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Ping Hu, Fengchang Qiao, Yan Wang, Lulu Meng, Xiuqing Ji, Chunyu Luo, Tianhui Xu, Ran Zhou, Jingjing Zhang, Bin Yu, Leilei Wang, Ting Wang, Qiong Pan, Dingyuan Ma, Dong Liang, Zhengfeng Xu
OBJECTIVES: This study aimed to determine the diagnostic yield of targeted next-generation sequencing (NGS) in prenatal diagnosis of congenital heart defects (CHDs) and for investigating the possible genetic etiology of prenatal CHD cases. METHODS: Forty-four fetuses with CHDs and normal molecular karyotypes underwent targeted NGS in this study. Fetal genomic DNA was directly extracted from amniotic fluid cells in each prenatal case. A customized targeted NGS panel containing 77 CHD-associated genes was designed to detect variants in the coding regions and the splicing sites of these genes...
March 13, 2018: Ultrasound in Obstetrics & Gynecology
Tanmoy Mondal, Prasanna Kumar Juvvuna, Agnete Kirkeby, Sanhita Mitra, Subazini Thankaswamy Kosalai, Larissa Traxler, Falk Hertwig, Sara Wernig-Zorc, Caroline Miranda, Lily Deland, Ruth Volland, Christoph Bartenhagen, Deniz Bartsch, Sashidhar Bandaru, Anne Engesser, Santhilal Subhash, Tommy Martinsson, Helena Carén, Levent M Akyürek, Leo Kurian, Meena Kanduri, Maite Huarte, Per Kogner, Matthias Fischer, Chandrasekhar Kanduri
Trait-associated loci often map to genomic regions encoding long noncoding RNAs (lncRNAs), but the role of these lncRNAs in disease etiology is largely unexplored. We show that a pair of sense/antisense lncRNA (6p22lncRNAs) encoded by CASC15 and NBAT1 located at the neuroblastoma (NB) risk-associated 6p22.3 locus are tumor suppressors and show reduced expression in high-risk NBs. Loss of functional synergy between 6p22lncRNAs results in an undifferentiated state that is maintained by a gene-regulatory network, including SOX9 located on 17q, a region frequently gained in NB...
March 12, 2018: Cancer Cell
Yuko Katoh-Fukui, Shuichi Yatsuga, Hirohito Shima, Atsushi Hattori, Akie Nakamura, Kohji Okamura, Kumiko Yanagi, Manami Iso, Tadashi Kaname, Yoichi Matsubara, Maki Fukami
CHARGE syndrome is a rare autosomal dominant disease that is typically caused by heterozygous CHD7 mutations. A de novo variant in a CHD7 splicing acceptor site (NM_017780.3:c.7165-4A>G) was identified in a Japanese boy with CHARGE syndrome. This variant has been considered to be an "unclassified variant" due to its position outside the consensus splicing sites. In this study, abnormal splicing derived from this known variant was confirmed by cDNA sequencing.
2018: Human Genome Variation
Hui Yao, Sophie F Hill, Jennifer M Skidmore, Ethan D Sperry, Donald L Swiderski, Gilson J Sanchez, Cynthia F Bartels, Yehoash Raphael, Peter C Scacheri, Shigeki Iwase, Donna M Martin
CHD7, an ATP-dependent chromatin remodeler, is disrupted in CHARGE syndrome, an autosomal dominant disorder characterized by variably penetrant abnormalities in craniofacial, cardiac, and nervous system tissues. The inner ear is uniquely sensitive to CHD7 levels and is the most commonly affected organ in individuals with CHARGE. Interestingly, upregulation or downregulation of retinoic acid (RA) signaling during embryogenesis also leads to developmental defects similar to those in CHARGE syndrome, suggesting that CHD7 and RA may have common target genes or signaling pathways...
February 22, 2018: JCI Insight
MuhChyi Chai, Tsukasa Sanosaka, Hironobu Okuno, Zhi Zhou, Ikuko Koya, Satoe Banno, Tomoko Andoh-Noda, Yoshikuni Tabata, Rieko Shimamura, Tetsutaro Hayashi, Masashi Ebisawa, Yohei Sasagawa, Itoshi Nikaido, Hideyuki Okano, Jun Kohyama
Multiple congenital disorders often present complex phenotypes, but how the mutation of individual genetic factors can lead to multiple defects remains poorly understood. In the present study, we used human neuroepithelial (NE) cells and CHARGE patient-derived cells as an in vitro model system to identify the function of chromodomain helicase DNA-binding 7 (CHD7) in NE-neural crest bifurcation, thus revealing an etiological link between the central nervous system (CNS) and craniofacial anomalies observed in CHARGE syndrome...
