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1. Genetic links between ovarian ageing, cancer risk and de novo mutation rates

Author

Stankovic, Stasa, Shekari, Saleh, Huang, Qin Qin, Gardner, Eugene J., Ivarsdottir, Erna V., Owens, Nick D. L., Mavaddat, Nasim, Azad, Ajuna, Hawkes, Gareth, Kentistou, Katherine A., Beaumont, Robin N., Day, Felix R., Zhao, Yajie, Jonsson, Hakon, Rafnar, Thorunn, Tragante, Vinicius, Sveinbjornsson, Gardar, Oddsson, Asmundur, Styrkarsdottir, Unnur, Gudmundsson, Julius, Stacey, Simon N., Gudbjartsson, Daniel F., Kennedy, Kitale, Wood, Andrew R., Weedon, Michael N., Ong, Ken K., Wright, Caroline F., Hoffmann, Eva R., Sulem, Patrick, Hurles, Matthew E., Ruth, Katherine S., Martin, Hilary C., Stefansson, Kari, Perry, John R. B., and Murray, Anna

Published
2024
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2. De novo variants in the RNU4-2 snRNA cause a frequent neurodevelopmental syndrome

Author

Chen, Yuyang, Dawes, Ruebena, Kim, Hyung Chul, Ljungdahl, Alicia, Stenton, Sarah L., Walker, Susan, Lord, Jenny, Lemire, Gabrielle, Martin-Geary, Alexandra C., Ganesh, Vijay S., Ma, Jialan, Ellingford, Jamie M., Delage, Erwan, D’Souza, Elston N., Dong, Shan, Adams, David R., Allan, Kirsten, Bakshi, Madhura, Baldwin, Erin E., Berger, Seth I., Bernstein, Jonathan A., Bhatnagar, Ishita, Blair, Ed, Brown, Natasha J., Burrage, Lindsay C., Chapman, Kimberly, Coman, David J., Compton, Alison G., Cunningham, Chloe A., D’Souza, Precilla, Danecek, Petr, Délot, Emmanuèle C., Dias, Kerith-Rae, Elias, Ellen R., Elmslie, Frances, Evans, Care-Anne, Ewans, Lisa, Ezell, Kimberly, Fraser, Jamie L., Gallacher, Lyndon, Genetti, Casie A., Goriely, Anne, Grant, Christina L., Haack, Tobias, Higgs, Jenny E., Hinch, Anjali G., Hurles, Matthew E., Kuechler, Alma, Lachlan, Katherine L., Lalani, Seema R., Lecoquierre, François, Leitão, Elsa, Fevre, Anna Le, Leventer, Richard J., Liebelt, Jan E., Lindsay, Sarah, Lockhart, Paul J., Ma, Alan S., Macnamara, Ellen F., Mansour, Sahar, Maurer, Taylor M., Mendez, Hector R., Metcalfe, Kay, Montgomery, Stephen B., Moosajee, Mariya, Nassogne, Marie-Cécile, Neumann, Serena, O’Donoghue, Michael, O’Leary, Melanie, Palmer, Elizabeth E., Pattani, Nikhil, Phillips, John, Pitsava, Georgia, Pysar, Ryan, Rehm, Heidi L., Reuter, Chloe M., Revencu, Nicole, Riess, Angelika, Rius, Rocio, Rodan, Lance, Roscioli, Tony, Rosenfeld, Jill A., Sachdev, Rani, Shaw-Smith, Charles J., Simons, Cas, Sisodiya, Sanjay M., Snell, Penny, St Clair, Laura, Stark, Zornitza, Stewart, Helen S., Tan, Tiong Yang, Tan, Natalie B., Temple, Suzanna E. L., Thorburn, David R., Tifft, Cynthia J., Uebergang, Eloise, VanNoy, Grace E., Vasudevan, Pradeep, Vilain, Eric, Viskochil, David H., Wedd, Laura, Wheeler, Matthew T., White, Susan M., Wojcik, Monica, Wolfe, Lynne A., Wolfenson, Zoe, Wright, Caroline F., Xiao, Changrui, Zocche, David, Rubenstein, John L., Markenscoff-Papadimitriou, Eirene, Fica, Sebastian M., Baralle, Diana, Depienne, Christel, MacArthur, Daniel G., Howson, Joanna M. M., Sanders, Stephan J., O’Donnell-Luria, Anne, and Whiffin, Nicola

Published
2024
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4. Using Organoids to Model Sex Differences in the Human Brain

Author

Baron-Cohen, Simon, Allison, Carrie, Warrier, Varun, Tsompanidis, Alex, Adhya, Dwaipayan, Holt, Rosie, Smith, Paula, Parsons, Tracey, Davis, Joanna, Hassall, Matthew, Geschwind, Daniel H., Heazell, Alexander EP., Mill, Jonathan, Franklin, Alice, Bamford, Rosie, Davies, Jonathan, Hurles, Matthew E., Martin, Hilary C., Mousa, Mahmoud, Rowitch, David H., Niakan, Kathy K., Burton, Graham J., Ghafari, Fateneh, Srivastava, Deepak P., Dutan-Polit, Lucia, Pavlinek, Adam, Lancaster, Madeline A., Chiaradia, Ilaria, Biron-Shental, Tal, Gabis, Lidia V., Vernon, Anthony C., and Lancaster, Madeline

Published
2024
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5. Saturation genome editing of DDX3X clarifies pathogenicity of germline and somatic variation

Author

Radford, Elizabeth J., Tan, Hong-Kee, Andersson, Malin H. L., Stephenson, James D., Gardner, Eugene J., Ironfield, Holly, Waters, Andrew J., Gitterman, Daniel, Lindsay, Sarah, Abascal, Federico, Martincorena, Iñigo, Kolesnik-Taylor, Anna, Ng-Cordell, Elise, Firth, Helen V., Baker, Kate, Perry, John R. B., Adams, David J., Gerety, Sebastian S., and Hurles, Matthew E.

Published
2023
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11. De novo mutations in regulatory elements in neurodevelopmental disorders.

Author

Short, Patrick J, McRae, Jeremy F, Gallone, Giuseppe, Sifrim, Alejandro, Won, Hyejung, Geschwind, Daniel H, Wright, Caroline F, Firth, Helen V, FitzPatrick, David R, Barrett, Jeffrey C, and Hurles, Matthew E

Subjects
Brain, Fetus, Humans, Developmental Disabilities, Evolution, Molecular, Regulatory Sequences, Nucleic Acid, Conserved Sequence, Mutation, Female, Male, Exome, Neurodevelopmental Disorders, Evolution, Molecular, Regulatory Sequences, Nucleic Acid, MD Multidisciplinary, General Science & Technology
Abstract

We previously estimated that 42% of patients with severe developmental disorders carry pathogenic de novo mutations in coding sequences. The role of de novo mutations in regulatory elements affecting genes associated with developmental disorders, or other genes, has been essentially unexplored. We identified de novo mutations in three classes of putative regulatory elements in almost 8,000 patients with developmental disorders. Here we show that de novo mutations in highly evolutionarily conserved fetal brain-active elements are significantly and specifically enriched in neurodevelopmental disorders. We identified a significant twofold enrichment of recurrently mutated elements. We estimate that, genome-wide, 1-3% of patients without a diagnostic coding variant carry pathogenic de novo mutations in fetal brain-active regulatory elements and that only 0.15% of all possible mutations within highly conserved fetal brain-active elements cause neurodevelopmental disorders with a dominant mechanism. Our findings represent a robust estimate of the contribution of de novo mutations in regulatory elements to this genetically heterogeneous set of disorders, and emphasize the importance of combining functional and evolutionary evidence to identify regulatory causes of genetic disorders.

