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https://www.readbyqxmd.com/read/28691782/a-novel-microduplication-of-arid1b-clinical-genetic-and-proteomic-findings
#1
Catarina M Seabra, Nicholas Szoko, Serkan Erdin, Ashok Ragavendran, Alexei Stortchevoi, Patrícia Maciel, Kathleen Lundberg, Daniela Schlatzer, Janice Smith, Michael E Talkowski, James F Gusella, Marvin R Natowicz
Genetic alterations of ARID1B have been recently recognized as one of the most common mendelian causes of intellectual disability and are associated with both syndromic and non-syndromic phenotypes. The ARID1B protein, a subunit of the chromatin remodeling complex SWI/SNF-A, is involved in the regulation of transcription and multiple downstream cellular processes. We report here the clinical, genetic, and proteomic phenotypes of an individual with a unique apparent de novo mutation of ARID1B due to an intragenic duplication...
July 10, 2017: American Journal of Medical Genetics. Part A
https://www.readbyqxmd.com/read/28558098/complex-and-dynamic-chromosomal-rearrangements-in-a-family-with-seemingly-non-mendelian-inheritance-of-dopa-responsive-dystonia
#2
Katja Lohmann, Claire Redin, Holger Tönnies, Susan B Bressman, Jose Ignacio Martin Subero, Karin Wiegers, Frauke Hinrichs, Yorck Hellenbroich, Aleksandar Rakovic, Deborah Raymond, Laurie J Ozelius, Eberhard Schwinger, Reiner Siebert, Michael E Talkowski, Rachel Saunders-Pullman, Christine Klein
Importance: Chromosomal rearrangements are increasingly recognized to underlie neurologic disorders and are often accompanied by additional clinical signs beyond the gene-specific phenotypic spectrum. Objective: To elucidate the causal genetic variant in a large US family with co-occurrence of dopa-responsive dystonia as well as skeletal and eye abnormalities (ie, ptosis, myopia, and retina detachment). Design, Setting, and Participants: We examined 10 members of a family, including 5 patients with dopa-responsive dystonia and skeletal and/or eye abnormalities, from a US tertiary referral center for neurological diseases using multiple conventional molecular methods, including fluorescence in situ hybridization and array comparative genomic hybridization as well as large-insert whole-genome sequencing to survey multiple classes of genomic variations...
July 1, 2017: JAMA Neurology
https://www.readbyqxmd.com/read/28546579/corrigendum-smchd1-mutations-associated-with-a-rare-muscular-dystrophy-can-also-cause-isolated-arhinia-and-bosma-arhinia-microphthalmia-syndrome
#3
Natalie D Shaw, Harrison Brand, Zachary A Kupchinsky, Hemant Bengani, Lacey Plummer, Takako I Jones, Serkan Erdin, Kathleen A Williamson, Joe Rainger, Alexei Stortchevoi, Kaitlin Samocha, Benjamin B Currall, Donncha S Dunican, Ryan L Collins, Jason R Willer, Angela Lek, Monkol Lek, Malik Nassan, Shahrin Pereira, Tammy Kammin, Diane Lucente, Alexandra Silva, Catarina M Seabra, Colby Chiang, Yu An, Morad Ansari, Jacqueline K Rainger, Shelagh Joss, Jill Clayton Smith, Margaret F Lippincott, Sylvia S Singh, Nirav Patel, Jenny W Jing, Jennifer R Law, Nalton Ferraro, Alain Verloes, Anita Rauch, Katharina Steindl, Markus Zweier, Ianina Scheer, Daisuke Sato, Nobuhiko Okamoto, Christina Jacobsen, Jeanie Tryggestad, Steven Chernausek, Lisa A Schimmenti, Benjamin Brasseur, Claudia Cesaretti, Jose E García-Ortiz, Tatiana Pineda Buitrago, Orlando Perez Silva, Jodi D Hoffman, Wolfgang Mühlbauer, Klaus W Ruprecht, Bart L Loeys, Masato Shino, Angela M Kaindl, Chie-Hee Cho, Cynthia C Morton, Richard R Meehan, Veronica van Heyningen, Eric C Liao, Ravikumar Balasubramanian, Janet E Hall, Stephanie B Seminara, Daniel Macarthur, Steven A Moore, Koh-Ichiro Yoshiura, James F Gusella, Joseph A Marsh, John M Graham, Angela E Lin, Nicholas Katsanis, Peter L Jones, William F Crowley, Erica E Davis, David R FitzPatrick, Michael E Talkowski
No abstract text is available yet for this article.
