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Gilles Maussion, Cristiana Cruceanu, Jill A Rosenfeld, Scott C Bell, Fabrice Jollant, Jin Szatkiewicz, Ryan L Collins, Carrie Hanscom, Ilaria Kolobova, Nicolas Menjot de Champfleur, Ian Blumenthal, Colby Chiang, Vanessa Ota, Christina Hultman, Colm O'Dushlaine, Steve McCarroll, Martin Alda, Sebastien Jacquemont, Zehra Ordulu, Christian R Marshall, Melissa T Carter, Lisa G Shaffer, Pamela Sklar, Santhosh Girirajan, Cynthia C Morton, James F Gusella, Gustavo Turecki, Dimitri J Stavropoulos, Patrick F Sullivan, Stephen W Scherer, Michael E Talkowski, Carl Ernst
We performed whole-genome sequencing on an individual from a family with variable psychiatric phenotypes that had a sensory processing disorder, apraxia, and autism. The proband harbored a maternally inherited balanced translocation (46,XY,t(11;14)(p12;p12)mat) that disrupted LRRC4C, a member of the highly specialized netrin G family of axon guidance molecules. The proband also inherited a paternally derived chromosomal inversion that disrupted DPP6, a potassium channel interacting protein. Copy Number (CN) analysis in 14,077 cases with neurodevelopmental disorders and 8,960 control subjects revealed that 60% of cases with exonic deletions in LRRC4C had a second clinically recognizable syndrome associated with variable clinical phenotypes, including 16p11...
October 19, 2016: American Journal of Medical Genetics. Part A
Zehra Ordulu, Tammy Kammin, Harrison Brand, Vamsee Pillalamarri, Claire E Redin, Ryan L Collins, Ian Blumenthal, Carrie Hanscom, Shahrin Pereira, India Bradley, Barbara F Crandall, Pamela Gerrol, Mark A Hayden, Naveed Hussain, Bibi Kanengisser-Pines, Sibel Kantarci, Brynn Levy, Michael J Macera, Fabiola Quintero-Rivera, Erica Spiegel, Blair Stevens, Janet E Ulm, Dorothy Warburton, Louise E Wilkins-Haug, Naomi Yachelevich, James F Gusella, Michael E Talkowski, Cynthia C Morton
In this exciting era of "next-gen cytogenetics," integrating genomic sequencing into the prenatal diagnostic setting is possible within an actionable time frame and can provide precise delineation of balanced chromosomal rearrangements at the nucleotide level. Given the increased risk of congenital abnormalities in newborns with de novo balanced chromosomal rearrangements, comprehensive interpretation of breakpoints could substantially improve prediction of phenotypic outcomes and support perinatal medical care...
October 5, 2016: American Journal of Human Genetics
Samantha Lp Schilit, Benjamin B Currall, Ruen Yao, Carrie Hanscom, Ryan L Collins, Vamsee Pillalamarri, Dong-Young Lee, Tammy Kammin, Cinthya J Zepeda-Mendoza, Tarja Mononen, Lisa S Nolan, James F Gusella, Michael E Talkowski, Jun Shen, Cynthia C Morton
Analysis of chromosomal rearrangements has been highly successful in identifying genes involved in many congenital abnormalities including hearing loss. Herein, we report a subject, designated DGAP242, with congenital hearing loss (HL) and a de novo balanced translocation 46,XX,t(1;5)(q32;q15)dn. Using multiple next-generation sequencing techniques, we obtained high resolution of the breakpoints. This revealed disruption of the orphan receptor ESRRG on chromosome 1, which is differentially expressed in inner ear hair cells and has previously been implicated in HL, and disruption of KIAA0825 on chromosome 5...
