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1,069 results on '"Beaudet, Arthur L"'

1. A resource of targeted mutant mouse lines for 5,061 genes

Author

Birling, Marie-Christine, Yoshiki, Atsushi, Adams, David J, Ayabe, Shinya, Beaudet, Arthur L, Bottomley, Joanna, Bradley, Allan, Brown, Steve DM, Bürger, Antje, Bushell, Wendy, Chiani, Francesco, Chin, Hsian-Jean Genie, Christou, Skevoulla, Codner, Gemma F, DeMayo, Francesco J, Dickinson, Mary E, Doe, Brendan, Donahue, Leah Rae, Fray, Martin D, Gambadoro, Alessia, Gao, Xiang, Gertsenstein, Marina, Gomez-Segura, Alba, Goodwin, Leslie O, Heaney, Jason D, Hérault, Yann, de Angelis, Martin Hrabe, Jiang, Si-Tse, Justice, Monica J, Kasparek, Petr, King, Ruairidh E, Kühn, Ralf, Lee, Ho, Lee, Young Jae, Liu, Zhiwei, Lloyd, KC Kent, Lorenzo, Isabel, Mallon, Ann-Marie, McKerlie, Colin, Meehan, Terrence F, Fuentes, Violeta Munoz, Newman, Stuart, Nutter, Lauryl MJ, Oh, Goo Taeg, Pavlovic, Guillaume, Ramirez-Solis, Ramiro, Rosen, Barry, Ryder, Edward J, Santos, Luis A, Schick, Joel, Seavitt, John R, Sedlacek, Radislav, Seisenberger, Claudia, Seong, Je Kyung, Skarnes, William C, Sorg, Tania, Steel, Karen P, Tamura, Masaru, Tocchini-Valentini, Glauco P, Wang, Chi-Kuang Leo, Wardle-Jones, Hannah, Wattenhofer-Donzé, Marie, Wells, Sara, Wiles, Michael V, Willis, Brandon J, Wood, Joshua A, Wurst, Wolfgang, Xu, Ying, Teboul, Lydia, and Murray, Stephen A

Subjects
Biological Sciences, Genetics, Infectious Diseases, Biotechnology, 2.1 Biological and endogenous factors, Animals, Gene Deletion, Genetic Association Studies, Genome, Genotype, Information Dissemination, International Cooperation, Internet, Mice, Mice, Knockout, Mouse Embryonic Stem Cells, Mutagenesis, Phenotype, International Mouse Phenotyping Consortium, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

The International Mouse Phenotyping Consortium reports the generation of new mouse mutant strains for over 5,000 genes, including 2,850 novel null, 2,987 novel conditional- ready, and 4,433 novel reporter alleles.

Published
2021

2. The Deep Genome Project

Author

Lloyd, KC Kent, Adams, David J, Baynam, Gareth, Beaudet, Arthur L, Bosch, Fatima, Boycott, Kym M, Braun, Robert E, Caulfield, Mark, Cohn, Ronald, Dickinson, Mary E, Dobbie, Michael S, Flenniken, Ann M, Flicek, Paul, Galande, Sanjeev, Gao, Xiang, Grobler, Anne, Heaney, Jason D, Herault, Yann, de Angelis, Martin Hrabě, Lupski, James R, Lyonnet, Stanislas, Mallon, Ann-Marie, Mammano, Fabio, MacRae, Calum A, McInnes, Roderick, McKerlie, Colin, Meehan, Terrence F, Murray, Stephen A, Nutter, Lauryl MJ, Obata, Yuichi, Parkinson, Helen, Pepper, Michael S, Sedlacek, Radislav, Seong, Je Kyung, Shiroishi, Toshihiko, Smedley, Damian, Tocchini-Valentini, Glauco, Valle, David, Wang, Chi-Kuang Leo, Wells, Sara, White, Jacqueline, Wurst, Wolfgang, Xu, Ying, and Brown, Steve DM

Subjects
Animals, Genes, Genome, Humans, Mice, Mutation, Phenotype, Proteins, Environmental Sciences, Biological Sciences, Information and Computing Sciences, Bioinformatics
Published
2020

3. Human and mouse essentiality screens as a resource for disease gene discovery

Author

Cacheiro, Pilar, Muñoz-Fuentes, Violeta, Murray, Stephen A, Dickinson, Mary E, Bucan, Maja, Nutter, Lauryl MJ, Peterson, Kevin A, Haselimashhadi, Hamed, Flenniken, Ann M, Morgan, Hugh, Westerberg, Henrik, Konopka, Tomasz, Hsu, Chih-Wei, Christiansen, Audrey, Lanza, Denise G, Beaudet, Arthur L, Heaney, Jason D, Fuchs, Helmut, Gailus-Durner, Valerie, Sorg, Tania, Prochazka, Jan, Novosadova, Vendula, Lelliott, Christopher J, Wardle-Jones, Hannah, Wells, Sara, Teboul, Lydia, Cater, Heather, Stewart, Michelle, Hough, Tertius, Wurst, Wolfgang, Sedlacek, Radislav, Adams, David J, Seavitt, John R, Tocchini-Valentini, Glauco, Mammano, Fabio, Braun, Robert E, McKerlie, Colin, Herault, Yann, de Angelis, Martin Hrabě, Mallon, Ann-Marie, Lloyd, KC Kent, Brown, Steve DM, Parkinson, Helen, Meehan, Terrence F, and Smedley, Damian

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Biomedical and Clinical Sciences, Genetics, Biotechnology, Human Genome, Prevention, 2.1 Biological and endogenous factors, Aetiology, Generic health relevance, Good Health and Well Being, Animals, Disease, Genes, Essential, Genetic Association Studies, Genomics, Humans, Mice, Mice, Knockout, Genomics England Research Consortium, International Mouse Phenotyping Consortium
Abstract

The identification of causal variants in sequencing studies remains a considerable challenge that can be partially addressed by new gene-specific knowledge. Here, we integrate measures of how essential a gene is to supporting life, as inferred from viability and phenotyping screens performed on knockout mice by the International Mouse Phenotyping Consortium and essentiality screens carried out on human cell lines. We propose a cross-species gene classification across the Full Spectrum of Intolerance to Loss-of-function (FUSIL) and demonstrate that genes in five mutually exclusive FUSIL categories have differing biological properties. Most notably, Mendelian disease genes, particularly those associated with developmental disorders, are highly overrepresented among genes non-essential for cell survival but required for organism development. After screening developmental disorder cases from three independent disease sequencing consortia, we identify potentially pathogenic variants in genes not previously associated with rare diseases. We therefore propose FUSIL as an efficient approach for disease gene discovery.

Published
2020

4. Bi-allelic Variants in TONSL Cause SPONASTRIME Dysplasia and a Spectrum of Skeletal Dysplasia Phenotypes

Author

Burrage, Lindsay C, Reynolds, John J, Baratang, Nissan Vida, Phillips, Jennifer B, Wegner, Jeremy, McFarquhar, Ashley, Higgs, Martin R, Christiansen, Audrey E, Lanza, Denise G, Seavitt, John R, Jain, Mahim, Li, Xiaohui, Parry, David A, Raman, Vandana, Chitayat, David, Chinn, Ivan K, Bertuch, Alison A, Karaviti, Lefkothea, Schlesinger, Alan E, Earl, Dawn, Bamshad, Michael, Savarirayan, Ravi, Doddapaneni, Harsha, Muzny, Donna, Jhangiani, Shalini N, Eng, Christine M, Gibbs, Richard A, Bi, Weimin, Emrick, Lisa, Rosenfeld, Jill A, Postlethwait, John, Westerfield, Monte, Dickinson, Mary E, Beaudet, Arthur L, Ranza, Emmanuelle, Huber, Celine, Cormier-Daire, Valérie, Shen, Wei, Mao, Rong, Heaney, Jason D, Orange, Jordan S, Genomics, University of Washington Center for Mendelian, Network, Undiagnosed Diseases, Adams, David R, Aday, Aaron, Alejandro, Mercedes E, Allard, Patrick, Ashley, Euan A, Azamian, Mahshid S, Bacino, Carlos A, Baker, Eva, Balasubramanyam, Ashok, Barseghyan, Hayk, Batzli, Gabriel F, Beggs, Alan H, Behnam, Babak, Bellen, Hugo J, Bernstein, Jonathan A, Berry, Gerard T, Bican, Anna, Bick, David P, Birch, Camille L, Bonner, Devon, Boone, Braden E, Bostwick, Bret L, Briere, Lauren C, Brokamp, Elly, Brown, Donna M, Brush, Matthew, Burke, Elizabeth A, Butte, Manish J, Chen, Shan, Clark, Gary D, Coakley, Terra R, Cogan, Joy D, Colley, Heather A, Cooper, Cynthia M, Cope, Heidi, Craigen, William J, D’Souza, Precilla, Davids, Mariska, Davidson, Jean M, Dayal, Jyoti G, Dell’Angelica, Esteban C, Dhar, Shweta U, Dipple, Katrina M, Donnell-Fink, Laurel A, Dorrani, Naghmeh, Dorset, Daniel C, Douine, Emilie D, Draper, David D, Dries, Annika M, Duncan, Laura, Eckstein, David J, Emrick, Lisa T, Enns, Gregory M, Eskin, Ascia, and Esteves, Cecilia