Published
2018

12. Somatic mutations reveal asymmetric cellular dynamics in the early human embryo.

Author

Ju, Young Seok, Martincorena, Inigo, Gerstung, Moritz, Petljak, Mia, Alexandrov, Ludmil B, Rahbari, Raheleh, Wedge, David C, Davies, Helen R, Ramakrishna, Manasa, Fullam, Anthony, Martin, Sancha, Alder, Christopher, Patel, Nikita, Gamble, Steve, O'Meara, Sarah, Giri, Dilip D, Sauer, Torril, Pinder, Sarah E, Purdie, Colin A, Borg, Åke, Stunnenberg, Henk, van de Vijver, Marc, Tan, Benita KT, Caldas, Carlos, Tutt, Andrew, Ueno, Naoto T, van 't Veer, Laura J, Martens, John WM, Sotiriou, Christos, Knappskog, Stian, Span, Paul N, Lakhani, Sunil R, Eyfjörd, Jórunn Erla, Børresen-Dale, Anne-Lise, Richardson, Andrea, Thompson, Alastair M, Viari, Alain, Hurles, Matthew E, Nik-Zainal, Serena, Campbell, Peter J, and Stratton, Michael R

Subjects
Blood Cells, Humans, Mutagenesis, Cell Lineage, Embryonic Development, Mutation, Mosaicism, Germ-Line Mutation, Genome, Human, Adult, Embryo, Mammalian, Mutation Rate, Embryo, Mammalian, Genome, Human, General Science & Technology
Abstract

Somatic cells acquire mutations throughout the course of an individual's life. Mutations occurring early in embryogenesis are often present in a substantial proportion of, but not all, cells in postnatal humans and thus have particular characteristics and effects. Depending on their location in the genome and the proportion of cells they are present in, these mosaic mutations can cause a wide range of genetic disease syndromes and predispose carriers to cancer. They have a high chance of being transmitted to offspring as de novo germline mutations and, in principle, can provide insights into early human embryonic cell lineages and their contributions to adult tissues. Although it is known that gross chromosomal abnormalities are remarkably common in early human embryos, our understanding of early embryonic somatic mutations is very limited. Here we use whole-genome sequences of normal blood from 241 adults to identify 163 early embryonic mutations. We estimate that approximately three base substitution mutations occur per cell per cell-doubling event in early human embryogenesis and these are mainly attributable to two known mutational signatures. We used the mutations to reconstruct developmental lineages of adult cells and demonstrate that the two daughter cells of many early embryonic cell-doubling events contribute asymmetrically to adult blood at an approximately 2:1 ratio. This study therefore provides insights into the mutation rates, mutational processes and developmental outcomes of cell dynamics that operate during early human embryogenesis.

Published
2017

13. 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., and Mathijssen, Inge B.

Published
2021
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14. Rare loss-of-function variants in SETD1A are associated with schizophrenia and developmental disorders

Author

Singh, Tarjinder, Kurki, Mitja I, Curtis, David, Purcell, Shaun M, Crooks, Lucy, McRae, Jeremy, Suvisaari, Jaana, Chheda, Himanshu, Blackwood, Douglas, Breen, Gerome, Pietiläinen, Olli, Gerety, Sebastian S, Ayub, Muhammad, Blyth, Moira, Cole, Trevor, Collier, David, Coomber, Eve L, Craddock, Nick, Daly, Mark J, Danesh, John, DiForti, Marta, Foster, Alison, Freimer, Nelson B, Geschwind, Daniel, Johnstone, Mandy, Joss, Shelagh, Kirov, Georg, Körkkö, Jarmo, Kuismin, Outi, Holmans, Peter, Hultman, Christina M, Iyegbe, Conrad, Lönnqvist, Jouko, Männikkö, Minna, McCarroll, Steve A, McGuffin, Peter, McIntosh, Andrew M, McQuillin, Andrew, Moilanen, Jukka S, Moore, Carmel, Murray, Robin M, Newbury-Ecob, Ruth, Ouwehand, Willem, Paunio, Tiina, Prigmore, Elena, Rees, Elliott, Roberts, David, Sambrook, Jennifer, Sklar, Pamela, Clair, David St, Veijola, Juha, Walters, James TR, Williams, Hywel, Sullivan, Patrick F, Hurles, Matthew E, O'Donovan, Michael C, Palotie, Aarno, Owen, Michael J, and Barrett, Jeffrey C

Subjects
Biological Psychology, Pharmacology and Pharmaceutical Sciences, Biomedical and Clinical Sciences, Psychology, Genetics, Serious Mental Illness, Human Genome, Schizophrenia, Biotechnology, Brain Disorders, Mental Health, 2.1 Biological and endogenous factors, Aetiology, Mental health, Case-Control Studies, Cohort Studies, Female, Finland, Genetic Association Studies, Genetic Predisposition to Disease, Genetic Variation, Histone-Lysine N-Methyltransferase, Humans, Male, Neurodevelopmental Disorders, Swedish Schizophrenia Study, INTERVAL Study, DDD Study, UK10 K Consortium, Neurosciences, Cognitive Sciences, Neurology & Neurosurgery, Biological psychology
Abstract

By analyzing the whole-exome sequences of 4,264 schizophrenia cases, 9,343 controls and 1,077 trios, we identified a genome-wide significant association between rare loss-of-function (LoF) variants in SETD1A and risk for schizophrenia (P = 3.3 × 10(-9)). We found only two heterozygous LoF variants in 45,376 exomes from individuals without a neuropsychiatric diagnosis, indicating that SETD1A is substantially depleted of LoF variants in the general population. Seven of the ten individuals with schizophrenia carrying SETD1A LoF variants also had learning difficulties. We further identified four SETD1A LoF carriers among 4,281 children with severe developmental disorders and two more carriers in an independent sample of 5,720 Finnish exomes, both with notable neuropsychiatric phenotypes. Together, our observations indicate that LoF variants in SETD1A cause a range of neurodevelopmental disorders, including schizophrenia. Combining these data with previous common variant evidence, we suggest that epigenetic dysregulation, specifically in the histone H3K4 methylation pathway, is an important mechanism in the pathogenesis of schizophrenia.

Published
2016

15. A brief history of human disease genetics

Author

Claussnitzer, Melina, Cho, Judy H., Collins, Rory, Cox, Nancy J., Dermitzakis, Emmanouil T., Hurles, Matthew E., and Kathiresan, Sekar

Subjects
Genomics -- Forecasts and trends, Diseases -- Genetic aspects -- History -- United States, Human genetics -- History -- Technology application, Market trend/market analysis, Technology application, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

A primary goal of human genetics is to identify DNA sequence variants that influence biomedical traits, particularly those related to the onset and progression of human disease. Over the past 25 years, progress in realizing this objective has been transformed by advances in technology, foundational genomic resources and analytical tools, and by access to vast amounts of genotype and phenotype data. Genetic discoveries have substantially improved our understanding of the mechanisms responsible for many rare and common diseases and driven development of novel preventative and therapeutic strategies. Medical innovation will increasingly focus on delivering care tailored to individual patterns of genetic predisposition. This Review describes progress in the study of human genetics, in which rapid advances in technology, foundational genomic resources and analytical tools have contributed to the understanding of the mechanisms responsible for many rare and common diseases and to preventative and therapeutic strategies for many of these conditions., Author(s): Melina Claussnitzer [sup.1] [sup.2] [sup.3] , Judy H. Cho [sup.4] [sup.5] [sup.6] , Rory Collins [sup.7] [sup.8] , Nancy J. Cox [sup.9] , Emmanouil T. Dermitzakis [sup.10] [sup.11] , [...]