May 26, 2017: Nature Genetics
https://www.readbyqxmd.com/read/28260531/defining-the-diverse-spectrum-of-inversions-complex-structural-variation-and-chromothripsis-in-the-morbid-human%C3%A2-genome
#4
Ryan L Collins, Harrison Brand, Claire E Redin, Carrie Hanscom, Caroline Antolik, Matthew R Stone, Joseph T Glessner, Tamara Mason, Giulia Pregno, Naghmeh Dorrani, Giorgia Mandrile, Daniela Giachino, Danielle Perrin, Cole Walsh, Michelle Cipicchio, Maura Costello, Alexei Stortchevoi, Joon-Yong An, Benjamin B Currall, Catarina M Seabra, Ashok Ragavendran, Lauren Margolin, Julian A Martinez-Agosto, Diane Lucente, Brynn Levy, Stephan J Sanders, Ronald J Wapner, Fabiola Quintero-Rivera, Wigard Kloosterman, Michael E Talkowski
BACKGROUND: Structural variation (SV) influences genome organization and contributes to human disease. However, the complete mutational spectrum of SV has not been routinely captured in disease association studies. RESULTS: We sequenced 689 participants with autism spectrum disorder (ASD) and other developmental abnormalities to construct a genome-wide map of large SV. Using long-insert jumping libraries at 105X mean physical coverage and linked-read whole-genome sequencing from 10X Genomics, we document seven major SV classes at ~5 kb SV resolution...
March 6, 2017: Genome Biology
https://www.readbyqxmd.com/read/28120936/potential-molecular-consequences-of-transgene-integration-the-r6-2-mouse-example
#5
Jessie C Jacobsen, Serkan Erdin, Colby Chiang, Carrie Hanscom, Renee R Handley, Douglas D Barker, Alex Stortchevoi, Ian Blumenthal, Suzanne J Reid, Russell G Snell, Marcy E MacDonald, A Jennifer Morton, Carl Ernst, James F Gusella, Michael E Talkowski
Integration of exogenous DNA into a host genome represents an important route to generate animal and cellular models for exploration into human disease and therapeutic development. In most models, little is known concerning structural integrity of the transgene, precise site of integration, or its impact on the host genome. We previously used whole-genome and targeted sequencing approaches to reconstruct transgene structure and integration sites in models of Huntington's disease, revealing complex structural rearrangements that can result from transgenesis...
January 25, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28102589/cover-image-volume-173a-number-2-february-2017
#6
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
The cover image, by Carl Ernst et al., is based on the Original Article Implication of LRRC4C and DPP6 in neurodevelopmental disorders, DOI: 10.1002/ajmg.a.38021.
February 2017: American Journal of Medical Genetics. Part A
https://www.readbyqxmd.com/read/28067909/smchd1-mutations-associated-with-a-rare-muscular-dystrophy-can-also-cause-isolated-arhinia-and-bosma-arhinia-microphthalmia-syndrome
#7
Natalie D Shaw, Harrison Brand, Zachary A Kupchinsky, Hemant Bengani, Lacey Plummer, Takako I Jones, Serkan Erdin, Kathleen A Williamson, Joe Rainger, Alexei Stortchevoi, Kaitlin Samocha, Benjamin B Currall, Donncha S Dunican, Ryan L Collins, Jason R Willer, Angela Lek, Monkol Lek, Malik Nassan, Shahrin Pereira, Tammy Kammin, Diane Lucente, Alexandra Silva, Catarina M Seabra, Colby Chiang, Yu An, Morad Ansari, Jacqueline K Rainger, Shelagh Joss, Jill Clayton Smith, Margaret F Lippincott, Sylvia S Singh, Nirav Patel, Jenny W Jing, Jennifer R Law, Nalton Ferraro, Alain Verloes, Anita Rauch, Katharina Steindl, Markus Zweier, Ianina Scheer, Daisuke Sato, Nobuhiko Okamoto, Christina Jacobsen, Jeanie Tryggestad, Steven Chernausek, Lisa A Schimmenti, Benjamin Brasseur, Claudia Cesaretti, Jose E García-Ortiz, Tatiana Pineda Buitrago, Orlando Perez Silva, Jodi D Hoffman, Wolfgang Mühlbauer, Klaus W Ruprecht, Bart L Loeys, Masato Shino, Angela M Kaindl, Chie-Hee Cho, Cynthia C Morton, Richard R Meehan, Veronica van Heyningen, Eric C Liao, Ravikumar Balasubramanian, Janet E Hall, Stephanie B Seminara, Daniel Macarthur, Steven A Moore, Koh-Ichiro Yoshiura, James F Gusella, Joseph A Marsh, John M Graham, Angela E Lin, Nicholas Katsanis, Peter L Jones, William F Crowley, Erica E Davis, David R FitzPatrick, Michael E Talkowski
Arhinia, or absence of the nose, is a rare malformation of unknown etiology that is often accompanied by ocular and reproductive defects. Sequencing of 40 people with arhinia revealed that 84% of probands harbor a missense mutation localized to a constrained region of SMCHD1 encompassing the ATPase domain. SMCHD1 mutations cause facioscapulohumeral muscular dystrophy type 2 (FSHD2) via a trans-acting loss-of-function epigenetic mechanism. We discovered shared mutations and comparable DNA hypomethylation patterning between these distinct disorders...