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Rare Diseases, Clinical Research, Congenital Structural Anomalies, Pediatric, Aetiology, 2.1 Biological and endogenous factors, Adolescent, Adult, Alleles, Animals, Cells, Cultured, Child, Child, Preschool, Chromosomal Instability, DNA Damage, Female, Fibroblasts, Genetic Association Studies, Genetic Variation, Humans, Mice, Mice, Knockout, Musculoskeletal Abnormalities, NF-kappa B, Osteochondrodysplasias, Exome Sequencing, Young Adult, Zebrafish, University of Washington Center for Mendelian Genomics, Undiagnosed Diseases Network, DNA repair, DNA replication, SPONASTRIME dysplasia, TONSL, exome sequencing, skeletal dysplasia, Medical and Health Sciences, Genetics & Heredity, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

SPONASTRIME dysplasia is an autosomal-recessive spondyloepimetaphyseal dysplasia characterized by spine (spondylar) abnormalities, midface hypoplasia with a depressed nasal bridge, metaphyseal striations, and disproportionate short stature. Scoliosis, coxa vara, childhood cataracts, short dental roots, and hypogammaglobulinemia have also been reported in this disorder. Although an autosomal-recessive inheritance pattern has been hypothesized, pathogenic variants in a specific gene have not been discovered in individuals with SPONASTRIME dysplasia. Here, we identified bi-allelic variants in TONSL, which encodes the Tonsoku-like DNA repair protein, in nine subjects (from eight families) with SPONASTRIME dysplasia, and four subjects (from three families) with short stature of varied severity and spondylometaphyseal dysplasia with or without immunologic and hematologic abnormalities, but no definitive metaphyseal striations at diagnosis. The finding of early embryonic lethality in a Tonsl-/- murine model and the discovery of reduced length, spinal abnormalities, reduced numbers of neutrophils, and early lethality in a tonsl-/- zebrafish model both support the hypomorphic nature of the identified TONSL variants. Moreover, functional studies revealed increased amounts of spontaneous replication fork stalling and chromosomal aberrations, as well as fewer camptothecin (CPT)-induced RAD51 foci in subject-derived cell lines. Importantly, these cellular defects were rescued upon re-expression of wild-type (WT) TONSL; this rescue is consistent with the hypothesis that hypomorphic TONSL variants are pathogenic. Overall, our studies in humans, mice, zebrafish, and subject-derived cell lines confirm that pathogenic variants in TONSL impair DNA replication and homologous recombination-dependent repair processes, and they lead to a spectrum of skeletal dysplasia phenotypes with numerous extra-skeletal manifestations.

Published
2019

5. Author Correction: Identification of genes required for eye development by high-throughput screening of mouse knockouts

Author

Moore, Bret A, Leonard, Brian C, Sebbag, Lionel, Edwards, Sydney G, Cooper, Ann, Imai, Denise M, Straiton, Ewan, Santos, Luis, Reilly, Christopher, Griffey, Stephen M, Bower, Lynette, Clary, David, Mason, Jeremy, Roux, Michel J, Meziane, Hamid, Herault, Yann, McKerlie, Colin, Flenniken, Ann M, Nutter, Lauryl MJ, Berberovic, Zorana, Owen, Celeste, Newbigging, Susan, Adissu, Hibret, Eskandarian, Mohammed, Hsu, Chih-Wei, Kalaga, Sowmya, Udensi, Uchechukwu, Asomugha, Chinwe, Bohat, Ritu, Gallegos, Juan J, Seavitt, John R, Heaney, Jason D, Beaudet, Arthur L, Dickinson, Mary E, Justice, Monica J, Philip, Vivek, Kumar, Vivek, Svenson, Karen L, Braun, Robert E, Wells, Sara, Cater, Heather, Stewart, Michelle, Clementson-Mobbs, Sharon, Joynson, Russell, Gao, Xiang, Suzuki, Tomohiro, Wakana, Shigeharu, Smedley, Damian, Seong, JK, Tocchini-Valentini, Glauco, Moore, Mark, Fletcher, Colin, Karp, Natasha, Ramirez-Solis, Ramiro, White, Jacqueline K, de Angelis, Martin Hrabe, Wurst, Wolfgang, Thomasy, Sara M, Flicek, Paul, Parkinson, Helen, Brown, Steve DM, Meehan, Terrence F, Nishina, Patsy M, Murray, Stephen A, Krebs, Mark P, Mallon, Ann-Marie, Kent Lloyd, KC, Murphy, Christopher J, and Moshiri, Ala

Subjects
Biomedical and Clinical Sciences, Genetics, International Mouse Phenotyping Consortium, Biological sciences, Biomedical and clinical sciences
Abstract

[This corrects the article DOI: 10.1038/s42003-018-0226-0.].

Published
2019

6. Erratum: Author Correction: Identification of genes required for eye development by high-throughput screening of mouse knockouts.

Author

Moore, Bret A, Leonard, Brian C, Sebbag, Lionel, Edwards, Sydney G, Cooper, Ann, Imai, Denise M, Straiton, Ewan, Santos, Luis, Reilly, Christopher, Griffey, Stephen M, Bower, Lynette, Clary, David, Mason, Jeremy, Roux, Michel J, Meziane, Hamid, Herault, Yann, International Mouse Phenotyping Consortium, McKerlie, Colin, Flenniken, Ann M, Nutter, Lauryl MJ, Berberovic, Zorana, Owen, Celeste, Newbigging, Susan, Adissu, Hibret, Eskandarian, Mohammed, Hsu, Chih-Wei, Kalaga, Sowmya, Udensi, Uchechukwu, Asomugha, Chinwe, Bohat, Ritu, Gallegos, Juan J, Seavitt, John R, Heaney, Jason D, Beaudet, Arthur L, Dickinson, Mary E, Justice, Monica J, Philip, Vivek, Kumar, Vivek, Svenson, Karen L, Braun, Robert E, Wells, Sara, Cater, Heather, Stewart, Michelle, Clementson-Mobbs, Sharon, Joynson, Russell, Gao, Xiang, Suzuki, Tomohiro, Wakana, Shigeharu, Smedley, Damian, Seong, JK, Tocchini-Valentini, Glauco, Moore, Mark, Fletcher, Colin, Karp, Natasha, Ramirez-Solis, Ramiro, White, Jacqueline K, de Angelis, Martin Hrabe, Wurst, Wolfgang, Thomasy, Sara M, Flicek, Paul, Parkinson, Helen, Brown, Steve DM, Meehan, Terrence F, Nishina, Patsy M, Murray, Stephen A, Krebs, Mark P, Mallon, Ann-Marie, Kent Lloyd, KC, Murphy, Christopher J, and Moshiri, Ala

Subjects
International Mouse Phenotyping Consortium, Genetics
Abstract

[This corrects the article DOI: 10.1038/s42003-018-0226-0.].

Published
2019

7. Extensive identification of genes involved in congenital and structural heart disorders and cardiomyopathy

Author

Spielmann, Nadine, Miller, Gregor, Oprea, Tudor I., Hsu, Chih-Wei, Fobo, Gisela, Frishman, Goar, Montrone, Corinna, Haseli Mashhadi, Hamed, Mason, Jeremy, Munoz Fuentes, Violeta, Leuchtenberger, Stefanie, Ruepp, Andreas, Wagner, Matias, Westphal, Dominik S., Wolf, Cordula, Görlach, Agnes, Sanz-Moreno, Adrián, Cho, Yi-Li, Teperino, Raffaele, Brandmaier, Stefan, Sharma, Sapna, Galter, Isabella Rikarda, Östereicher, Manuela A., Zapf, Lilly, Mayer-Kuckuk, Philipp, Rozman, Jan, Teboul, Lydia, Bunton-Stasyshyn, Rosie K. A., Cater, Heather, Stewart, Michelle, Christou, Skevoulla, Westerberg, Henrik, Willett, Amelia M., Wotton, Janine M., Roper, Willson B., Christiansen, Audrey E., Ward, Christopher S., Heaney, Jason D., Reynolds, Corey L., Prochazka, Jan, Bower, Lynette, Clary, David, Selloum, Mohammed, Bou About, Ghina, Wendling, Olivia, Jacobs, Hugues, Leblanc, Sophie, Meziane, Hamid, Sorg, Tania, Audain, Enrique, Gilly, Arthur, Rayner, Nigel W., Hitz, Marc-Phillip, Zeggini, Eleftheria, Wolf, Eckhard, Sedlacek, Radislav, Murray, Steven A., Svenson, Karen L., Braun, Robert E., White, Jaqueline K., Kelsey, Lois, Gao, Xiang, Shiroishi, Toshihiko, Xu, Ying, Seong, Je Kyung, Mammano, Fabio, Tocchini-Valentini, Glauco P., Beaudet, Arthur L., Meehan, Terrence F., Parkinson, Helen, Smedley, Damian, Mallon, Ann-Marie, Wells, Sara E., Grallert, Harald, Wurst, Wolfgang, Marschall, Susan, Fuchs, Helmut, Brown, Steve D. M., Flenniken, Ann M., Nutter, Lauryl M. J., McKerlie, Colin, Herault, Yann, Lloyd, K. C. Kent, Dickinson, Mary E., Gailus-Durner, Valerie, and Hrabe de Angelis, Martin