Published
2020
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16. The Matchmaker Exchange: A Platform for Rare Disease Gene Discovery

Author

Philippakis, Anthony A, Azzariti, Danielle R, Beltran, Sergi, Brookes, Anthony J, Brownstein, Catherine A, Brudno, Michael, Brunner, Han G, Buske, Orion J, Carey, Knox, Doll, Cassie, Dumitriu, Sergiu, Dyke, Stephanie OM, den Dunnen, Johan T, Firth, Helen V, Gibbs, Richard A, Girdea, Marta, Gonzalez, Michael, Haendel, Melissa A, Hamosh, Ada, Holm, Ingrid A, Huang, Lijia, Hurles, Matthew E, Hutton, Ben, Krier, Joel B, Misyura, Andriy, Mungall, Christopher J, Paschall, Justin, Paten, Benedict, Robinson, Peter N, Schiettecatte, François, Sobreira, Nara L, Swaminathan, Ganesh J, Taschner, Peter E, Terry, Sharon F, Washington, Nicole L, Züchner, Stephan, Boycott, Kym M, and Rehm, Heidi L

Subjects
Biological Sciences, Genetics, Human Genome, Database Management Systems, Databases, Genetic, Genetic Association Studies, Genetic Predisposition to Disease, Humans, Information Dissemination, Rare Diseases, Software, matchmaking, rare disease, genomic API, gene discovery, Matchmaker Exchange, GA4GH, IRDiRC, Clinical Sciences, Genetics & Heredity, Clinical sciences
Abstract

There are few better examples of the need for data sharing than in the rare disease community, where patients, physicians, and researchers must search for "the needle in a haystack" to uncover rare, novel causes of disease within the genome. Impeding the pace of discovery has been the existence of many small siloed datasets within individual research or clinical laboratory databases and/or disease-specific organizations, hoping for serendipitous occasions when two distant investigators happen to learn they have a rare phenotype in common and can "match" these cases to build evidence for causality. However, serendipity has never proven to be a reliable or scalable approach in science. As such, the Matchmaker Exchange (MME) was launched to provide a robust and systematic approach to rare disease gene discovery through the creation of a federated network connecting databases of genotypes and rare phenotypes using a common application programming interface (API). The core building blocks of the MME have been defined and assembled. Three MME services have now been connected through the API and are available for community use. Additional databases that support internal matching are anticipated to join the MME network as it continues to grow.

Published
2015

17. A global reference for human genetic variation

Author

Auton, Adam, Abecasis, Gonçalo R, Altshuler, David M, Durbin, Richard M, Bentley, David R, Chakravarti, Aravinda, Clark, Andrew G, Donnelly, Peter, Eichler, Evan E, Flicek, Paul, Gabriel, Stacey B, Gibbs, Richard A, Green, Eric D, Hurles, Matthew E, Knoppers, Bartha M, Korbel, Jan O, Lander, Eric S, Lee, Charles, Lehrach, Hans, Mardis, Elaine R, Marth, Gabor T, McVean, Gil A, Nickerson, Deborah A, Schmidt, Jeanette P, Sherry, Stephen T, Wang, Jun, Wilson, Richard K, Barnes, Kathleen C, Beiswanger, Christine, Burchard, Esteban G, Bustamante, Carlos D, Cai, Hongyu, Cao, Hongzhi, Gerry, Norman P, Gharani, Neda, Gignoux, Christopher R, Gravel, Simon, Henn, Brenna, Jones, Danielle, Jorde, Lynn, Kaye, Jane S, Keinan, Alon, Kent, Alastair, Kerasidou, Angeliki, Li, Yingrui, Mathias, Rasika, Moreno-Estrada, Andres, Ossorio, Pilar N, Parker, Michael, Resch, Alissa M, Rotimi, Charles N, Royal, Charmaine D, Sandoval, Karla, Su, Yeyang, Sudbrak, Ralf, Tian, Zhongming, Tishkoff, Sarah, Toji, Lorraine H, Tyler-Smith, Chris, Via, Marc, Wang, Yuhong, Yang, Huanming, Yang, Ling, Zhu, Jiayong, Brooks, Lisa D, Felsenfeld, Adam L, McEwen, Jean E, Vaydylevich, Yekaterina, Duncanson, Audrey, Dunn, Michael, Schloss, Jeffery A, Garrison, Erik P, Min Kang, Hyun, Marchini, Jonathan L, and McCarthy, Shane

Subjects
Human Genome, Genetics, Biotechnology, 2.1 Biological and endogenous factors, Aetiology, Datasets as Topic, Demography, Disease Susceptibility, Exome, Genetic Variation, Genetics, Medical, Genetics, Population, Genome, Human, Genome-Wide Association Study, Genomics, Genotype, Haplotypes, High-Throughput Nucleotide Sequencing, Humans, INDEL Mutation, Internationality, Physical Chromosome Mapping, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Rare Diseases, Reference Standards, Sequence Analysis, DNA, Genomes Project Consortium, General Science & Technology
Abstract

The 1000 Genomes Project set out to provide a comprehensive description of common human genetic variation by applying whole-genome sequencing to a diverse set of individuals from multiple populations. Here we report completion of the project, having reconstructed the genomes of 2,504 individuals from 26 populations using a combination of low-coverage whole-genome sequencing, deep exome sequencing, and dense microarray genotyping. We characterized a broad spectrum of genetic variation, in total over 88 million variants (84.7 million single nucleotide polymorphisms (SNPs), 3.6 million short insertions/deletions (indels), and 60,000 structural variants), all phased onto high-quality haplotypes. This resource includes >99% of SNP variants with a frequency of >1% for a variety of ancestries. We describe the distribution of genetic variation across the global sample, and discuss the implications for common disease studies.

Published
2015

18. Heterozygous Loss-of-Function Mutations in YAP1 Cause Both Isolated and Syndromic Optic Fissure Closure Defects

Author

Williamson, Kathleen A, Rainger, Joe, Floyd, James AB, Ansari, Morad, Meynert, Alison, Aldridge, Kishan V, Rainger, Jacqueline K, Anderson, Carl A, Moore, Anthony T, Hurles, Matthew E, Clarke, Angus, van Heyningen, Veronica, Verloes, Alain, Taylor, Martin S, Wilkie, Andrew OM, Consortium, UK10K, and FitzPatrick, David R

Subjects
Genetics, Brain Disorders, Clinical Research, Biotechnology, Dental/Oral and Craniofacial Disease, 2.1 Biological and endogenous factors, Aetiology, Adaptor Proteins, Signal Transducing, Adolescent, Adult, Aged, Alleles, Animals, Cell Cycle Proteins, Child, Child, Preschool, Codon, Nonsense, Exome, Eye Abnormalities, Female, Heterozygote, Humans, Introns, Male, Mice, Middle Aged, Nonsense Mediated mRNA Decay, Pedigree, Phenotype, Phosphoproteins, Transcription Factors, Transcription Initiation Site, YAP-Signaling Proteins, Young Adult, UK10K Consortium, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract

Exome sequence analysis of affected individuals from two families with autosomal-dominant inheritance of coloboma identified two different cosegregating heterozygous nonsense mutations (c.370C>T [p.Arg124*] and c. 1066G>T [p.Glu356*]) in YAP1. The phenotypes of the affected families differed in that one included no extraocular features and the other manifested with highly variable multisystem involvement, including hearing loss, intellectual disability, hematuria, and orofacial clefting. A combined LOD score of 4.2 was obtained for the association between YAP1 loss-of-function mutations and the phenotype in these families. YAP1 encodes an effector of the HIPPO-pathway-induced growth response, and whole-mount in situ hybridization in mouse embryos has shown that Yap1 is strongly expressed in the eye, brain, and fusing facial processes. RT-PCR showed that an alternative transcription start site (TSS) in intron 1 of YAP1 and Yap1 is widely used in human and mouse development, respectively. Transcripts from the alternative TSS are predicted to initiate at codon Met179 relative to the canonical transcript (RefSeq NM_001130145). In these alternative transcripts, the c.370C>T mutation in family 1305 is within the 5' UTR and cannot result in nonsense-mediated decay (NMD). The c. 1066G>T mutation in family 132 should result in NMD in transcripts from either TSS. Amelioration of the phenotype by the alternative transcripts provides a plausible explanation for the phenotypic differences between the families.

