frances, Thornborough, Chris, Devriendt, Koenraad, Breckpot, Jeroen, Hofbeck, Michael, Lathrop, Mark, Rauch, Anita, Blue, Gillian M., Winlaw, David S., Hurles, Matthew, Santibanez-Koref, Mauro, Cordell, Heather J., Goodship, Judith A., and Keavney, Bernard D.

Abstract

Recurrent rearrangements of chromosome 1q21.1 that occur via non-allelic homologous recombination have been associated with variable phenotypes exhibiting incomplete penetrance, including congenital heart disease (CHD). However, the gene or genes within the ∼1 Mb critical region responsible for each of the associated phenotypes remains unknown. We examined the 1q21.1 locus in 948 patients with tetralogy of Fallot (TOF), 1488 patients with other forms of CHD and 6760 ethnically matched controls using single nucleotide polymorphism genotyping arrays (Illumina 660W and Affymetrix 6.0) and multiplex ligation-dependent probe amplification. We found that duplication of 1q21.1 was more common in cases of TOF than in controls [odds ratio (OR) 30.9, 95% confidence interval (CI) 8.9-107.6); P = 2.2 × 10−7], but deletion was not. In contrast, deletion of 1q21.1 was more common in cases of non-TOF CHD than in controls [OR 5.5 (95% CI 1.4-22.0); P = 0.04] while duplication was not. We also detected rare (n = 3) 100-200 kb duplications within the critical region of 1q21.1 in cases of TOF. These small duplications encompassed a single gene in common, GJA5, and were enriched in cases of TOF in comparison to controls [OR = 10.7 (95% CI 1.8-64.3), P = 0.01]. These findings show that duplication and deletion at chromosome 1q21.1 exhibit a degree of phenotypic specificity in CHD, and implicate GJA5 as the gene responsible for the CHD phenotypes observed with copy number imbalances at this locus

Published
2017

43. 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 MM, Bentham, Jamie, Berger, Felix, Bhattacharya, Shoumo, Bu'Lock, Frances, Canham, Natalie, Colgiu, Irina-Gabriela, Cosgrove, Catherine, Cox, Helen, Daehnert, Ingo, Daly, Allan, Danesh, John, Fryer, Alan, Gewillig, Marc, Hobson, Emma, Hoff, Kirstin, Homfray, Tessa, INTERVAL Study, Kahlert, Anne-Karin, Ketley, Ami, Kramer, Hans-Heiner, Lachlan, Katherine, Lampe, Anne Katrin, Louw, Jacoba J, Manickara, Ashok Kumar, Manase, Dorin, McCarthy, Karen P, Metcalfe, Kay, Moore, Carmel, Newbury-Ecob, Ruth, Omer, Seham Osman, Ouwehand, Willem H, Park, Soo-Mi, Parker, Michael J, Pickardt, Thomas, Pollard, Martin O, Robert, Leema, Roberts, David J, Sambrook, Jennifer, Setchfield, Kerry, Stiller, Brigitte, Thornborough, Chris, Toka, Okan, Watkins, Hugh, Williams, Denise, Wright, Michael, Mital, Seema, Daubeney, Piers EF, Keavney, Bernard, Goodship, Judith, UK10K Consortium, Abu-Sulaiman, Riyadh Mahdi, Klaassen, Sabine, Wright, Caroline F, Firth, Helen V, Barrett, Jeffrey C, Devriendt, Koenraad, FitzPatrick, David R, Brook, J David, Deciphering Developmental Disorders Study, Hurles, Matthew E, Sifrim, Alejandro [0000-0001-8247-4020], Thienpont, Bernard [0000-0002-8772-6845], Banka, Siddharth [0000-0002-8527-2210], Pollard, Martin O [0000-0001-8738-0920], Mital, Seema [0000-0002-7643-4484], Keavney, Bernard [0000-0001-9573-0812], Barrett, Jeffrey C [0000-0002-1152-370X], and Apollo - University of Cambridge Repository

Subjects
Heart Defects, Congenital, Male, Protein Conformation, Syndrome, Autoantigens, CDC2 Protein Kinase, Mutation, Humans, Exome, Female, cardiovascular diseases, Protein Kinase C, Mi-2 Nucleosome Remodeling and Deacetylase Complex, Sequence Deletion
Abstract

Congenital heart defects (CHDs) have a neonatal incidence of 0.8-1% (refs. 1,2). 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.