Published
2022
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8. Identification of genetic elements in metabolism by high-throughput mouse phenotyping

Author

Rozman, Jan, Rathkolb, Birgit, Oestereicher, Manuela A, Schütt, Christine, Ravindranath, Aakash Chavan, Leuchtenberger, Stefanie, Sharma, Sapna, Kistler, Martin, Willershäuser, Monja, Brommage, Robert, Meehan, Terrence F, Mason, Jeremy, Haselimashhadi, Hamed, IMPC Consortium, Hough, Tertius, Mallon, Ann-Marie, Wells, Sara, Santos, Luis, Lelliott, Christopher J, White, Jacqueline K, Sorg, Tania, Champy, Marie-France, Bower, Lynette R, Reynolds, Corey L, Flenniken, Ann M, Murray, Stephen A, Nutter, Lauryl MJ, Svenson, Karen L, West, David, Tocchini-Valentini, Glauco P, Beaudet, Arthur L, Bosch, Fatima, Braun, Robert B, Dobbie, Michael S, Gao, Xiang, Herault, Yann, Moshiri, Ala, Moore, Bret A, Kent Lloyd, KC, McKerlie, Colin, Masuya, Hiroshi, Tanaka, Nobuhiko, Flicek, Paul, Parkinson, Helen E, Sedlacek, Radislav, Seong, Je Kyung, Wang, Chi-Kuang Leo, Moore, Mark, Brown, Steve D, Tschöp, Matthias H, Wurst, Wolfgang, Klingenspor, Martin, Wolf, Eckhard, Beckers, Johannes, Machicao, Fausto, Peter, Andreas, Staiger, Harald, Häring, Hans-Ulrich, Grallert, Harald, Campillos, Monica, Maier, Holger, Fuchs, Helmut, Gailus-Durner, Valerie, Werner, Thomas, and Hrabe de Angelis, Martin

Subjects
Biochemistry and Cell Biology, Bioinformatics and Computational Biology, Genetics, Biological Sciences, Human Genome, Nutrition, 2.1 Biological and endogenous factors, Generic health relevance, Animals, Area Under Curve, Basal Metabolism, Blood Glucose, Body Weight, Diabetes Mellitus, Type 2, Gene Regulatory Networks, Genome-Wide Association Study, High-Throughput Screening Assays, Humans, Metabolic Diseases, Mice, Mice, Knockout, Obesity, Oxygen Consumption, Phenotype, Triglycerides, IMPC Consortium
Abstract

Metabolic diseases are a worldwide problem but the underlying genetic factors and their relevance to metabolic disease remain incompletely understood. Genome-wide research is needed to characterize so-far unannotated mammalian metabolic genes. Here, we generate and analyze metabolic phenotypic data of 2016 knockout mouse strains under the aegis of the International Mouse Phenotyping Consortium (IMPC) and find 974 gene knockouts with strong metabolic phenotypes. 429 of those had no previous link to metabolism and 51 genes remain functionally completely unannotated. We compared human orthologues of these uncharacterized genes in five GWAS consortia and indeed 23 candidate genes are associated with metabolic disease. We further identify common regulatory elements in promoters of candidate genes. As each regulatory element is composed of several transcription factor binding sites, our data reveal an extensive metabolic phenotype-associated network of co-regulated genes. Our systematic mouse phenotype analysis thus paves the way for full functional annotation of the genome.

Published
2018

9. Identification of genes required for eye development by high-throughput screening of mouse knockouts

Author

Moore, Bret A, Leonard, Brian C, Sebbag, Lionel, Edwards, Sydney G, Cooper, Ann, Imai, Denise M, Straiton, Ewan, Santos, Luis, Reilly, Christopher, Griffey, Stephen M, Bower, Lynette, Clary, David, Mason, Jeremy, Roux, Michel J, Meziane, Hamid, Herault, Yann, McKerlie, Colin, Flenniken, Ann M, Nutter, Lauryl MJ, Berberovic, Zorana, Owen, Celeste, Newbigging, Susan, Adissu, Hibret, Eskandarian, Mohammed, Hsu, Chih-Wei, Kalaga, Sowmya, Udensi, Uchechukwu, Asomugha, Chinwe, Bohat, Ritu, Gallegos, Juan J, Seavitt, John R, Heaney, Jason D, Beaudet, Arthur L, Dickinson, Mary E, Justice, Monica J, Philip, Vivek, Kumar, Vivek, Svenson, Karen L, Braun, Robert E, Wells, Sara, Cater, Heather, Stewart, Michelle, Clementson-Mobbs, Sharon, Joynson, Russell, Gao, Xiang, Suzuki, Tomohiro, Wakana, Shigeharu, Smedley, Damian, Seong, JK, Tocchini-Valentini, Glauco, Moore, Mark, Fletcher, Colin, Karp, Natasha, Ramirez-Solis, Ramiro, White, Jacqueline K, de Angelis, Martin Hrabe, Wurst, Wolfgang, Thomasy, Sara M, Flicek, Paul, Parkinson, Helen, Brown, Steve DM, Meehan, Terrence F, Nishina, Patsy M, Murray, Stephen A, Krebs, Mark P, Mallon, Ann-Marie, Lloyd, KC Kent, Murphy, Christopher J, and Moshiri, Ala

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Biomedical and Clinical Sciences, Genetics, Ophthalmology and Optometry, Human Genome, Biotechnology, Eye Disease and Disorders of Vision, Aetiology, 2.1 Biological and endogenous factors, Eye, International Mouse Phenotyping Consortium, Biological sciences, Biomedical and clinical sciences
Abstract

Despite advances in next generation sequencing technologies, determining the genetic basis of ocular disease remains a major challenge due to the limited access and prohibitive cost of human forward genetics. Thus, less than 4,000 genes currently have available phenotype information for any organ system. Here we report the ophthalmic findings from the International Mouse Phenotyping Consortium, a large-scale functional genetic screen with the goal of generating and phenotyping a null mutant for every mouse gene. Of 4364 genes evaluated, 347 were identified to influence ocular phenotypes, 75% of which are entirely novel in ocular pathology. This discovery greatly increases the current number of genes known to contribute to ophthalmic disease, and it is likely that many of the genes will subsequently prove to be important in human ocular development and disease.

Published
2018

10. Publisher Correction: Extensive identification of genes involved in congenital and structural heart disorders and cardiomyopathy

Author

Spielmann, Nadine, Miller, Gregor, Oprea, Tudor I., Hsu, Chih-Wei, Fobo, Gisela, Frishman, Goar, Montrone, Corinna, Haseli Mashhadi, Hamed, Mason, Jeremy, Munoz Fuentes, Violeta, Leuchtenberger, Stefanie, Ruepp, Andreas, Wagner, Matias, Westphal, Dominik S., Wolf, Cordula, Görlach, Agnes, Sanz-Moreno, Adrián, Cho, Yi-Li, Teperino, Raffaele, Brandmaier, Stefan, Sharma, Sapna, Galter, Isabella Rikarda, Östereicher, Manuela A., Zapf, Lilly, Mayer-Kuckuk, Philipp, Rozman, Jan, Teboul, Lydia, Bunton-Stasyshyn, Rosie K. A., Cater, Heather, Stewart, Michelle, Christou, Skevoulla, Westerberg, Henrik, Willett, Amelia M., Wotton, Janine M., Roper, Willson B., Christiansen, Audrey E., Ward, Christopher S., Heaney, Jason D., Reynolds, Corey L., Prochazka, Jan, Bower, Lynette, Clary, David, Selloum, Mohammed, Bou About, Ghina, Wendling, Olivia, Jacobs, Hugues, Leblanc, Sophie, Meziane, Hamid, Sorg, Tania, Audain, Enrique, Gilly, Arthur, Rayner, Nigel W., Hitz, Marc-Phillip, Zeggini, Eleftheria, Wolf, Eckhard, Sedlacek, Radislav, Murray, Steven A., Svenson, Karen L., Braun, Robert E., White, Jaqueline K., Kelsey, Lois, Gao, Xiang, Shiroishi, Toshihiko, Xu, Ying, Seong, Je Kyung, Mammano, Fabio, Tocchini-Valentini, Glauco P., Beaudet, Arthur L., Meehan, Terrence F., Parkinson, Helen, Smedley, Damian, Mallon, Ann-Marie, Wells, Sara E., Grallert, Harald, Wurst, Wolfgang, Marschall, Susan, Fuchs, Helmut, Brown, Steve D. M., Flenniken, Ann M., Nutter, Lauryl M. J., McKerlie, Colin, Herault, Yann, Lloyd, K. C. Kent, Dickinson, Mary E., Gailus-Durner, Valerie, and Hrabe de Angelis, Martin

Published
2022
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11. Correction: Corrigendum: High-throughput discovery of novel developmental phenotypes