Published
2014

19. Prevalence of deleterious variants in MC3R in patients with constitutional delay of growth and puberty

Author

Duckett, Katie, Williamson, Alice, Kincaid, John WR, Rainbow, Kara, Corbin, Laura J, Martin, Hilary C, Eberhardt, Ruth Y, Huang, Qin Qin, Hurles, Matthew E, He, Wen, Brauner, Raja, Delaney, Angela, Dunkel, Leo, Grinspon, Romina P, Hall, Janet E, Hirschhorn, Joel N, Howard, Sasha R, Latronico, Ana C, Jorge, Alexander AL, McElreavey, Ken, Mericq, Verónica, Merino, Paulina M, Palmert, Mark R, Plummer, Lacey, Rey, Rodolfo A, Rezende, Raíssa C, Seminara, Stephanie B, Salnikov, Kathryn, Banerjee, Indraneel, Lam, Brian YH, Perry, John RB, Timpson, Nicholas J, Clayton, Peter, Chan, Yee-Ming, Ong, Ken K, O'Rahilly, Stephen, Duckett, Katie [0000-0002-0222-1689], Williamson, Alice [0000-0002-7599-9301], Kincaid, John WR [0000-0003-0660-9813], Rainbow, Kara [0000-0002-8089-0693], Corbin, Laura J [0000-0002-4032-9500], Martin, Hilary C [0000-0002-4454-9084], Eberhardt, Ruth Y [0000-0001-6152-1369], Huang, Qin Qin [0000-0003-3073-717X], Hurles, Matthew E [0000-0002-2333-7015], Brauner, Raja [0000-0002-4456-4508], Delaney, Angela [0000-0002-0632-6365], Grinspon, Romina P [0000-0002-6291-1518], Hall, Janet E [0000-0003-4644-3061], Hirschhorn, Joel N [0000-0002-1650-7901], Palmert, Mark R [0000-0002-4096-0685], Lam, Brian YH [0000-0002-3638-9025], Timpson, Nicholas J [0000-0002-7141-9189], Clayton, Peter [0000-0003-1225-4537], Chan, Yee-Ming [0000-0003-0554-8502], Ong, Ken K [0000-0003-4689-7530], O'Rahilly, Stephen [0000-0003-2199-4449], and Apollo - University of Cambridge Repository

Subjects
UK Biobank, constitutional delay, MC3R, ALSPAC, delayed puberty
Abstract

ContextThe melanocortin 3 receptor (MC3R) has recently emerged as a critical regulator of pubertal timing, linear growth and the acquisition of lean mass in humans and mice. In population-based studies, heterozygous carriers of deleterious variants in MC3R report a later onset of puberty than non-carriers. However, the frequency of such variants in patients who present with clinical disorders of pubertal development is currently unknown.ObjectiveTo determine whether deleterious MC3R variants are more frequently found in patients clinically presenting with constitutional delay of growth and puberty (CDGP) or normosmic idiopathic hypogonadotropic hypogonadism (nIHH).Design, Setting and ParticipantsWe examined the sequence of MC3R in 362 adolescents with a clinical diagnosis of CDGP and 657 patients with nIHH, experimentally characterised the signalling properties of all non-synonymous variants found and compared their frequency to that in 5774 controls from a population-based cohort. Additionally, we established the relative frequency of predicted deleterious variants in individuals with self-reported delayed vs normally timed menarche/voice breaking in the UK Biobank cohort.ResultsMC3R loss-of-function variants were infrequent but overrepresented in patients with CDGP (8/362 (2.2%), OR = 4.17, p = 0.001). There was no strong evidence of overrepresentation in patients with nIHH (4/657 (0.6%), OR = 1.15, p = 0.779). In 246,328 women from UK Biobank, predicted deleterious variants were more frequently found in those self-reporting delayed (≥16 years) vs normal age at menarche (OR = 1.66, p = 3.90E-07).ConclusionsWe have found evidence that functionally damaging variants in MC3R are overrepresented in individuals with CDGP but are not a common cause of this phenotype.

Published
2023
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20. Mutations in the Gene Encoding IFT Dynein Complex Component WDR34 Cause Jeune Asphyxiating Thoracic Dystrophy

Author

Schmidts, Miriam, Vodopiutz, Julia, Christou-Savina, Sonia, Cortés, Claudio R, McInerney-Leo, Aideen M, Emes, Richard D, Arts, Heleen H, Tüysüz, Beyhan, D’Silva, Jason, Leo, Paul J, Giles, Tom C, Oud, Machteld M, Harris, Jessica A, Koopmans, Marije, Marshall, Mhairi, Elçioglu, Nursel, Kuechler, Alma, Bockenhauer, Detlef, Moore, Anthony T, Wilson, Louise C, Janecke, Andreas R, Hurles, Matthew E, Emmet, Warren, Gardiner, Brooke, Streubel, Berthold, Dopita, Belinda, Zankl, Andreas, Kayserili, Hülya, Scambler, Peter J, Brown, Matthew A, Beales, Philip L, Wicking, Carol, UK10K, Duncan, Emma L, and Mitchison, Hannah M

Subjects
Rare Diseases, Pediatric, Underpinning research, 1.1 Normal biological development and functioning, Generic health relevance, Animals, Asians, Axoneme, Carrier Proteins, Child, Chlamydomonas, Cilia, Cytoplasmic Dyneins, Cytoskeleton, Ellis-Van Creveld Syndrome, Exome, Exons, Humans, Infant, Infant, Newborn, Intracellular Signaling Peptides and Proteins, Mutation, Protein Conformation, Proteomics, Whites, UK10K, Asian People, White People, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract

Bidirectional (anterograde and retrograde) motor-based intraflagellar transport (IFT) governs cargo transport and delivery processes that are essential for primary cilia growth and maintenance and for hedgehog signaling functions. The IFT dynein-2 motor complex that regulates ciliary retrograde protein transport contains a heavy chain dynein ATPase/motor subunit, DYNC2H1, along with other less well functionally defined subunits. Deficiency of IFT proteins, including DYNC2H1, underlies a spectrum of skeletal ciliopathies. Here, by using exome sequencing and a targeted next-generation sequencing panel, we identified a total of 11 mutations in WDR34 in 9 families with the clinical diagnosis of Jeune syndrome (asphyxiating thoracic dystrophy). WDR34 encodes a WD40 repeat-containing protein orthologous to Chlamydomonas FAP133, a dynein intermediate chain associated with the retrograde intraflagellar transport motor. Three-dimensional protein modeling suggests that the identified mutations all affect residues critical for WDR34 protein-protein interactions. We find that WDR34 concentrates around the centrioles and basal bodies in mammalian cells, also showing axonemal staining. WDR34 coimmunoprecipitates with the dynein-1 light chain DYNLL1 in vitro, and mining of proteomics data suggests that WDR34 could represent a previously unrecognized link between the cytoplasmic dynein-1 and IFT dynein-2 motors. Together, these data show that WDR34 is critical for ciliary functions essential to normal development and survival, most probably as a previously unrecognized component of the mammalian dynein-IFT machinery.