July 6, 2016: European Journal of Human Genetics: EJHG
Monika Macakova, Bozena Bohuslavova, Petra Vochozkova, Antonin Pavlok, Miroslava Sedlackova, Daniela Vidinska, Klara Vochyanova, Irena Liskova, Ivona Valekova, Monika Baxa, Zdenka Ellederova, Jiri Klima, Stefan Juhas, Jana Juhasova, Jana Klouckova, Martin Haluzik, Jiri Klempir, Hana Hansikova, Jana Spacilova, Ryan Collins, Ian Blumenthal, Michael Talkowski, James F Gusella, David S Howland, Marian DiFiglia, Jan Motlik
BACKGROUND: Huntington's disease is induced by CAG expansion in a single gene coding the huntingtin protein. The mutated huntingtin (mtHtt) primarily causes degeneration of neurons in the brain, but it also affects peripheral tissues, including testes. OBJECTIVE: We studied sperm and testes of transgenic boars expressing the N-terminal region of human mtHtt. METHODS: In this study, measures of reproductive parameters and electron microscopy (EM) images of spermatozoa and testes of transgenic (TgHD) and wild-type (WT) boars of F1 (24-48 months old) and F2 (12-36 months old) generations were compared...
2016: Neuro-degenerative Diseases
Derek J C Tai, Ashok Ragavendran, Poornima Manavalan, Alexei Stortchevoi, Catarina M Seabra, Serkan Erdin, Ryan L Collins, Ian Blumenthal, Xiaoli Chen, Yiping Shen, Mustafa Sahin, Chengsheng Zhang, Charles Lee, James F Gusella, Michael E Talkowski
Recurrent, reciprocal genomic disorders resulting from non-allelic homologous recombination (NAHR) between near-identical segmental duplications (SDs) are a major cause of human disease, often producing phenotypically distinct syndromes. The genomic architecture of flanking SDs presents a challenge for modeling these syndromes; however, the capability to efficiently generate reciprocal copy number variants (CNVs) that mimic NAHR would represent a valuable modeling tool. We describe here a CRISPR/Cas9 genome engineering method, single-guide CRISPR/Cas targeting of repetitive elements (SCORE), to model reciprocal genomic disorders and demonstrate its capabilities by generating reciprocal CNVs of 16p11...
March 2016: Nature Neuroscience
Jordan W Smoller, Elizabeth W Karlson, Robert C Green, Sekar Kathiresan, Daniel G MacArthur, Michael E Talkowski, Shawn N Murphy, Scott T Weiss
The integration of electronic medical records (EMRs) and genomic research has become a major component of efforts to advance personalized and precision medicine. The Electronic Medical Records and Genomics (eMERGE) network, initiated in 2007, is an NIH-funded consortium devoted to genomic discovery and implementation research by leveraging biorepositories linked to EMRs. In its most recent phase, eMERGE III, the network is focused on facilitating implementation of genomic medicine by detecting and disclosing rare pathogenic variants in clinically relevant genes...
2016: Journal of Personalized Medicine
Kusumika Mukherjee, Kana Ishii, Vamsee Pillalamarri, Tammy Kammin, Joan F Atkin, Scott E Hickey, Qiongchao J Xi, Cinthya J Zepeda, James F Gusella, Michael E Talkowski, Cynthia C Morton, Richard L Maas, Eric C Liao
CAPZB is an actin-capping protein that caps the growing end of F-actin and modulates the cytoskeleton and tethers actin filaments to the Z-line of the sarcomere in muscles. Whole-genome sequencing was performed on a subject with micrognathia, cleft palate and hypotonia that harbored a de novo, balanced chromosomal translocation that disrupts the CAPZB gene. The function of capzb was analyzed in the zebrafish model. capzb(-/-) mutants exhibit both craniofacial and muscle defects that recapitulate the phenotypes observed in the human subject...
April 1, 2016: Human Molecular Genetics
Stephan J Sanders, Xin He, A Jeremy Willsey, A Gulhan Ercan-Sencicek, Kaitlin E Samocha, A Ercument Cicek, Michael T Murtha, Vanessa H Bal, Somer L Bishop, Shan Dong, Arthur P Goldberg, Cai Jinlu, John F Keaney, Lambertus Klei, Jeffrey D Mandell, Daniel Moreno-De-Luca, Christopher S Poultney, Elise B Robinson, Louw Smith, Tor Solli-Nowlan, Mack Y Su, Nicole A Teran, Michael F Walker, Donna M Werling, Arthur L Beaudet, Rita M Cantor, Eric Fombonne, Daniel H Geschwind, Dorothy E Grice, Catherine Lord, Jennifer K Lowe, Shrikant M Mane, Donna M Martin, Eric M Morrow, Michael E Talkowski, James S Sutcliffe, Christopher A Walsh, Timothy W Yu, David H Ledbetter, Christa Lese Martin, Edwin H Cook, Joseph D Buxbaum, Mark J Daly, Bernie Devlin, Kathryn Roeder, Matthew W State
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...