Author

Dickinson, Mary E, Flenniken, Ann M, Ji, Xiao, Teboul, Lydia, Wong, Michael D, White, Jacqueline K, Meehan, Terrence F, Weninger, Wolfgang J, Westerberg, Henrik, Adissu, Hibret, Baker, Candice N, Bower, Lynette, Brown, James M, Caddle, L Brianna, Chiani, Francesco, Clary, Dave, Cleak, James, Daly, Mark J, Denegre, James M, Doe, Brendan, Dolan, Mary E, Edie Helmut Fuchs, Sarah M, Gailus-Durner, Valerie, Galli, Antonella, Gambadoro, Alessia, Gallegos, Juan, Guo, Shiying, Horner, Neil R, Hsu, Chih-Wei, Johnson, Sara J, Kalaga, Sowmya, Keith, Lance C, Lanoue, Louise, Lawson, Thomas N, Lek, Monkol, Mark, Manuel, Marschall, Susan, Mason, Jeremy, McElwee, Melissa L, Nutter, Susan Newbigging Lauryl MJ, Peterson, Kevin A, Ramirez-Solis, Ramiro, Rowland, Douglas J, Ryder, Edward, Samocha, Kaitlin E, Seavitt, John R, Selloum, Mohammed, Szoke-Kovacs, Zsombor, Tamura, Masaru, Trainor, Amanda G, Tudose, Ilinca, Wakana, Shigeharu, Warren, Jonathan, Wendling, Olivia, West, David B, Wong, Leeyean, Yoshiki, Atsushi, Wurst, Wolfgang, MacArthur, Daniel G, Tocchini-Valentini, Glauco P, Gao, Xiang, Flicek, Paul, Bradley, Allan, Skarnes, William C, Justice, Monica J, Parkinson, Helen E, Moore, Mark, Wells, Sara, Braun, Robert E, Svenson, Karen L, de Angelis, Martin Hrabe, Herault, Yann, Mohun, Tim, Mallon, Ann-Marie, Henkelman, R Mark, Brown, Steve DM, Adams, David J, Lloyd, KC Kent, McKerlie, Colin, Beaudet, Arthur L, and Murray, Maja Bućan Stephen A

Subjects
International Mouse Phenotyping Consortium, General Science & Technology
Abstract

This corrects the article DOI: 10.1038/nature19356.

Published
2017

12. Disease model discovery from 3,328 gene knockouts by The International Mouse Phenotyping Consortium.

Author

Meehan, Terrence F, Conte, Nathalie, West, David B, Jacobsen, Julius O, Mason, Jeremy, Warren, Jonathan, Chen, Chao-Kung, Tudose, Ilinca, Relac, Mike, Matthews, Peter, Karp, Natasha, Santos, Luis, Fiegel, Tanja, Ring, Natalie, Westerberg, Henrik, Greenaway, Simon, Sneddon, Duncan, Morgan, Hugh, Codner, Gemma F, Stewart, Michelle E, Brown, James, Horner, Neil, International Mouse Phenotyping Consortium, Haendel, Melissa, Washington, Nicole, Mungall, Christopher J, Reynolds, Corey L, Gallegos, Juan, Gailus-Durner, Valerie, Sorg, Tania, Pavlovic, Guillaume, Bower, Lynette R, Moore, Mark, Morse, Iva, Gao, Xiang, Tocchini-Valentini, Glauco P, Obata, Yuichi, Cho, Soo Young, Seong, Je Kyung, Seavitt, John, Beaudet, Arthur L, Dickinson, Mary E, Herault, Yann, Wurst, Wolfgang, de Angelis, Martin Hrabe, Lloyd, KC Kent, Flenniken, Ann M, Nutter, Lauryl MJ, Newbigging, Susan, McKerlie, Colin, Justice, Monica J, Murray, Stephen A, Svenson, Karen L, Braun, Robert E, White, Jacqueline K, Bradley, Allan, Flicek, Paul, Wells, Sara, Skarnes, William C, Adams, David J, Parkinson, Helen, Mallon, Ann-Marie, Brown, Steve DM, and Smedley, Damian

Subjects
International Mouse Phenotyping Consortium, Animals, Mice, Knockout, Humans, Mice, Genetic Diseases, Inborn, Disease Models, Animal, Genetic Predisposition to Disease, Phenotype, Female, Male, Gene Knockout Techniques, Knockout, Genetic Diseases, Inborn, Disease Models, Animal, Developmental Biology, Biological Sciences, Medical and Health Sciences
Abstract

Although next-generation sequencing has revolutionized the ability to associate variants with human diseases, diagnostic rates and development of new therapies are still limited by a lack of knowledge of the functions and pathobiological mechanisms of most genes. To address this challenge, the International Mouse Phenotyping Consortium is creating a genome- and phenome-wide catalog of gene function by characterizing new knockout-mouse strains across diverse biological systems through a broad set of standardized phenotyping tests. All mice will be readily available to the biomedical community. Analyzing the first 3,328 genes identified models for 360 diseases, including the first models, to our knowledge, for type C Bernard-Soulier, Bardet-Biedl-5 and Gordon Holmes syndromes. 90% of our phenotype annotations were novel, providing functional evidence for 1,092 genes and candidates in genetically uncharacterized diseases including arrhythmogenic right ventricular dysplasia 3. Finally, we describe our role in variant functional validation with The 100,000 Genomes Project and others.

Published
2017

13. A large scale hearing loss screen reveals an extensive unexplored genetic landscape for auditory dysfunction

Author

Bowl, Michael R, Simon, Michelle M, Ingham, Neil J, Greenaway, Simon, Santos, Luis, Cater, Heather, Taylor, Sarah, Mason, Jeremy, Kurbatova, Natalja, Pearson, Selina, Bower, Lynette R, Clary, Dave A, Meziane, Hamid, Reilly, Patrick, Minowa, Osamu, Kelsey, Lois, The International Mouse Phenotyping Consortium, Tocchini-Valentini, Glauco P, Gao, Xiang, Bradley, Allan, Skarnes, William C, Moore, Mark, Beaudet, Arthur L, Justice, Monica J, Seavitt, John, Dickinson, Mary E, Wurst, Wolfgang, de Angelis, Martin Hrabe, Herault, Yann, Wakana, Shigeharu, Nutter, Lauryl MJ, Flenniken, Ann M, McKerlie, Colin, Murray, Stephen A, Svenson, Karen L, Braun, Robert E, West, David B, Lloyd, KC Kent, Adams, David J, White, Jacqui, Karp, Natasha, Flicek, Paul, Smedley, Damian, Meehan, Terrence F, Parkinson, Helen E, Teboul, Lydia M, Wells, Sara, Steel, Karen P, Mallon, Ann-Marie, and Brown, Steve DM

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Allied Health and Rehabilitation Science, Clinical Sciences, Health Sciences, Clinical Research, Hearing Loss, Human Genome, Neurosciences, 2.1 Biological and endogenous factors, 1.1 Normal biological development and functioning, Neurological, Ear, Animals, Datasets as Topic, Genetic Testing, Hearing Tests, Mice, Mice, Knockout, Phenotype, Protein Interaction Maps, International Mouse Phenotyping Consortium
Abstract

The developmental and physiological complexity of the auditory system is likely reflected in the underlying set of genes involved in auditory function. In humans, over 150 non-syndromic loci have been identified, and there are more than 400 human genetic syndromes with a hearing loss component. Over 100 non-syndromic hearing loss genes have been identified in mouse and human, but we remain ignorant of the full extent of the genetic landscape involved in auditory dysfunction. As part of the International Mouse Phenotyping Consortium, we undertook a hearing loss screen in a cohort of 3006 mouse knockout strains. In total, we identify 67 candidate hearing loss genes. We detect known hearing loss genes, but the vast majority, 52, of the candidate genes were novel. Our analysis reveals a large and unexplored genetic landscape involved with auditory function.The full extent of the genetic basis for hearing impairment is unknown. Here, as part of the International Mouse Phenotyping Consortium, the authors perform a hearing loss screen in 3006 mouse knockout strains and identify 52 new candidate genes for genetic hearing loss.

Published
2017

14. Prevalence of sexual dimorphism in mammalian phenotypic traits

Author

Karp, Natasha A, Mason, Jeremy, Beaudet, Arthur L, Benjamini, Yoav, Bower, Lynette, Braun, Robert E, Brown, Steve DM, Chesler, Elissa J, Dickinson, Mary E, Flenniken, Ann M, Fuchs, Helmut, Angelis, Martin Hrabe de, Gao, Xiang, Guo, Shiying, Greenaway, Simon, Heller, Ruth, Herault, Yann, Justice, Monica J, Kurbatova, Natalja, Lelliott, Christopher J, Lloyd, KC Kent, Mallon, Ann-Marie, Mank, Judith E, Masuya, Hiroshi, McKerlie, Colin, Meehan, Terrence F, Mott, Richard F, Murray, Stephen A, Parkinson, Helen, Ramirez-Solis, Ramiro, Santos, Luis, Seavitt, John R, Smedley, Damian, Sorg, Tania, Speak, Anneliese O, Steel, Karen P, Svenson, Karen L, Wakana, Shigeharu, West, David, Wells, Sara, Westerberg, Henrik, Yaacoby, Shay, and White, Jacqueline K

Subjects
Biological Psychology, Biological Sciences, Biomedical and Clinical Sciences, Psychology, Genetics, Animals, Body Weight, Female, Genes, Modifier, Genotype, Mammals, Mice, Phenotype, Quantitative Trait, Heritable, Sex Characteristics, International Mouse Phenotyping Consortium
Abstract

The role of sex in biomedical studies has often been overlooked, despite evidence of sexually dimorphic effects in some biological studies. Here, we used high-throughput phenotype data from 14,250 wildtype and 40,192 mutant mice (representing 2,186 knockout lines), analysed for up to 234 traits, and found a large proportion of mammalian traits both in wildtype and mutants are influenced by sex. This result has implications for interpreting disease phenotypes in animal models and humans.