Published
2016

46. A genome-wide association study of congenital cardiovascular left-sided lesions shows association with a locus on chromosome 20

Author

Hanchard, Neil A., primary, Swaminathan, Shanker, additional, Bucasas, Kristine, additional, Furthner, Dieter, additional, Fernbach, Susan, additional, Azamian, Mahshid S., additional, Wang, Xueqing, additional, Lewin, Mark, additional, Towbin, Jeffrey A., additional, D'Alessandro, Lisa C.A., additional, Morris, Shaine A., additional, Dreyer, William, additional, Denfield, Susan, additional, Ayres, Nancy A., additional, Franklin, Wayne J., additional, Justino, Henri, additional, Lantin-Hermoso, M. Regina, additional, Ocampo, Elena C., additional, Santos, Alexia B., additional, Parekh, Dhaval, additional, Moodie, Douglas, additional, Jeewa, Aamir, additional, Lawrence, Emily, additional, Allen, Hugh D., additional, Penny, Daniel J., additional, Fraser, Charles D., additional, Lupski, James R., additional, Popoola, Mojisola, additional, Wadhwa, Lalita, additional, Brook, J. David, additional, Bu'Lock, Frances A., additional, Bhattacharya, Shoumo, additional, Lalani, Seema R., additional, Zender, Gloria A., additional, Fitzgerald-Butt, Sara M., additional, Bowman, Jessica, additional, Corsmeier, Don, additional, White, Peter, additional, Lecerf, Kelsey, additional, Zapata, Gladys, additional, Hernandez, Patricia, additional, Goodship, Judith A., additional, Garg, Vidu, additional, Keavney, Bernard D., additional, Leal, Suzanne M., additional, Cordell, Heather J., additional, Belmont, John W., additional, and McBride, Kim L., additional

Published
2016
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47. Rare Variants in NR2F2 Cause Congenital Heart Defects in Humans

Author

Al Turki, Saeed, primary, Manickaraj, Ashok K., additional, Mercer, Catherine L., additional, Gerety, Sebastian S., additional, Hitz, Marc-Phillip, additional, Lindsay, Sarah, additional, D’Alessandro, Lisa C.A., additional, Swaminathan, G. Jawahar, additional, Bentham, Jamie, additional, Arndt, Anne-Karin, additional, Louw, Jacoba, additional, Breckpot, Jeroen, additional, Gewillig, Marc, additional, Thienpont, Bernard, additional, Abdul-Khaliq, Hashim, additional, Harnack, Christine, additional, Hoff, Kirstin, additional, Kramer, Hans-Heiner, additional, Schubert, Stephan, additional, Siebert, Reiner, additional, Toka, Okan, additional, Cosgrove, Catherine, additional, Watkins, Hugh, additional, Lucassen, Anneke M., additional, O’Kelly, Ita M., additional, Salmon, Anthony P., additional, Bu’Lock, Frances A., additional, Granados-Riveron, Javier, additional, Setchfield, Kerry, additional, Thornborough, Chris, additional, Brook, J. David, additional, Mulder, Barbara, additional, Klaassen, Sabine, additional, Bhattacharya, Shoumo, additional, Devriendt, Koen, additional, FitzPatrick, David R., additional, Wilson, David I., additional, Mital, Seema, additional, and Hurles, Matthew E., additional

Published
2016
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49. 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, University of Zurich, and Keavney, Bernard D

Subjects
2716 Genetics (clinical), 1311 Genetics, 10039 Institute of Medical Genetics, 1312 Molecular Biology, 570 Life sciences, biology, 610 Medicine & health
Published
2013

50. Formation, Contraction, and Mechanotransduction of Myofribrils in Cardiac Development: Clues from Genetics

Author

Granados-Riveron, Javier T. and Brook, J. David

Subjects
Article Subject
Abstract

Congenital heart disease (CHD) is the most common birth defect in humans. It is a leading infant mortality factor worldwide, caused by defective cardiac development. Mutations in transcription factors, signalling and structural molecules have been shown to contribute to the genetic component of CHD. Recently, mutations in genes encoding myofibrillar proteins expressed in the embryonic heart have also emerged as an important genetic causative factor of the disease, which implies that the contraction of the early heart primordium contributes to its morphogenesis. This notion is supported by increasing evidence suggesting that not only contraction but also formation, mechanosensing, and mechanotransduction of the cardiac myofibrillar proteins influence heart development. In this paper, we summarize the genetic clues supporting this idea.

Published
2012
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