February 2017: Nature Genetics
https://www.readbyqxmd.com/read/27984722/an-ancient-unified-mechanism-for-metformin-growth-inhibition-in-c-%C3%A2-elegans-and-cancer
#8
COMMENT
Lianfeng Wu, Ben Zhou, Noriko Oshiro-Rapley, Man Li, Joao A Paulo, Christopher M Webster, Fan Mou, Michael C Kacergis, Michael E Talkowski, Christopher E Carr, Steven P Gygi, Bin Zheng, Alexander A Soukas
Metformin has utility in cancer prevention and treatment, though the mechanisms for these effects remain elusive. Through genetic screening in C. elegans, we uncover two metformin response elements: the nuclear pore complex (NPC) and acyl-CoA dehydrogenase family member-10 (ACAD10). We demonstrate that biguanides inhibit growth by inhibiting mitochondrial respiratory capacity, which restrains transit of the RagA-RagC GTPase heterodimer through the NPC. Nuclear exclusion renders RagC incapable of gaining the GDP-bound state necessary to stimulate mTORC1...
December 15, 2016: Cell
https://www.readbyqxmd.com/read/27759917/implication-of-lrrc4c-and-dpp6-in-neurodevelopmental-disorders
#9
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...
February 2017: American Journal of Medical Genetics. Part A
https://www.readbyqxmd.com/read/27745839/structural-chromosomal-rearrangements-require-nucleotide-level-resolution-lessons-from-next-generation-sequencing-in-prenatal-diagnosis
#10
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...
November 3, 2016: American Journal of Human Genetics
https://www.readbyqxmd.com/read/27381092/estrogen-related-receptor-gamma-implicated-in-a-phenotype-including-hearing-loss-and-mild-developmental-delay
#11
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...
November 2016: European Journal of Human Genetics: EJHG
https://www.readbyqxmd.com/read/26959244/mutated-huntingtin-causes-testicular-pathology-in-transgenic-minipig-boars
#12
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
https://www.readbyqxmd.com/read/26829649/engineering-microdeletions-and-microduplications-by-targeting-segmental-duplications-with-crispr
#13
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
https://www.readbyqxmd.com/read/26805891/an-emerge-clinical-center-at-partners-personalized-medicine
#14
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
https://www.readbyqxmd.com/read/26758871/actin-capping-protein-capzb-regulates-cell-morphology-differentiation-and-neural-crest-migration-in-craniofacial-morphogenesis%C3%A2
#15
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
https://www.readbyqxmd.com/read/26402605/insights-into-autism-spectrum-disorder-genomic-architecture-and-biology-from-71-risk-loci
#16
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
https://www.readbyqxmd.com/read/26258302/mutations-in-dchs1-cause-mitral-valve-prolapse
#17
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
https://www.readbyqxmd.com/read/26094575/paired-duplication-signatures-mark-cryptic-inversions-and-other-complex-structural-variation
#18
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
https://www.readbyqxmd.com/read/25937446/a-potential-contributory-role-for-ciliary-dysfunction-in-the-16p11-2-600-kb-bp4-bp5-pathology
#19
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
https://www.readbyqxmd.com/read/25807484/loss-of-%C3%AE-catenin-function-in-severe-autism
#20
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
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