Published
2017

15. CNVs cause autosomal recessive genetic diseases with or without involvement of SNV/indels

Author

Yuan, Bo, Wang, Lei, Liu, Pengfei, Shaw, Chad, Dai, Hongzheng, Cooper, Lance, Zhu, Wenmiao, Anderson, Stephanie A., Meng, Linyan, Wang, Xia, Wang, Yue, Xia, Fan, Xiao, Rui, Braxton, Alicia, Peacock, Sandra, Schmitt, Eric, Ward, Patricia A., Vetrini, Francesco, He, Weimin, Chiang, Theodore, Muzny, Donna, Gibbs, Richard A., Beaudet, Arthur L., Breman, Amy M., Smith, Janice, Cheung, Sau Wai, Bacino, Carlos A., Eng, Christine M., Yang, Yaping, Lupski, James R., and Bi, Weimin

Published
2020
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16. Noninvasive single‐cell‐based prenatal genetic testing: A proof of concept clinical study

Author

Bellair, Michelle, primary, Amaral, Elisabete, additional, Ouren, Mason, additional, Roark, Cameron, additional, Kim, Jaeweon, additional, O'Connor, April, additional, Soriano, Adrianna, additional, Schindler, Margaret L., additional, Wapner, Ronald J., additional, Stone, Joanne L., additional, Tavella, Nicola, additional, Merriam, Audrey, additional, Perley, Lauren, additional, Breman, Amy M., additional, and Beaudet, Arthur L., additional

Published
2024
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17. High-throughput discovery of novel developmental phenotypes.

Author

Dickinson, Mary E, Flenniken, Ann M, Ji, Xiao, Teboul, Lydia, Wong, Michael D, White, Jacqueline K, Meehan, Terrence F, Weninger, Wolfgang J, Westerberg, Henrik, Adissu, Hibret, Baker, Candice N, Bower, Lynette, Brown, James M, Caddle, L Brianna, Chiani, Francesco, Clary, Dave, Cleak, James, Daly, Mark J, Denegre, James M, Doe, Brendan, Dolan, Mary E, Edie, Sarah M, Fuchs, Helmut, Gailus-Durner, Valerie, Galli, Antonella, Gambadoro, Alessia, Gallegos, Juan, Guo, Shiying, Horner, Neil R, Hsu, Chih-Wei, Johnson, Sara J, Kalaga, Sowmya, Keith, Lance C, Lanoue, Louise, Lawson, Thomas N, Lek, Monkol, Mark, Manuel, Marschall, Susan, Mason, Jeremy, McElwee, Melissa L, Newbigging, Susan, Nutter, Lauryl MJ, Peterson, Kevin A, Ramirez-Solis, Ramiro, Rowland, Douglas J, Ryder, Edward, Samocha, Kaitlin E, Seavitt, John R, Selloum, Mohammed, Szoke-Kovacs, Zsombor, Tamura, Masaru, Trainor, Amanda G, Tudose, Ilinca, Wakana, Shigeharu, Warren, Jonathan, Wendling, Olivia, West, David B, Wong, Leeyean, Yoshiki, Atsushi, International Mouse Phenotyping Consortium, Jackson Laboratory, Infrastructure Nationale PHENOMIN, Institut Clinique de la Souris (ICS), Charles River Laboratories, MRC Harwell, Toronto Centre for Phenogenomics, Wellcome Trust Sanger Institute, RIKEN BioResource Center, MacArthur, Daniel G, Tocchini-Valentini, Glauco P, Gao, Xiang, Flicek, Paul, Bradley, Allan, Skarnes, William C, Justice, Monica J, Parkinson, Helen E, Moore, Mark, Wells, Sara, Braun, Robert E, Svenson, Karen L, de Angelis, Martin Hrabe, Herault, Yann, Mohun, Tim, Mallon, Ann-Marie, Henkelman, R Mark, Brown, Steve DM, Adams, David J, Lloyd, KC Kent, McKerlie, Colin, Beaudet, Arthur L, Bućan, Maja, and Murray, Stephen A

Subjects
International Mouse Phenotyping Consortium, Jackson Laboratory, Infrastructure Nationale PHENOMIN, Institut Clinique de la Souris, Charles River Laboratories, MRC Harwell, Toronto Centre for Phenogenomics, Wellcome Trust Sanger Institute, RIKEN BioResource Center, Animals, Mice, Inbred C57BL, Mice, Knockout, Humans, Mice, Disease, Imaging, Three-Dimensional, Conserved Sequence, Sequence Homology, Phenotype, Penetrance, Mutation, Polymorphism, Single Nucleotide, Genes, Essential, Genes, Lethal, Embryo, Mammalian, Genome-Wide Association Study, High-Throughput Screening Assays, Biotechnology, Human Genome, Pediatric, Congenital Structural Anomalies, Genetics, 2.1 Biological and endogenous factors, General Science & Technology
Abstract

Approximately one-third of all mammalian genes are essential for life. Phenotypes resulting from knockouts of these genes in mice have provided tremendous insight into gene function and congenital disorders. As part of the International Mouse Phenotyping Consortium effort to generate and phenotypically characterize 5,000 knockout mouse lines, here we identify 410 lethal genes during the production of the first 1,751 unique gene knockouts. Using a standardized phenotyping platform that incorporates high-resolution 3D imaging, we identify phenotypes at multiple time points for previously uncharacterized genes and additional phenotypes for genes with previously reported mutant phenotypes. Unexpectedly, our analysis reveals that incomplete penetrance and variable expressivity are common even on a defined genetic background. In addition, we show that human disease genes are enriched for essential genes, thus providing a dataset that facilitates the prioritization and validation of mutations identified in clinical sequencing efforts.

Published
2016

18. Insights into Autism Spectrum Disorder Genomic Architecture and Biology from 71 Risk Loci

Author

Sanders, Stephan J, He, Xin, Willsey, A Jeremy, Ercan-Sencicek, A Gulhan, Samocha, Kaitlin E, Cicek, A Ercument, Murtha, Michael T, Bal, Vanessa H, Bishop, Somer L, Dong, Shan, Goldberg, Arthur P, Jinlu, Cai, Keaney, John F, Klei, Lambertus, Mandell, Jeffrey D, Moreno-De-Luca, Daniel, Poultney, Christopher S, Robinson, Elise B, Smith, Louw, Solli-Nowlan, Tor, Su, Mack Y, Teran, Nicole A, Walker, Michael F, Werling, Donna M, Beaudet, Arthur L, Cantor, Rita M, Fombonne, Eric, Geschwind, Daniel H, Grice, Dorothy E, Lord, Catherine, Lowe, Jennifer K, Mane, Shrikant M, Martin, Donna M, Morrow, Eric M, Talkowski, Michael E, Sutcliffe, James S, Walsh, Christopher A, Yu, Timothy W, Consortium, Autism Sequencing, Ledbetter, David H, Martin, Christa Lese, Cook, Edwin H, Buxbaum, Joseph D, Daly, Mark J, Devlin, Bernie, Roeder, Kathryn, and State, Matthew W

Subjects
Biological Psychology, Biomedical and Clinical Sciences, Neurosciences, Psychology, Pediatric, Prevention, Biotechnology, Brain Disorders, Genetics, Mental Health, Intellectual and Developmental Disabilities (IDD), Human Genome, Autism, 2.1 Biological and endogenous factors, Aetiology, Mental health, Autism Spectrum Disorder, Female, Genetic Loci, Genetic Variation, Humans, Male, Protein Interaction Maps, Autism Sequencing Consortium, Cognitive Sciences, Neurology & Neurosurgery, Biological psychology
Abstract

Analysis of de novo CNVs (dnCNVs) from the full Simons Simplex Collection (SSC) (N = 2,591 families) replicates prior findings of strong association with autism spectrum disorders (ASDs) and confirms six risk loci (1q21.1, 3q29, 7q11.23, 16p11.2, 15q11.2-13, and 22q11.2). The addition of published CNV data from the Autism Genome Project (AGP) and exome sequencing data from the SSC and the Autism Sequencing Consortium (ASC) shows that genes within small de novo deletions, but not within large dnCNVs, significantly overlap the high-effect risk genes identified by sequencing. Alternatively, large dnCNVs are found likely to contain multiple modest-effect risk genes. Overall, we find strong evidence that de novo mutations are associated with ASD apart from the risk for intellectual disability. Extending the transmission and de novo association test (TADA) to include small de novo deletions reveals 71 ASD risk loci, including 6 CNV regions (noted above) and 65 risk genes (FDR ≤ 0.1).

Published
2015

19. A genome-wide association study of autism using the Simons Simplex Collection: Does reducing phenotypic heterogeneity in autism increase genetic homogeneity?