September 23, 2015: Neuron
Ronen Durst, Kimberly Sauls, David S Peal, Annemarieke deVlaming, Katelynn Toomer, Maire Leyne, Monica Salani, Michael E Talkowski, Harrison Brand, Maëlle Perrocheau, Charles Simpson, Christopher Jett, Matthew R Stone, Florie Charles, Colby Chiang, Stacey N Lynch, Nabila Bouatia-Naji, Francesca N Delling, Lisa A Freed, Christophe Tribouilloy, Thierry Le Tourneau, Hervé LeMarec, Leticia Fernandez-Friera, Jorge Solis, Daniel Trujillano, Stephan Ossowski, Xavier Estivill, Christian Dina, Patrick Bruneval, Adrian Chester, Jean-Jacques Schott, Kenneth D Irvine, Yaopan Mao, Andy Wessels, Tahirali Motiwala, Michel Puceat, Yoshikazu Tsukasaki, Donald R Menick, Harinath Kasiganesan, Xingju Nie, Ann-Marie Broome, Katherine Williams, Amanda Johnson, Roger R Markwald, Xavier Jeunemaitre, Albert Hagege, Robert A Levine, David J Milan, Russell A Norris, Susan A Slaugenhaupt
Mitral valve prolapse (MVP) is a common cardiac valve disease that affects nearly 1 in 40 individuals. It can manifest as mitral regurgitation and is the leading indication for mitral valve surgery. Despite a clear heritable component, the genetic aetiology leading to non-syndromic MVP has remained elusive. Four affected individuals from a large multigenerational family segregating non-syndromic MVP underwent capture sequencing of the linked interval on chromosome 11. We report a missense mutation in the DCHS1 gene, the human homologue of the Drosophila cell polarity gene dachsous (ds), that segregates with MVP in the family...
September 3, 2015: Nature
Harrison Brand, Ryan L Collins, Carrie Hanscom, Jill A Rosenfeld, Vamsee Pillalamarri, Matthew R Stone, Fontina Kelley, Tamara Mason, Lauren Margolin, Stacey Eggert, Elyse Mitchell, Jennelle C Hodge, James F Gusella, Stephan J Sanders, Michael E Talkowski
Copy-number variants (CNVs) have been the predominant focus of genetic studies of structural variation, and chromosomal microarray (CMA) for genome-wide CNV detection is the recommended first-tier genetic diagnostic screen in neurodevelopmental disorders. We compared CNVs observed by CMA to the structural variation detected by whole-genome large-insert sequencing in 259 individuals diagnosed with autism spectrum disorder (ASD) from the Simons Simplex Collection. These analyses revealed a diverse landscape of complex duplications in the human genome...
July 2, 2015: American Journal of Human Genetics
Eugenia Migliavacca, Christelle Golzio, Katrin Männik, Ian Blumenthal, Edwin C Oh, Louise Harewood, Jack A Kosmicki, Maria Nicla Loviglio, Giuliana Giannuzzi, Loyse Hippolyte, Anne M Maillard, Ali Abdullah Alfaiz, Mieke M van Haelst, Joris Andrieux, James F Gusella, Mark J Daly, Jacques S Beckmann, Sébastien Jacquemont, Michael E Talkowski, Nicholas Katsanis, Alexandre Reymond
The 16p11.2 600 kb copy-number variants (CNVs) are associated with mirror phenotypes on BMI, head circumference, and brain volume and represent frequent genetic lesions in autism spectrum disorders (ASDs) and schizophrenia. Here we interrogated the transcriptome of individuals carrying reciprocal 16p11.2 CNVs. Transcript perturbations correlated with clinical endophenotypes and were enriched for genes associated with ASDs, abnormalities of head size, and ciliopathies. Ciliary gene expression was also perturbed in orthologous mouse models, raising the possibility that ciliary dysfunction contributes to 16p11...