Published
2013

22. An integrated map of genetic variation from 1,092 human genomes

Author

McVean, Gil A, Altshuler (Co-Chair), David M, Durbin (Co-Chair), Richard M, Abecasis, Gonçalo R, Bentley, David R, Chakravarti, Aravinda, Clark, Andrew G, Donnelly, Peter, Eichler, Evan E, Flicek, Paul, Gabriel, Stacey B, Gibbs, Richard A, Green, Eric D, Hurles, Matthew E, Knoppers, Bartha M, Korbel, Jan O, Lander, Eric S, Lee, Charles, Lehrach, Hans, Mardis, Elaine R, Marth, Gabor T, Nickerson, Deborah A, Schmidt, Jeanette P, Sherry, Stephen T, Wang, Jun, and Wilson, Richard K

Subjects
Genetics, Human Genome, 2.1 Biological and endogenous factors, 1.1 Normal biological development and functioning, Underpinning research, Aetiology, Generic health relevance, Alleles, Binding Sites, Conserved Sequence, Evolution, Molecular, Genetic Variation, Genetics, Medical, Genetics, Population, Genome, Human, Genome-Wide Association Study, Genomics, Haplotypes, Humans, Nucleotide Motifs, Polymorphism, Single Nucleotide, Racial Groups, Sequence Deletion, Transcription Factors, Genomes Project Consortium, General Science & Technology
Abstract

By characterizing the geographic and functional spectrum of human genetic variation, the 1000 Genomes Project aims to build a resource to help to understand the genetic contribution to disease. Here we describe the genomes of 1,092 individuals from 14 populations, constructed using a combination of low-coverage whole-genome and exome sequencing. By developing methods to integrate information across several algorithms and diverse data sources, we provide a validated haplotype map of 38 million single nucleotide polymorphisms, 1.4 million short insertions and deletions, and more than 14,000 larger deletions. We show that individuals from different populations carry different profiles of rare and common variants, and that low-frequency variants show substantial geographic differentiation, which is further increased by the action of purifying selection. We show that evolutionary conservation and coding consequence are key determinants of the strength of purifying selection, that rare-variant load varies substantially across biological pathways, and that each individual contains hundreds of rare non-coding variants at conserved sites, such as motif-disrupting changes in transcription-factor-binding sites. This resource, which captures up to 98% of accessible single nucleotide polymorphisms at a frequency of 1% in related populations, enables analysis of common and low-frequency variants in individuals from diverse, including admixed, populations.

Published
2012

23. Genome-wide Transcriptome Profiling Reveals the Functional Impact of Rare De Novo and Recurrent CNVs in Autism Spectrum Disorders

Author

Luo, Rui, Sanders, Stephan J, Tian, Yuan, Voineagu, Irina, Huang, Ni, Chu, Su H, Klei, Lambertus, Cai, Chaochao, Ou, Jing, Lowe, Jennifer K, Hurles, Matthew E, Devlin, Bernie, State, Matthew W, and Geschwind, Daniel H

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Biomedical and Clinical Sciences, Genetics, Mental Health, Brain Disorders, Autism, Neurosciences, Pediatric, Human Genome, Intellectual and Developmental Disabilities (IDD), Aetiology, 2.1 Biological and endogenous factors, Child, Child Development Disorders, Pervasive, Child, Preschool, Chromosomes, Human, Pair 16, DNA Copy Number Variations, Gene Expression Profiling, Humans, Mutation, Medical and Health Sciences, Genetics & Heredity, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

Copy-number variants (CNVs) are a major contributor to the pathophysiology of autism spectrum disorders (ASDs), but the functional impact of CNVs remains largely unexplored. Because brain tissue is not available from most samples, we interrogated gene expression in lymphoblasts from 244 families with discordant siblings in the Simons Simplex Collection in order to identify potentially pathogenic variation. Our results reveal that the overall frequency of significantly misexpressed genes (which we refer to here as outliers) identified in probands and unaffected siblings does not differ. However, in probands, but not their unaffected siblings, the group of outlier genes is significantly enriched in neural-related pathways, including neuropeptide signaling, synaptogenesis, and cell adhesion. We demonstrate that outlier genes cluster within the most pathogenic CNVs (rare de novo CNVs) and can be used for the prioritization of rare CNVs of potentially unknown significance. Several nonrecurrent CNVs with significant gene-expression alterations are identified (these include deletions in chromosomal regions 3q27, 3p13, and 3p26 and duplications at 2p15), suggesting that these are potential candidate ASD loci. In addition, we identify distinct expression changes in 16p11.2 microdeletions, 16p11.2 microduplications, and 7q11.23 duplications, and we show that specific genes within the 16p CNV interval correlate with differences in head circumference, an ASD-relevant phenotype. This study provides evidence that pathogenic structural variants have a functional impact via transcriptome alterations in ASDs at a genome-wide level and demonstrates the utility of integrating gene expression with mutation data for the prioritization of genes disrupted by potentially pathogenic mutations.

Published
2012

24. Mapping copy number variation by population-scale genome sequencing

Author

Mills, Ryan E, Walter, Klaudia, Stewart, Chip, Handsaker, Robert E, Chen, Ken, Alkan, Can, Abyzov, Alexej, Yoon, Seungtai Chris, Ye, Kai, Cheetham, R Keira, Chinwalla, Asif, Conrad, Donald F, Fu, Yutao, Grubert, Fabian, Hajirasouliha, Iman, Hormozdiari, Fereydoun, Iakoucheva, Lilia M, Iqbal, Zamin, Kang, Shuli, Kidd, Jeffrey M, Konkel, Miriam K, Korn, Joshua, Khurana, Ekta, Kural, Deniz, Lam, Hugo YK, Leng, Jing, Li, Ruiqiang, Li, Yingrui, Lin, Chang-Yun, Luo, Ruibang, Mu, Xinmeng Jasmine, Nemesh, James, Peckham, Heather E, Rausch, Tobias, Scally, Aylwyn, Shi, Xinghua, Stromberg, Michael P, Stütz, Adrian M, Urban, Alexander Eckehart, Walker, Jerilyn A, Wu, Jiantao, Zhang, Yujun, Zhang, Zhengdong D, Batzer, Mark A, Ding, Li, Marth, Gabor T, McVean, Gil, Sebat, Jonathan, Snyder, Michael, Wang, Jun, Ye, Kenny, Eichler, Evan E, Gerstein, Mark B, Hurles, Matthew E, Lee, Charles, McCarroll, Steven A, and Korbel, Jan O

Subjects
Biotechnology, Human Genome, Genetics, Generic health relevance, DNA Copy Number Variations, Gene Duplication, Genetic Predisposition to Disease, Genetics, Population, Genome, Human, Genomics, Genotype, Humans, Mutagenesis, Insertional, Reproducibility of Results, Sequence Analysis, DNA, Sequence Deletion, Genomes Project, General Science & Technology
Abstract

Genomic structural variants (SVs) are abundant in humans, differing from other forms of variation in extent, origin and functional impact. Despite progress in SV characterization, the nucleotide resolution architecture of most SVs remains unknown. We constructed a map of unbalanced SVs (that is, copy number variants) based on whole genome DNA sequencing data from 185 human genomes, integrating evidence from complementary SV discovery approaches with extensive experimental validations. Our map encompassed 22,025 deletions and 6,000 additional SVs, including insertions and tandem duplications. Most SVs (53%) were mapped to nucleotide resolution, which facilitated analysing their origin and functional impact. We examined numerous whole and partial gene deletions with a genotyping approach and observed a depletion of gene disruptions amongst high frequency deletions. Furthermore, we observed differences in the size spectra of SVs originating from distinct formation mechanisms, and constructed a map of SV hotspots formed by common mechanisms. Our analytical framework and SV map serves as a resource for sequencing-based association studies.