Author

Chaste, Pauline, Klei, Lambertus, Sanders, Stephan J, Hus, Vanessa, Murtha, Michael T, Lowe, Jennifer K, Willsey, A Jeremy, Moreno-De-Luca, Daniel, Yu, Timothy W, Fombonne, Eric, Geschwind, Daniel, Grice, Dorothy E, Ledbetter, David H, Mane, Shrikant M, Martin, Donna M, Morrow, Eric M, Walsh, Christopher A, Sutcliffe, James S, Lese Martin, Christa, Beaudet, Arthur L, Lord, Catherine, State, Matthew W, Cook, Edwin H, and Devlin, Bernie

Subjects
Humans, Genetic Predisposition to Disease, Family, Autistic Disorder, Phenotype, Polymorphism, Single Nucleotide, Female, Male, Genetic Variation, Genome-Wide Association Study, Autism Spectrum Disorder, Autism, GWAS, Genetics, Heterogeneity, Power, Genetic Testing, Pediatric, Intellectual and Developmental Disabilities (IDD), Mental Health, Human Genome, Brain Disorders, Biological Sciences, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry
Abstract

BackgroundPhenotypic heterogeneity in autism has long been conjectured to be a major hindrance to the discovery of genetic risk factors, leading to numerous attempts to stratify children based on phenotype to increase power of discovery studies. This approach, however, is based on the hypothesis that phenotypic heterogeneity closely maps to genetic variation, which has not been tested. Our study examines the impact of subphenotyping of a well-characterized autism spectrum disorder (ASD) sample on genetic homogeneity and the ability to discover common genetic variants conferring liability to ASD.MethodsGenome-wide genotypic data of 2576 families from the Simons Simplex Collection were analyzed in the overall sample and phenotypic subgroups defined on the basis of diagnosis, IQ, and symptom profiles. We conducted a family-based association study, as well as estimating heritability and evaluating allele scores for each phenotypic subgroup.ResultsAssociation analyses revealed no genome-wide significant association signal. Subphenotyping did not increase power substantially. Moreover, allele scores built from the most associated single nucleotide polymorphisms, based on the odds ratio in the full sample, predicted case status in subsets of the sample equally well and heritability estimates were very similar for all subgroups.ConclusionsIn genome-wide association analysis of the Simons Simplex Collection sample, reducing phenotypic heterogeneity had at most a modest impact on genetic homogeneity. Our results are based on a relatively small sample, one with greater homogeneity than the entire population; if they apply more broadly, they imply that analysis of subphenotypes is not a productive path forward for discovering genetic risk variants in ASD.

Published
2015

20. Modest impact on risk for autism spectrum disorder of rare copy number variants at 15q11.2, specifically breakpoints 1 to 2.

Author

Chaste, Pauline, Sanders, Stephan J, Mohan, Kommu N, Klei, Lambertus, Song, Youeun, Murtha, Michael T, Hus, Vanessa, Lowe, Jennifer K, Willsey, A Jeremy, Moreno-De-Luca, Daniel, Yu, Timothy W, Fombonne, Eric, Geschwind, Daniel, Grice, Dorothy E, Ledbetter, David H, Lord, Catherine, Mane, Shrikant M, Martin, Donna M, Morrow, Eric M, Walsh, Christopher A, Sutcliffe, James S, State, Matthew W, Martin, Christa Lese, Devlin, Bernie, Beaudet, Arthur L, Cook, Edwin H, and Kim, Soo-Jeong

Subjects
Chromosomes, Human, Pair 15, Humans, Chromosome Deletion, Genetic Predisposition to Disease, Child Development Disorders, Pervasive, Adult, Child, Female, Male, DNA Copy Number Variations, 15q11.2, autism, deletion, duplication, penetrance, Developmental & Child Psychology, Clinical Sciences, Neurosciences, Psychology
Abstract

The proximal region of chromosome 15 is one of the genomic hotspots for copy number variants (CNVs). Among the rearrangements observed in this region, CNVs from the interval between the common breakpoints 1 and 2 (BP1 and BP2) have been reported cosegregating with autism spectrum disorder (ASD). Although evidence supporting an association between BP1-BP2 CNVs and autism accumulates, the magnitude of the effect of BP1-BP2 CNVs remains elusive, posing a great challenge to recurrence-risk counseling. To gain further insight into their pathogenicity for ASD, we estimated the penetrance of the BP1-BP2 CNVs for ASD as well as their effects on ASD-related phenotypes in a well-characterized ASD sample (n = 2525 families). Transmission disequilibrium test revealed significant preferential transmission only for the duplicated chromosome in probands (20T:9NT). The penetrance of the BP1-BP2 CNVs for ASD was low, conferring additional risks of 0.3% (deletion) and 0.8% (duplication). Stepwise regression analyses suggest a greater effect of the CNVs on ASD-related phenotype in males and when maternally inherited. Taken together, the results are consistent with BP1-BP2 CNVs as risk factors for autism. However, their effect is modest, more akin to that seen for common variants. To be consistent with the current American College of Medical Genetics guidelines for interpretation of postnatal CNV, the BP1-BP2 deletion and duplication CNVs would probably best be classified as variants of uncertain significance (VOUS): they appear to have an impact on risk, but one so modest that these CNVs do not merit pathogenic status.

Published
2014

22. Quantifying the Effects of 16p11.2 Copy Number Variants on Brain Structure: A Multisite Genetic-First Study

Author

Addor, Marie-Claude, Andrieux, Joris, Arveiler, Benoît, Baujat, Geneviève, Sloan-Béna, Frédérique, Belfiore, Marco, Bonneau, Dominique, Bouquillon, Sonia, Boute, Odile, Brusco, Alfredo, Busa, Tiffany, Caberg, Jean-Hubert, Campion, Dominique, Colombert, Vanessa, Cordier, Marie-Pierre, David, Albert, Debray, François-Guillaume, Delrue, Marie-Ange, Doco-Fenzy, Martine, Dunkhase-Heinl, Ulrike, Edery, Patrick, Fagerberg, Christina, Faivre, Laurence, Forzano, Francesca, Genevieve, David, Gérard, Marion, Giachino, Daniela, Guichet, Agnès, Guillin, Olivier, Héron, Delphine, Isidor, Bertrand, Jacquette, Aurélia, Jaillard, Sylvie, Journel, Hubert, Keren, Boris, Lacombe, Didier, Lebon, Sébastien, Le Caignec, Cédric, Lemaître, Marie-Pierre, Lespinasse, James, Mathieu-Dramart, Michèle, Mercier, Sandra, Mignot, Cyril, Missirian, Chantal, Petit, Florence, Pilekær Sørensen, Kristina, Pinson, Lucile, Plessis, Ghislaine, Prieur, Fabienne, Rooryck-Thambo, Caroline, Rossi, Massimiliano, Sanlaville, Damien, Schlott Kristiansen, Britta, Schluth-Bolard, Caroline, Till, Marianne, Van Haelst, Mieke, Van Maldergem, Lionel, Alupay, Hanalore, Aaronson, Benjamin, Ackerman, Sean, Ankenman, Katy, Anwar, Ayesha, Atwell, Constance, Bowe, Alexandra, Beaudet, Arthur L., Benedetti, Marta, Berg, Jessica, Berman, Jeffrey, Berry, Leandra N., Bibb, Audrey L., Blaskey, Lisa, Brennan, Jonathan, Brewton, Christie M., Buckner, Randy, Bukshpun, Polina, Burko, Jordan, Cali, Phil, Cerban, Bettina, Chang, Yishin, Cheong, Maxwell, Chow, Vivian, Chu, Zili, Chudnovskaya, Darina, Cornew, Lauren, Dale, Corby, Dell, John, Dempsey, Allison G., Deschamps, Trent, Earl, Rachel, Edgar, James, Elgin, Jenna, Olson, Jennifer Endre, Evans, Yolanda L., Findlay, Anne, Fischbach, Gerald D., Fisk, Charlie, Fregeau, Brieana, Gaetz, Bill, Gaetz, Leah, Garza, Silvia, Gerdts, Jennifer, Glenn, Orit, Gobuty, Sarah E., Golembski, Rachel, Greenup, Marion, Heiken, Kory, Hines, Katherine, Hinkley, Leighton, Jackson, Frank I., Jenkins, Julian, III, Jeremy, Rita J., Johnson, Kelly, Kanne, Stephen M., Kessler, Sudha, Khan, Sarah Y., Ku, Matthew, Kuschner, Emily, Laakman, Anna L., Lam, Peter, Lasala, Morgan W., Lee, Hana, LaGuerre, Kevin, Levy, Susan, Cavanagh, Alyss Lian, Llorens, Ashlie V., Campe, Katherine Loftus, Luks, Tracy L., Marco, Elysa J., Martin, Stephen, Martin, Alastair J., Marzano, Gabriela, Masson, Christina, McGovern, Kathleen E., McNally Keehn, Rebecca, Miller, David T., Miller, Fiona K., Moss, Timothy J., Murray, Rebecca, Nagarajan, Srikantan S., Nowell, Kerri P., Owen, Julia, Paal, Andrea M., Packer, Alan, Page, Patricia Z., Paul, Brianna M., Peters, Alana, Peterson, Danica, Poduri, Annapurna, Pojman, Nicholas J., Porche, Ken, Proud, Monica B., Qasmieh, Saba, Ramocki, Melissa B., Reilly, Beau, Roberts, Timothy P.L., Shaw, Dennis, Sinha, Tuhin, Smith-Packard, Bethanny, Gallagher, Anne Snow, Swarnakar, Vivek, Thieu, Tony, Triantafallou, Christina, Vaughan, Roger, Wakahiro, Mari, Wallace, Arianne, Ward, Tracey, Wenegrat, Julia, Wolken, Anne, Martin-Brevet, Sandra, Rodríguez-Herreros, Borja, Nielsen, Jared A., Moreau, Clara, Modenato, Claudia, Maillard, Anne M., Pain, Aurélie, Richetin, Sonia, Jønch, Aia E., Qureshi, Abid Y., Zürcher, Nicole R., Conus, Philippe, Chung, Wendy K., Sherr, Elliott H., Spiro, John E., Kherif, Ferath, Beckmann, Jacques S., Hadjikhani, Nouchine, Reymond, Alexandre, Buckner, Randy L., Draganski, Bogdan, and Jacquemont, Sébastien