May 7, 2015: American Journal of Human Genetics
Tychele N Turner, Kamal Sharma, Edwin C Oh, Yangfan P Liu, Ryan L Collins, Maria X Sosa, Dallas R Auer, Harrison Brand, Stephan J Sanders, Daniel Moreno-De-Luca, Vasyl Pihur, Teri Plona, Kristen Pike, Daniel R Soppet, Michael W Smith, Sau Wai Cheung, Christa Lese Martin, Matthew W State, Michael E Talkowski, Edwin Cook, Richard Huganir, Nicholas Katsanis, Aravinda Chakravarti
Autism is a multifactorial neurodevelopmental disorder affecting more males than females; consequently, under a multifactorial genetic hypothesis, females are affected only when they cross a higher biological threshold. We hypothesize that deleterious variants at conserved residues are enriched in severely affected patients arising from female-enriched multiplex families with severe disease, enhancing the detection of key autism genes in modest numbers of cases. Here we show the use of this strategy by identifying missense and dosage sequence variants in the gene encoding the adhesive junction-associated δ-catenin protein (CTNND2) in female-enriched multiplex families and demonstrating their loss-of-function effect by functional analyses in zebrafish embryos and cultured hippocampal neurons from wild-type and Ctnnd2 null mouse embryos...
April 2, 2015: Nature
Marta Biagioli, Francesco Ferrari, Eric M Mendenhall, Yijing Zhang, Serkan Erdin, Ravi Vijayvargia, Sonia M Vallabh, Nicole Solomos, Poornima Manavalan, Ashok Ragavendran, Fatih Ozsolak, Jong Min Lee, Michael E Talkowski, James F Gusella, Marcy E Macdonald, Peter J Park, Ihn Sik Seong
The CAG repeat expansion in the Huntington's disease gene HTT extends a polyglutamine tract in mutant huntingtin that enhances its ability to facilitate polycomb repressive complex 2 (PRC2). To gain insight into this dominant gain of function, we mapped histone modifications genome-wide across an isogenic panel of mouse embryonic stem cell (ESC) and neuronal progenitor cell (NPC) lines, comparing the effects of Htt null and different size Htt CAG mutations. We found that Htt is required in ESC for the proper deposition of histone H3K27me3 at a subset of 'bivalent' loci but in NPC it is needed at 'bivalent' loci for both the proper maintenance and the appropriate removal of this mark...
May 1, 2015: Human Molecular Genetics
Pankaj K Mandal, Leonardo M R Ferreira, Ryan Collins, Torsten B Meissner, Christian L Boutwell, Max Friesen, Vladimir Vrbanac, Brian S Garrison, Alexei Stortchevoi, David Bryder, Kiran Musunuru, Harrison Brand, Andrew M Tager, Todd M Allen, Michael E Talkowski, Derrick J Rossi, Chad A Cowan
Genome editing via CRISPR/Cas9 has rapidly become the tool of choice by virtue of its efficacy and ease of use. However, CRISPR/Cas9-mediated genome editing in clinically relevant human somatic cells remains untested. Here, we report CRISPR/Cas9 targeting of two clinically relevant genes, B2M and CCR5, in primary human CD4+ T cells and CD34+ hematopoietic stem and progenitor cells (HSPCs). Use of single RNA guides led to highly efficient mutagenesis in HSPCs but not in T cells. A dual guide approach improved gene deletion efficacy in both cell types...
November 6, 2014: Cell Stem Cell
Sebastiaan van Heesch, Marieke Simonis, Markus J van Roosmalen, Vamsee Pillalamarri, Harrison Brand, Ewart W Kuijk, Kim L de Luca, Nico Lansu, A Koen Braat, Androniki Menelaou, Wensi Hao, Jeroen Korving, Simone Snijder, Lars T van der Veken, Ron Hochstenbach, Alida C Knegt, Karen Duran, Ivo Renkens, Najla Alekozai, Myrthe Jager, Sarah Vergult, Björn Menten, Ewart de Bruijn, Sander Boymans, Elly Ippel, Ellen van Binsbergen, Michael E Talkowski, Klaske Lichtenbelt, Edwin Cuppen, Wigard P Kloosterman
Genomic rearrangements are a common cause of human congenital abnormalities. However, their origin and consequences are poorly understood. We performed molecular analysis of two patients with congenital disease who carried de novo genomic rearrangements. We found that the rearrangements in both patients hit genes that are recurrently rearranged in cancer (ETV1, FOXP1, and microRNA cluster C19MC) and drive formation of fusion genes similar to those described in cancer. Subsequent analysis of a large set of 552 de novo germline genomic rearrangements underlying congenital disorders revealed enrichment for genes rearranged in cancer and overlap with somatic cancer breakpoints...