Published
2011

25. Prevalence of Deleterious Variants in MC3R in Patients With Constitutional Delay of Growth and Puberty

Author

Duckett, Katie, primary, Williamson, Alice, additional, Kincaid, John W R, additional, Rainbow, Kara, additional, Corbin, Laura J, additional, Martin, Hilary C, additional, Eberhardt, Ruth Y, additional, Huang, Qin Qin, additional, Hurles, Matthew E, additional, He, Wen, additional, Brauner, Raja, additional, Delaney, Angela, additional, Dunkel, Leo, additional, Grinspon, Romina P, additional, Hall, Janet E, additional, Hirschhorn, Joel N, additional, Howard, Sasha R, additional, Latronico, Ana C, additional, Jorge, Alexander A L, additional, McElreavey, Ken, additional, Mericq, Verónica, additional, Merino, Paulina M, additional, Palmert, Mark R, additional, Plummer, Lacey, additional, Rey, Rodolfo A, additional, Rezende, Raíssa C, additional, Seminara, Stephanie B, additional, Salnikov, Kathryn, additional, Banerjee, Indraneel, additional, Lam, Brian Y H, additional, Perry, John R B, additional, Timpson, Nicholas J, additional, Clayton, Peter, additional, Chan, Yee-Ming, additional, Ong, Ken K, additional, and O’Rahilly, Stephen, additional

Published
2023
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26. Dynamic changes in the epigenomic landscape regulate human organogenesis and link to developmental disorders

Author

Gerrard, Dave T., Berry, Andrew A., Jennings, Rachel E., Birket, Matthew J., Zarrineh, Peyman, Garstang, Myles G., Withey, Sarah L., Short, Patrick, Jiménez-Gancedo, Sandra, Firbas, Panos N., Donaldson, Ian, Sharrocks, Andrew D., Hanley, Karen Piper, Hurles, Matthew E., Gomez-Skarmeta, José Luis, Bobola, Nicoletta, and Hanley, Neil A.

Published
2020
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28. Models of KPTN-related disorder implicate mTOR signalling in cognitive and overgrowth phenotypes

Author

Levitin, Maria O., Rawlins, Lettie E., Sanchez-Andrade, Gabriela, Arshad, Osama A., Collins, Stephan C., Sawiak, Stephen J., Iffland, Phillip H., Andersson, Malin H.L., Bupp, Caleb, Cambridge, Emma L., Coomber, Eve L., Ellis, Ian, Herkert, Johanna C., Ironfield, Holly, Jory, Logan, Kretz, Perrine F., Kant, Sarina G., Neaverson, Alexandra, Nibbeling, Esther, Rowley, Christine, Relton, Emily, Sanderson, Mark, Scott, Ethan M., Stewart, Helen, Shuen, Andrew Y., Schreiber, John, Tuck, Liz, Tonks, James, Terkelsen, Thorkild, van Ravenswaaij-Arts, Conny, Vasudevan, Pradeep, Wenger, Olivia, Wright, Michael, Day, Andrew, Hunter, Adam, Patel, Minal, Lelliott, Christopher J., Crino, Peter B., Yalcin, Binnaz, Crosby, Andrew H., Baple, Emma L., Logan, Darren W., Hurles, Matthew E., Gerety, Sebastian S., Levitin, Maria O., Rawlins, Lettie E., Sanchez-Andrade, Gabriela, Arshad, Osama A., Collins, Stephan C., Sawiak, Stephen J., Iffland, Phillip H., Andersson, Malin H.L., Bupp, Caleb, Cambridge, Emma L., Coomber, Eve L., Ellis, Ian, Herkert, Johanna C., Ironfield, Holly, Jory, Logan, Kretz, Perrine F., Kant, Sarina G., Neaverson, Alexandra, Nibbeling, Esther, Rowley, Christine, Relton, Emily, Sanderson, Mark, Scott, Ethan M., Stewart, Helen, Shuen, Andrew Y., Schreiber, John, Tuck, Liz, Tonks, James, Terkelsen, Thorkild, van Ravenswaaij-Arts, Conny, Vasudevan, Pradeep, Wenger, Olivia, Wright, Michael, Day, Andrew, Hunter, Adam, Patel, Minal, Lelliott, Christopher J., Crino, Peter B., Yalcin, Binnaz, Crosby, Andrew H., Baple, Emma L., Logan, Darren W., Hurles, Matthew E., and Gerety, Sebastian S.

Abstract

Models

Published
2023

29. The impact of rare protein coding genetic variation on adult cognitive function

Author

Chen, Chia-Yen, Tian, Ruoyu, Ge, Tian, Lam, Max, Sanchez-Andrade, Gabriela, Singh, Tarjinder, Urpa, Lea, Liu, Jimmy Z., Sanderson, Mark, Rowley, Christine, Ironfield, Holly, Fang, Terry, Daly, Mark, Palotie, Aarno, Tsai, Ellen A., Huang, Hailiang, Hurles, Matthew E., Gerety, Sebastian S., Lencz, Todd, Runz, Heiko, Faculty of Medicine, Institute for Molecular Medicine Finland, Genomics of Neurological and Neuropsychiatric Disorders, Centre of Excellence in Complex Disease Genetics, Research Programs Unit, and Aarno Palotie / Principal Investigator

Subjects
1184 Genetics, developmental biology, physiology
Abstract

Compelling evidence suggests that human cognitive function is strongly influenced by genetics. Here, we conduct a large-scale exome study to examine whether rare protein-coding variants impact cognitive function in the adult population (n = 485,930). We identify eight genes (ADGRB2, KDM5B, GIGYF1, ANKRD12, SLC8A1, RC3H2, CACNA1A and BCAS3) that are associated with adult cognitive function through rare coding variants with large effects. Rare genetic architecture for cognitive function partially overlaps with that of neurodevelopmental disorders. In the case of KDM5B we show how the genetic dosage of one of these genes may determine the variability of cognitive, behavioral and molecular traits in mice and humans. We further provide evidence that rare and common variants overlap in association signals and contribute additively to cognitive function. Our study introduces the relevance of rare coding variants for cognitive function and unveils high-impact monogenic contributions to how cognitive function is distributed in the normal adult population.Analysis of rare coding variants in the UK Biobank identifies eight genes associated with adult cognitive function, including KDM5B. Rare and common variant signals overlap and contribute additively to the phenotype.

Published
2023

30. Optimizing the Diagnosis of Rare Genomic Disease in the UK and Ireland

Author

Wright, Caroline F, Campbell, Patrick, Eberhardt, Ruth Y., Aitken, Stuart, Perrett, Daniel, Brent, Simon, Danecek, Petr, Gardner, Eugene J., Chundru, V Kartik, Lindsay, Sarah J, Andrews, Katrina A, Hampstead, Juliet, Kaplanis, Joanna, Samocha, Kaitlin E., Middleton, Anna, Foreman, Julia, Hobson, Rachel J., Parker, Michael J., Martin, Hilary C, FitzPatrick, David R, Hurles, Matthew E, and Firth, Helen V.