Published
2018
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24. Double‐blind therapeutic trial in Angelman syndrome using betaine and folic acid

Author

Peters, Sarika U, Bird, Lynne M, Kimonis, Virginia, Glaze, Daniel G, Shinawi, Lina M, Bichell, Terry Jo, Barbieri‐Welge, Rene, Nespeca, Mark, Anselm, Irina, Waisbren, Susan, Sanborn, Erica, Sun, Qin, O'Brien, William E, Beaudet, Arthur L, and Bacino, Carlos A

Subjects
Nutrition, Pediatric, Clinical Research, Rare Diseases, Brain Disorders, Biotechnology, Intellectual and Developmental Disabilities (IDD), Neurosciences, Clinical Trials and Supportive Activities, Human Genome, Genetics, Adolescent, Angelman Syndrome, Betaine, Child, Child, Preschool, Chromosomes, Human, Pair 15, DNA Methylation, Double-Blind Method, Drug Combinations, Female, Folic Acid, Genomic Imprinting, Humans, Infant, Lipotropic Agents, Male, Phenotype, Placebos, Ubiquitin-Protein Ligases, Vitamin B Complex, Angelman syndrome, methylation, high dose folic acid, betaine, imprinting disorders, treatment, promotion of methylation, Clinical Sciences
Abstract

Angelman syndrome (AS) is caused by reduced or absent expression of the maternally inherited ubiquitin protein ligase 3A gene (UBE3A), which maps to chromosome 15q11-q13. UBE3A is subject to genomic imprinting in neurons in most regions of the brain. Expression of UBE3A from the maternal chromosome is essential to prevent AS, because the paternally inherited gene is not expressed, probably mediated by antisense UBE3A RNA. We hypothesized that increasing methylation might reduce expression of the antisense UBE3A RNA, thereby increasing UBE3A expression from the paternal gene and ameliorating the clinical phenotype. We conducted a trial using two dietary supplements, betaine and folic acid to promote global levels of methylation and attempt to activate the paternally inherited UBE3A gene. We performed a number of investigations at regular intervals including general clinical and developmental evaluations, biochemical determinations on blood and urine, and electroencephalographic studies. We report herein the data on 48 children with AS who were enrolled in a double-blind placebo-controlled protocol using betaine and folic acid for 1 year. There were no statistically significant changes between treated and untreated children; however, in a small subset of patients we observed some positive trends.

Published
2010

25. Validation study for noninvasive single-cell-based prenatal genetic testing

Author

Bellair, Michelle, primary, Amaral, Elisabete, additional, Ouren, Mason, additional, Roark, Cameron, additional, Kim, Jaeweon, additional, O'Connor, April, additional, Soriano, Adrianna, additional, Schindler, Margaret L, additional, Wapner, Ronald J, additional, Stone, joanne L, additional, Tavella, Nicola, additional, Merriam, Audrey, additional, Breman, Amy, additional, and Beaudet, Arthur L, additional

Published
2023
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26. Identification of novel deletions of 15q11q13 in Angelman syndrome by array-CGH: molecular characterization and genotype–phenotype correlations

Author

Sahoo, Trilochan, Bacino, Carlos A, German, Jennifer R, Shaw, Chad A, Bird, Lynne M, Kimonis, Virginia, Anselm, Irinia, Waisbren, Susan, Beaudet, Arthur L, and Peters, Sarika U

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Rare Diseases, Clinical Research, Brain Disorders, Pediatric, Intellectual and Developmental Disabilities (IDD), Biotechnology, Angelman Syndrome, Child, Preschool, Chromosome Breakage, Chromosome Deletion, Chromosomes, Human, Pair 15, Female, Genotype, Humans, Infant, Male, Oligonucleotide Array Sequence Analysis, Phenotype, Psychological Tests, Angelman syndrome, autism, chromosome 15 deletions, comparative genomic hybridization, Clinical Sciences, Genetics & Heredity, Clinical sciences
Abstract

Angelman syndrome (AS) is a neurodevelopmental disorder characterized by mental retardation, absent speech, ataxia, and a happy disposition. Deletions of the 15q11q13 region are found in approximately 70% of AS patients. The deletions are sub-classified into class I and class II based on their sizes of approximately 6.8 and approximately 6.0, respectively, with two different proximal breakpoints and a common distal breakpoint. Utilizing a chromosome 15-specific comparative genomic hybridization genomic microarray (array-CGH), we have identified, determined the deletion sizes, and mapped the breakpoints in a cohort of 44 cases, to relate those breakpoints to the genomic architecture and derive more precise genotype-phenotype correlations. Interestingly four patients of the 44 studied (9.1%) had novel and unusually large deletions, and are reported here. This is the first report of very large deletions of 15q11q13 resulting in AS; the largest deletion being >10.6 Mb. These novel deletions involve three different distal breakpoints, two of which have been earlier shown to be involved in the generation of isodicentric 15q chromosomes (idic15). Additionally, precise determination of the deletion breakpoints reveals the presence of directly oriented low-copy repeats (LCRs) flanking the recurrent and novel breakpoints. The LCRs are adequate in size, orientation, and homology to enable abnormal recombination events leading to deletions and duplications. This genomic organization provides evidence for a common mechanism for the generation of both common and rare deletion types. Larger deletions result in a loss of several genes outside the common Angelman syndrome-Prader-Willi syndrome (AS-PWS) critical interval, and a more severe phenotype.

Published
2007

37. Contributors

Author

Allen, Stephanie, primary, Beaudet, Arthur L., additional, Charnock-Jones, D. Stephen, additional, Cheng, S.H., additional, Clarke, Angus, additional, Clarke, Caroline S., additional, Clausen, Frederik B., additional, de Wert, Guido, additional, Deans, Zandra C., additional, Dennis Lo, Y.M., additional, Dondorp, Wybo, additional, Fisher, Jane, additional, Gaccioli, Francesca, additional, Gerrish, Amy, additional, Harasim, T., additional, Haselmann, Verena, additional, Hastings, Ros J., additional, Henneman, Lidewij, additional, Hudson, Emma, additional, Kilby, Mark D., additional, Mackie, Fiona L., additional, Morris, Stephen, additional, Muzzey, Dale, additional, Neofytou, Maria, additional, Oepkes, D., additional, Pandya, Pranav, additional, Pertile, Mark D., additional, Quinlan-Jones, Elizabeth, additional, Sacco, Adalina, additional, Schenk, Peter W., additional, Smith, Gordon C.S., additional, van der Schoot, C. Ellen, additional, van El, Carla, additional, Vermeesch, Joris Robert, additional, Verweij, E.J.T., additional, Vossaert, Liesbeth, additional, Wagner, A., additional, Winkelhorst, Dian, additional, Wolstenholme, Nicola, additional, and Young, Elizabeth, additional

Published
2018
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38. Copy number variant and runs of homozygosity detection by microarrays enabled more precise molecular diagnoses in 11,020 clinical exome cases

Author

Dharmadhikari, Avinash V., Ghosh, Rajarshi, Yuan, Bo, Liu, Pengfei, Dai, Hongzheng, Al Masri, Sami, Scull, Jennifer, Posey, Jennifer E., Jiang, Allen H., He, Weimin, Vetrini, Francesco, Braxton, Alicia A., Ward, Patricia, Chiang, Theodore, Qu, Chunjing, Gu, Shen, Shaw, Chad A., Smith, Janice L., Lalani, Seema, Stankiewicz, Pawel, Cheung, Sau-Wai, Bacino, Carlos A., Patel, Ankita, Breman, Amy M., Wang, Xia, Meng, Linyan, Xiao, Rui, Xia, Fan, Muzny, Donna, Gibbs, Richard A., Beaudet, Arthur L., Eng, Christine M., Lupski, James R., Yang, Yaping, and Bi, Weimin

Published
2019
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39. Antisense oligonucleotide therapy rescues disturbed brain rhythms and sleep in juvenile and adult mouse models of Angelman syndrome

Author

Lee, Dongwon, primary, Chen, Wu, primary, Kaku, Heet Naresh, primary, Zhuo, Xinming, primary, Chao, Eugene S, additional, Soriano, Armand, additional, Kuncheria, Allen, additional, Flores, Stephanie, additional, Kim, Joo Hyun, additional, Rivera, Armando, additional, Rigo, Frank, additional, Jafar-nejad, Paymaan, additional, Beaudet, Arthur L, additional, Caudill, Matthew S, additional, and Xue, Mingshan, additional

Published
2023
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40. Author response: Antisense oligonucleotide therapy rescues disturbed brain rhythms and sleep in juvenile and adult mouse models of Angelman syndrome

Author

Lee, Dongwon, primary, Chen, Wu, primary, Kaku, Heet Naresh, primary, Zhuo, Xinming, primary, Chao, Eugene S, additional, Soriano, Armand, additional, Kuncheria, Allen, additional, Flores, Stephanie, additional, Kim, Joo Hyun, additional, Rivera, Armando, additional, Rigo, Frank, additional, Jafar-nejad, Paymaan, additional, Beaudet, Arthur L, additional, Caudill, Matthew S, additional, and Xue, Mingshan, additional

Published
2022
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42. Supplement to: Resolution of disease phenotypes resulting from multilocus genomic variation.