December 24, 2014: Cell Reports
Aarathi Sugathan, Marta Biagioli, Christelle Golzio, Serkan Erdin, Ian Blumenthal, Poornima Manavalan, Ashok Ragavendran, Harrison Brand, Diane Lucente, Judith Miles, Steven D Sheridan, Alexei Stortchevoi, Manolis Kellis, Stephen J Haggarty, Nicholas Katsanis, James F Gusella, Michael E Talkowski
Truncating mutations of chromodomain helicase DNA-binding protein 8 (CHD8), and of many other genes with diverse functions, are strong-effect risk factors for autism spectrum disorder (ASD), suggesting multiple mechanisms of pathogenesis. We explored the transcriptional networks that CHD8 regulates in neural progenitor cells (NPCs) by reducing its expression and then integrating transcriptome sequencing (RNA sequencing) with genome-wide CHD8 binding (ChIP sequencing). Suppressing CHD8 to levels comparable with the loss of a single allele caused altered expression of 1,756 genes, 64...
October 21, 2014: Proceedings of the National Academy of Sciences of the United States of America
Harrison Brand, Vamsee Pillalamarri, Ryan L Collins, Stacey Eggert, Colm O'Dushlaine, Ellen B Braaten, Matthew R Stone, Kimberly Chambert, Nathan D Doty, Carrie Hanscom, Jill A Rosenfeld, Hillary Ditmars, Jessica Blais, Ryan Mills, Charles Lee, James F Gusella, Steven McCarroll, Jordan W Smoller, Michael E Talkowski, Alysa E Doyle
Structural variation (SV) is a significant component of the genetic etiology of both neurodevelopmental and psychiatric disorders; however, routine guidelines for clinical genetic screening have been established only in the former category. Genome-wide chromosomal microarray (CMA) can detect genomic imbalances such as copy-number variants (CNVs), but balanced chromosomal abnormalities (BCAs) still require karyotyping for clinical detection. Moreover, submicroscopic BCAs and subarray threshold CNVs are intractable, or cryptic, to both CMA and karyotyping...
October 2, 2014: American Journal of Human Genetics
M J Macera, A Sobrino, B Levy, V Jobanputra, V Aggarwal, A Mills, C Esteves, C Hanscom, S Pereira, V Pillalamarri, Z Ordulu, C C Morton, M Talkowski, D Warburton
No abstract text is available yet for this article.
March 2015: Prenatal Diagnosis
Adrian Veres, Bridget S Gosis, Qiurong Ding, Ryan Collins, Ashok Ragavendran, Harrison Brand, Serkan Erdin, Chad A Cowan, Michael E Talkowski, Kiran Musunuru
Genome editing has attracted wide interest for the generation of cellular models of disease using human pluripotent stem cells and other cell types. CRISPR-Cas systems and TALENs can target desired genomic sites with high efficiency in human cells, but recent publications have led to concern about the extent to which these tools may cause off-target mutagenic effects that could potentially confound disease-modeling studies. Using CRISPR-Cas9 and TALEN targeted human pluripotent stem cell clones, we performed whole-genome sequencing at high coverage in order to assess the degree of mutagenesis across the entire genome...
July 3, 2014: Cell Stem Cell
Ian Blumenthal, Ashok Ragavendran, Serkan Erdin, Lambertus Klei, Aarathi Sugathan, Jolene R Guide, Poornima Manavalan, Julian Q Zhou, Vanessa C Wheeler, Joshua Z Levin, Carl Ernst, Kathryn Roeder, Bernie Devlin, James F Gusella, Michael E Talkowski
Reciprocal copy-number variation (CNV) of a 593 kb region of 16p11.2 is a common genetic cause of autism spectrum disorder (ASD), yet it is not completely penetrant and can manifest in a wide array of phenotypes. To explore its molecular consequences, we performed RNA sequencing of cerebral cortex from mouse models with CNV of the syntenic 7qF3 region and lymphoblast lines from 34 members of 7 multiplex ASD-affected families harboring the 16p11.2 CNV. Expression of all genes in the CNV region correlated well with their DNA copy number, with no evidence of dosage compensation...
June 5, 2014: American Journal of Human Genetics
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