Published
2023

31. De novo variants in the RNU4-2snRNA cause a frequent neurodevelopmental syndrome

Author

Chen, Yuyang, Dawes, Ruebena, Kim, Hyung Chul, Ljungdahl, Alicia, Stenton, Sarah L., Walker, Susan, Lord, Jenny, Lemire, Gabrielle, Martin-Geary, Alexandra C., Ganesh, Vijay S., Ma, Jialan, Ellingford, Jamie M., Delage, Erwan, D’Souza, Elston N., Dong, Shan, Adams, David R., Allan, Kirsten, Bakshi, Madhura, Baldwin, Erin E., Berger, Seth I., Bernstein, Jonathan A., Bhatnagar, Ishita, Blair, Ed, Brown, Natasha J., Burrage, Lindsay C., Chapman, Kimberly, Coman, David J., Compton, Alison G., Cunningham, Chloe A., D’Souza, Precilla, Danecek, Petr, Délot, Emmanuèle C., Dias, Kerith-Rae, Elias, Ellen R., Elmslie, Frances, Evans, Care-Anne, Ewans, Lisa, Ezell, Kimberly, Fraser, Jamie L., Gallacher, Lyndon, Genetti, Casie A., Goriely, Anne, Grant, Christina L., Haack, Tobias, Higgs, Jenny E., Hinch, Anjali G., Hurles, Matthew E., Kuechler, Alma, Lachlan, Katherine L., Lalani, Seema R., Lecoquierre, François, Leitão, Elsa, Fevre, Anna Le, Leventer, Richard J., Liebelt, Jan E., Lindsay, Sarah, Lockhart, Paul J., Ma, Alan S., Macnamara, Ellen F., Mansour, Sahar, Maurer, Taylor M., Mendez, Hector R., Metcalfe, Kay, Montgomery, Stephen B., Moosajee, Mariya, Nassogne, Marie-Cécile, Neumann, Serena, O’Donoghue, Michael, O’Leary, Melanie, Palmer, Elizabeth E., Pattani, Nikhil, Phillips, John, Pitsava, Georgia, Pysar, Ryan, Rehm, Heidi L., Reuter, Chloe M., Revencu, Nicole, Riess, Angelika, Rius, Rocio, Rodan, Lance, Roscioli, Tony, Rosenfeld, Jill A., Sachdev, Rani, Shaw-Smith, Charles J., Simons, Cas, Sisodiya, Sanjay M., Snell, Penny, St Clair, Laura, Stark, Zornitza, Stewart, Helen S., Tan, Tiong Yang, Tan, Natalie B., Temple, Suzanna E. L., Thorburn, David R., Tifft, Cynthia J., Uebergang, Eloise, VanNoy, Grace E., Vasudevan, Pradeep, Vilain, Eric, Viskochil, David H., Wedd, Laura, Wheeler, Matthew T., White, Susan M., Wojcik, Monica, Wolfe, Lynne A., Wolfenson, Zoe, Wright, Caroline F., Xiao, Changrui, Zocche, David, Rubenstein, John L., Markenscoff-Papadimitriou, Eirene, Fica, Sebastian M., Baralle, Diana, Depienne, Christel, MacArthur, Daniel G., Howson, Joanna M. M., Sanders, Stephan J., O’Donnell-Luria, Anne, and Whiffin, Nicola

Abstract

Around 60% of individuals with neurodevelopmental disorders (NDD) remain undiagnosed after comprehensive genetic testing, primarily of protein-coding genes1. Large genome-sequenced cohorts are improving our ability to discover new diagnoses in the non-coding genome. Here we identify the non-coding RNA RNU4-2as a syndromic NDD gene. RNU4-2encodes the U4 small nuclear RNA (snRNA), which is a critical component of the U4/U6.U5 tri-snRNP complex of the major spliceosome2. We identify an 18 base pair region of RNU4-2mapping to two structural elements in the U4/U6 snRNA duplex (the T-loop and stem III) that is severely depleted of variation in the general population, but in which we identify heterozygous variants in 115 individuals with NDD. Most individuals (77.4%) have the same highly recurrent single base insertion (n.64_65insT). In 54 individuals in whom it could be determined, the de novo variants were all on the maternal allele. We demonstrate that RNU4-2is highly expressed in the developing human brain, in contrast to RNU4-1and other U4 homologues. Using RNA sequencing, we show how 5′ splice-site use is systematically disrupted in individuals with RNU4-2variants, consistent with the known role of this region during spliceosome activation. Finally, we estimate that variants in this 18 base pair region explain 0.4% of individuals with NDD. This work underscores the importance of non-coding genes in rare disorders and will provide a diagnosis to thousands of individuals with NDD worldwide.

Published
2024
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32. Contribution of retrotransposition to developmental disorders

Author

Gardner, Eugene J., Prigmore, Elena, Gallone, Giuseppe, Danecek, Petr, Samocha, Kaitlin E., Handsaker, Juliet, Gerety, Sebastian S., Ironfield, Holly, Short, Patrick J., Sifrim, Alejandro, Singh, Tarjinder, Chandler, Kate E., Clement, Emma, Lachlan, Katherine L., Prescott, Katrina, Rosser, Elisabeth, FitzPatrick, David R., Firth, Helen V., and Hurles, Matthew E.

Published
2019
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36. Differentiation of human induced pluripotent stem cells into cortical neural stem cells

Author

Neaverson, Alexandra, primary, Andersson, Malin H. L., additional, Arshad, Osama A., additional, Foulser, Luke, additional, Goodwin-Trotman, Mary, additional, Hunter, Adam, additional, Newman, Ben, additional, Patel, Minal, additional, Roth, Charlotte, additional, Thwaites, Tristan, additional, Kilpinen, Helena, additional, Hurles, Matthew E., additional, Day, Andrew, additional, and Gerety, Sebastian S., additional

Published
2023
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38. A minimal role for synonymous variation in human disease

Author

Dhindsa, Ryan S., primary, Wang, Quanli, additional, Vitsios, Dimitrios, additional, Burren, Oliver S., additional, Hu, Fengyuan, additional, DiCarlo, James E., additional, Kruglyak, Leonid, additional, MacArthur, Daniel G., additional, Hurles, Matthew E., additional, and Petrovski, Slavé, additional

Published
2022
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39. A cross-disorder dosage sensitivity map of the human genome

Author

Collins, Ryan L., primary, Glessner, Joseph T., additional, Porcu, Eleonora, additional, Lepamets, Maarja, additional, Brandon, Rhonda, additional, Lauricella, Christopher, additional, Han, Lide, additional, Morley, Theodore, additional, Niestroj, Lisa-Marie, additional, Ulirsch, Jacob, additional, Everett, Selin, additional, Howrigan, Daniel P., additional, Boone, Philip M., additional, Fu, Jack, additional, Karczewski, Konrad J., additional, Kellaris, Georgios, additional, Lowther, Chelsea, additional, Lucente, Diane, additional, Mohajeri, Kiana, additional, Nõukas, Margit, additional, Nuttle, Xander, additional, Samocha, Kaitlin E., additional, Trinh, Mi, additional, Ullah, Farid, additional, Võsa, Urmo, additional, Hurles, Matthew E., additional, Aradhya, Swaroop, additional, Davis, Erica E., additional, Finucane, Hilary, additional, Gusella, James F., additional, Janze, Aura, additional, Katsanis, Nicholas, additional, Matyakhina, Ludmila, additional, Neale, Benjamin M., additional, Sanders, David, additional, Warren, Stephanie, additional, Hodge, Jennelle C., additional, Lal, Dennis, additional, Ruderfer, Douglas M., additional, Meck, Jeanne, additional, Mägi, Reedik, additional, Esko, Tõnu, additional, Reymond, Alexandre, additional, Kutalik, Zoltán, additional, Hakonarson, Hakon, additional, Sunyaev, Shamil, additional, Brand, Harrison, additional, Talkowski, Michael E., additional, Metspalu, Andres, additional, Nelis, Mari, additional, and Milani, Lili, additional

Published
2022
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40. Erratum:Germline variants in HEY2 functional domains lead to congenital heart defects and thoracic aortic aneurysms(Genet Med (2021)23(103-110)(s41436020009394)(10.1038/s41436-020-00939-4))

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., Pediatric surgery, Human genetics, ACS - Atherosclerosis & ischemic syndromes, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Compulsivity, Impulsivity & Attention, Amsterdam Reproduction & Development (AR&D), AII - Cancer immunology, Graduate School, Human Genetics, ACS - Heart failure & arrhythmias, Medical Biology, Amsterdam Cardiovascular Sciences, Paediatric Cardiology, Cardiology, Pathology, and ACS - Pulmonary hypertension & thrombosis

Abstract

Correction to: Genetics in Medicine 2021; https://doi.org/10.1038/s41436-020-00939-4 In the article “Germline variants in HEY2 functional domains lead to congenital heart defects and thoracic aortic aneurysms” by van Walree ES et al (Genet Med 2021;23:103-110), there was an error in a sentence in the Methods section of the abstract. This sentence should read “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 controls, and the other 326 cases with familial thoracic aortic aneurysms (FTAA) and dissections versus 570 ancestry-matched controls.”