Author

Posey, Jennifer E., Harel, Tamar, Liu, Pengfei, Rosenfeld, Jill A., James, Regis A., Coban Akdemir, Zeynep H., Walkiewicz, Magdalena, Bi, Weimin, Xiao, Rui, Ding, Yan, Xia, Fan, Beaudet, Arthur L., Muzny, Donna M., Gibbs, Richard A., Boerwinkle, Eric, Eng, Christine M., Sutton, Reid V., Shaw, Chad A., Plon, Sharon E., Yang, Yaping, and Lupski, James R.

Published
2017

43. The Utility of Chromosomal Microarray Analysis in Developmental and Behavioral Pediatrics

Author

Beaudet, Arthur L.

Abstract

Chromosomal microarray analysis (CMA) has emerged as a powerful new tool to identify genomic abnormalities associated with a wide range of developmental disabilities including congenital malformations, cognitive impairment, and behavioral abnormalities. CMA includes array comparative genomic hybridization (CGH) and single nucleotide polymorphism (SNP) arrays, both of which are useful for detection of genomic copy number variants (CNV) such as microdeletions and microduplications. The frequency of disease-causing CNVs is highest (20%-25%) in children with moderate to severe intellectual disability accompanied by malformations or dysmorphic features. Disease-causing CNVs are found in 5%-10% of cases of autism, being more frequent in severe phenotypes. CMA has replaced Giemsa-banded karyotype as the first-tier test for genetic evaluation of children with developmental and behavioral disabilities. (Contains 3 tables and 4 figures.)

Published
2013
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45. Autism Spectrum Disorder, Developmental and Psychiatric Features in 16p11.2 Duplication

Author

Green Snyder, LeeAnne, D’Angelo, Debra, Chen, Qixuan, Bernier, Raphael, Goin-Kochel, Robin P., Wallace, Arianne Stevens, Gerdts, Jennifer, Kanne, Stephen, Berry, Leandra, Blaskey, Lisa, Kuschner, Emily, Roberts, Timothy, Sherr, Elliot, Martin, Christa L., Ledbetter, David H., Spiro, John E., Chung, Wendy K., Hanson, Ellen, Alupay, Hanalore, Aaronson, Benjamin, Ackerman, Sean, Ankenman, Katy, Anwar, Ayesha, Atwell, Constance, Bowe, Alexandra, Beaudet, Arthur L., Benedetti, Marta, Berg, Jessica, Berman, Jeffrey, Berry, Leandra N., Bibb, Audrey L., Blaskey, Lisa, Brennan, Jonathan, Brewton, Christie M., Buckner, Randy, Bukshpun, Polina, Burko, Jordan, Cali, Phil, Cerban, Bettina, Chang, Yishin, Cheong, Maxwell, Chow, Vivian, Chu, Zili, Chudnovskaya, Darina, Cornew, Lauren, Dale, Corby, Dell, John, Dempsey, Allison G., Deschamps, Trent, Earl, Rachel, Edgar, James, Elgin, Jenna, Olson, Jennifer Endre, Evans, Yolanda L., Findlay, Anne, Fischbach, Gerald D., Fisk, Charlie, Fregeau, Brieana, Gaetz, Bill, Gaetz, Leah, Garza, Silvia, Gerdts, Jennifer, Glenn, Orit, Gobuty, Sarah E., Golembski, Rachel, Greenup, Marion, Heiken, Kory, Hines, Katherine, Hinkley, Leighton, Jackson, Frank I., Jenkins, III, Julian, Jeremy, Rita J., Johnson, Kelly, Kanne, Stephen M., Kessler, Sudha, Khan, Sarah Y., Ku, Matthew, Kuschner, Emily, Laakman, Anna L., Lam, Peter, Lasala, Morgan W., Lee, Hana, LeGuerre, Kevin, Levy, Susan, Cavanagh, Alyss Lian, Llorens, Ashlie V., Campe, Katherine Loftus, Luks, Tracy L., Marco, Elysa J., Martin, Stephen, Martin, Alastair J., Marzano, Gabriela, Masson, Christina, McGovern, Kathleen E., Keehn, Rebecca McNally, Miller, David T., Miller, Fiona K., Moss, Timothy J., Murray, Rebecca, Nagarajan, Srikantan S., Nowell, Kerri P., Owen, Julia, Paal, Andrea M., Packer, Alan, Page, Patricia Z., Paul, Brianna M., Peters, Alana, Peterson, Danica, Poduri, Annapurna, Pojman, Nicholas J., Porche, Ken, Proud, Monica B., Qasmieh, Saba, Ramocki, Melissa B., Reilly, Beau, Roberts, Timothy P. L., Shaw, Dennis, Sinha, Tuhin, Smith-Packard, Bethanny, Gallagher, Anne Snow, Swarnakar, Vivek, Thieu, Tony, Triantafallou, Christina, Vaughan, Roger, Visyak, Nicole, Wakahiro, Mari, Wallace, Arianne, Ward, Tracey, Wenegrat, Julia, Wolken, Anne, and on behalf of the Simons VIP consortium

Published
2016
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47. Antisense oligonucleotide therapy rescues disturbed brain rhythms and sleep in juvenile and adult mouse models of Angelman syndrome

Author

Lee, Dongwon, primary, Chen, Wu, additional, Kaku, Heet Naresh, additional, Zhuo, Xinming, additional, Chao, Eugene S., additional, Soriano, Armand, additional, Kuncheria, Allen, additional, Flores, Stephanie, additional, Kim, Joo Hyun, additional, Rigo, Frank, additional, Jafar-nejad, Paymaan, additional, Beaudet, Arthur L., additional, Caudill, Matthew S., additional, and Xue, Mingshan, additional

Published
2022
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49. Corrigendum: High-throughput discovery of novel developmental phenotypes

Author

Dickinson, Mary E., Flenniken, Ann M., Ji, Xiao, Teboul, Lydia, Wong, Michael D., White, Jacqueline K., Meehan, Terrence F., Weninger, Wolfgang J., Westerberg, Henrik, Adissu, Hibret, Baker, Candice N., Bower, Lynette, Brown, James M., Caddle, Brianna L., Chiani, Francesco, Clary, Dave, Cleak, James, Daly, Mark J., Denegre, James M., Doe, Brendan, Dolan, Mary E., Helmut Fuchs, Sarah M. Edie, Gailus-Durner, Valerie, Galli, Antonella, Gambadoro, Alessia, Gallegos, Juan, Guo, Shiying, Horner, Neil R., Hsu, Chih-Wei, Johnson, Sara J., Kalaga, Sowmya, Keith, Lance C., Lanoue, Louise, Lawson, Thomas N., Lek, Monkol, Mark, Manuel, Marschall, Susan, Mason, Jeremy, McElwee, Melissa L., Nutter, Susan Newbigging Lauryl M. J., Peterson, Kevin A., Ramirez-Solis, Ramiro, Rowland, Douglas J., Ryder, Edward, Samocha, Kaitlin E., Seavitt, John R., Selloum, Mohammed, Szoke-Kovacs, Zsombor, Tamura, Masaru, Trainor, Amanda G., Tudose, Ilinca, Wakana, Shigeharu, Warren, Jonathan, Wendling, Olivia, West, David B., Wong, Leeyean, Yoshiki, Atsushi, Wurst, Wolfgang, MacArthur, Daniel G., Tocchini-Valentini, Glauco P., Gao, Xiang, Flicek, Paul, Bradley, Allan, Skarnes, William C., Justice, Monica J., Parkinson, Helen E., Moore, Mark, Wells, Sara, Braun, Robert E., Svenson, Karen L., de Angelis, Martin Hrabe, Herault, Yann, Mohun, Tim, Mallon, Ann-Marie, Henkelman, Mark R., Brown, Steve D. M., Adams, David J., Lloyd, Kent K.C., McKerlie, Colin, Beaudet, Arthur L., and Murray, Maja Bućan Stephen A.

Published
2017
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