Published
2022

41. A cross-disorder dosage sensitivity map of the human genome

Author

Collins, Ryan L., Glessner, Joseph T., Porcu, Eleonora, Lepamets, Maarja, Brandon, Rhonda, Lauricella, Christopher, Han, Lide, Morley, Theodore, Niestroj, Lisa-Marie, Ulirsch, Jacob, Everett, Selin, Howrigan, Daniel P., Boone, Philip M., Fu, Jack, Karczewski, Konrad J., Kellaris, Georgios, Lowther, Chelsea, Lucente, Diane, Mohajeri, Kiana, Noukas, Margit, Nuttle, Xander, Samocha, Kaitlin E., Trinh, Mi, Ullah, Farid, Vosa, Urmo, Hurles, Matthew E., Aradhya, Swaroop, Davis, Erica E., Finucane, Hilary, Gusella, James F., Janze, Aura, Katsanis, Nicholas, Matyakhina, Ludmila, Neale, Benjamin M., Sanders, David, Warren, Stephanie, Hodge, Jennelle C., Lal, Dennis, Ruderfer, Douglas M., Meck, Jeanne, Magi, Reedik, Esko, Tonu, Reymond, Alexandre, Kutalik, Zoltan, Hakonarson, Hakon, Sunyaev, Shamil, Brand, Harrison, Talkowski, Michael E., Collins, Ryan L., Glessner, Joseph T., Porcu, Eleonora, Lepamets, Maarja, Brandon, Rhonda, Lauricella, Christopher, Han, Lide, Morley, Theodore, Niestroj, Lisa-Marie, Ulirsch, Jacob, Everett, Selin, Howrigan, Daniel P., Boone, Philip M., Fu, Jack, Karczewski, Konrad J., Kellaris, Georgios, Lowther, Chelsea, Lucente, Diane, Mohajeri, Kiana, Noukas, Margit, Nuttle, Xander, Samocha, Kaitlin E., Trinh, Mi, Ullah, Farid, Vosa, Urmo, Hurles, Matthew E., Aradhya, Swaroop, Davis, Erica E., Finucane, Hilary, Gusella, James F., Janze, Aura, Katsanis, Nicholas, Matyakhina, Ludmila, Neale, Benjamin M., Sanders, David, Warren, Stephanie, Hodge, Jennelle C., Lal, Dennis, Ruderfer, Douglas M., Meck, Jeanne, Magi, Reedik, Esko, Tonu, Reymond, Alexandre, Kutalik, Zoltan, Hakonarson, Hakon, Sunyaev, Shamil, Brand, Harrison, and Talkowski, Michael E.

Abstract

Rare copy-number variants (rCNVs) include deletions and duplications that occur infrequently in the global human population and can confer substantial risk for disease. In this study, we aimed to quantify the prop-erties of haploinsufficiency (i.e., deletion intolerance) and triplosensitivity (i.e., duplication intolerance) throughout the human genome. We harmonized and meta-analyzed rCNVs from nearly one million individuals to construct a genome-wide catalog of dosage sensitivity across 54 disorders, which defined 163 dosage sensitive segments associated with at least one disorder. These segments were typically gene dense and often harbored dominant dosage sensitive driver genes, which we were able to prioritize using statistical fine-mapping. Finally, we designed an ensemble machine-learning model to predict probabilities of dosage sensitivity (pHaplo & pTriplo) for all autosomal genes, which identified 2,987 haploinsufficient and 1,559 trip-losensitive genes, including 648 that were uniquely triplosensitive. This dosage sensitivity resource will pro-vide broad utility for human disease research and clinical genetics.

Published
2022

42. 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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43. Prevalence and architecture of de novo mutations in developmental disorders

Author

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

Published
2017
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44. Identification of a human synaptotagmin-1 mutation that perturbs synaptic vesicle cycling

Author

Baker, Kate, Gordon, Sarah L., Grozeva, Detelina, van Kogelenberg, Margriet, Roberts, Nicola Y., Pike, Michael, Blair, Edward, Hurles, Matthew E., Chong, W. Kling, Baldeweg, Torsten, Kurian, Manju A., Boyd, Stewart G., Cousin, Michael A., and Raymond, F. Lucy

Subjects
Genetic variation -- Health aspects, Cellular proteins -- Health aspects, Cellular control mechanisms -- Genetic aspects, Health care industry
Abstract

Synaptotagmin-1 (SYT1) is a calcium-binding synaptic vesicle protein that is required for both exocytosis and endocytosis. Here, we describe a human condition associated with a rare variant in SYT1. The individual harboring this variant presented with an early onset dyskinetic movement disorder, severe motor delay, and profound cognitive impairment. Structural MRI was normal, but EEG showed extensive neurophysiological disturbances that included the unusual features of low-frequency oscillatory bursts and enhanced paired-pulse depression of visual evoked potentials. Trio analysis of whole- exome sequence identified a de novo SYT1 missense variant (I368T). Expression of rat SYT1 containing the equivalent human variant in WT mouse primary hippocampal cultures revealed that the mutant form of SYT1 correctly localizes to nerve terminals and is expressed at levels that are approximately equal to levels of endogenous WT protein. The presence of the mutant SYT1 slowed synaptic vesicle fusion kinetics, a finding that agrees with the previously demonstrated role for I368 in calcium-dependent membrane penetration. Expression of the I368T variant also altered the kinetics of synaptic vesicle endocytosis. Together, the clinical features, electrophysiological phenotype, and in vitro neuronal phenotype associated with this dominant negative SYT1 mutation highlight presynaptic mechanisms that mediate human motor control and cognitive development., Introduction Many postsynaptic genes and processes have been linked to neurodevelopmental disorders (1), and it is increasingly apparent that presynaptic dysfunction is another major contributory pathway. Rare variants have been [...]

Published
2015
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46. A common X-linked inborn error of carnitine biosynthesis may be a risk factor for nondysmorphic autism

Author

Celestino-Soper, Patrícia B. S., Violante, Sara, Crawford, Emily L., Luo, Rui, Lionel, Anath C., Delaby, Elsa, Cai, Guiqing, Sadikovic, Bekim, Lee, Kwanghyuk, Lo, Charlene, Gao, Kun, Person, Richard E., Moss, Timothy J., German, Jennifer R., Huang, Ni, Shinawi, Marwan, Treadwell-Deering, Diane, Szatmari, Peter, Roberts, Wendy, Fernandez, Bridget, Schroer, Richard J., Stevenson, Roger E., Buxbaum, Joseph D., Betancur, Catalina, Scherer, Stephen W., Sanders, Stephan J., Geschwind, Daniel H., Sutcliffe, James S., Hurles, Matthew E., Wanders, Ronald J. A., Shaw, Chad A., Leal, Suzanne M., Cook,, Edwin H., Goin-Kochel, Robin P., Vaz, Frédéric M., and Beaudet, Arthur L.

Published
2012

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

Author

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

Published
2022
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48. Paired-End Mapping Reveals Extensive Structural Variation in the Human Genome

Author

Korbel, Jan O., Urban, Alexander Eckehart, Affourtit, Jason P., Godwin, Brian, Grubert, Fabian, Simons, Jan Fredrik, Kim, Philip M., Palejev, Dean, Carriero, Nicholas J., Du, Lei, Taillon, Bruce E., Chen, Zhoutao, Tanzer, Andrea, Saunders, A. C. Eugenia, Chi, Jianxiang, Yang, Fengtang, Carter, Nigel P., Hurles, Matthew E., Weissman, Sherman M., Harkins, Timothy T., Gerstein, Mark B., Egholm, Michael, and Snyder, Michael

Published
2007
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50. 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

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