January 15, 2018: Genes & Development
Olatz Villate, Nekane Ibarluzea, Eugenia Fraile-Bethencourt, Alberto Valenzuela, Eladio A Velasco, Detelina Grozeva, F L Raymond, María P Botella, María-Isabel Tejada
Mutations in CHD7 have been shown to be a major cause of CHARGE syndrome, which presents many symptoms and features common to other syndromes making its diagnosis difficult. Next generation sequencing (NGS) of a panel of intellectual disability related genes was performed in an adult patient without molecular diagnosis. A splice donor variant in CHD7 (c.5665 + 1G > T) was identified. To study its potential pathogenicity, exons and flanking intronic sequences were amplified from patient DNA and cloned into the pSAD® splicing vector...
2018: Frontiers in Genetics
Roser Ufartes, Janina Schwenty-Lara, Luisa Freese, Christiane Neuhofer, Janika Möller, Peter Wehner, Conny M A van Ravenswaaij-Arts, Monica T Y Wong, Ina Schanze, Andreas Tzschach, Oliver Bartsch, Annette Borchers, Silke Pauli
CHARGE syndrome is an autosomal dominant malformation disorder caused by heterozygous loss of function mutations in the chromatin remodeler CHD7. Chd7 regulates the expression of Sema3a, which also contributes to the pathogenesis of Kallmann syndrome, a heterogeneous condition with the typical features hypogonadotropic hypogonadism and an impaired sense of smell. Both features are common in CHARGE syndrome suggesting that SEMA3A may provide a genetic link between these syndromes. Indeed, we find evidence that SEMA3A plays a role in the pathogenesis of CHARGE syndrome...
February 8, 2018: Human Molecular Genetics
Kazuhito Sekiguchi, Tomoyo Itonaga, Maeda Tomoki, Maki Fukami, Tohru Yorifuji, Kenji Ihara
CHARGE syndrome is a rare autosomal dominant disorder involving multiple organs. Chromodomain helicase DNA binding protein-7 (CHD7) is a major causative gene of CHARGE syndrome. We herein report a male infant born at full term with asphyxia who was diagnosed with CHARGE syndrome based on the typical anomalies. He showed a poor sucking ability and suffered from continuous hypoglycemia in early infancy, ultimately requiring tube feeding. While in a hypoglycemic status, inappropriate high insulin and low growth hormone levels were noticed...
January 17, 2018: European Journal of Medical Genetics
Zhi-Zhi Liu, Zi-Long Wang, Tae-Ik Choi, Wen-Ting Huang, Han-Tsing Wang, Ying-Ying Han, Lou-Yin Zhu, Hyun-Taek Kim, Jung-Hwa Choi, Jin-Soo Lee, Hyung-Goo Kim, Jian Zhao, Yue Chen, Zhuo Lu, Xiao-Li Tian, Bing-Xing Pan, Bao-Ming Li, Cheol-Hee Kim, Hong Xu
CHARGE syndrome is a congenital disorder affecting multiple organs and mainly caused by mutations in CHD7, a gene encoding a chromatin-remodeling protein. Immunodeficiency and reduced T-cells have been noted in CHARGE syndrome. However, the mechanisms underlying T-lymphopenia are largely unexplored. Here, we observed dramatic decrease of T cells in both chd7-knockdown and -knockout zebrafish embryos. Unexpectedly, hematopoietic stem and progenitor cells and, particularly, lymphoid progenitor cells were increased peripherally in nonthymic areas in chd7-deficient embryos, unlikely to contribute to the T cell decrease...
January 15, 2018: American Journal of Pathology
Valerie K Jordan, Brieana Fregeau, Xiaoyan Ge, Jessica Giordano, Ronald J Wapner, Tugce B Balci, Melissa T Carter, John A Bernat, Amanda N Moccia, Anshika Srivastava, Donna M Martin, Stephanie L Bielas, John Pappas, Melissa D Svoboda, Marlène Rio, Nathalie Boddaert, Vincent Cantagrel, Andrea M Lewis, Fernando Scaglia, Jennefer N Kohler, Jonathan A Bernstein, Annika M Dries, Jill A Rosenfeld, Colette DeFilippo, Willa Thorson, Yaping Yang, Elliott H Sherr, Weimin Bi, Daryl A Scott
Heterozygous variants in the arginine-glutamic acid dipeptide repeats gene (RERE) have been shown to cause neurodevelopmental disorder with or without anomalies of the brain, eye, or heart (NEDBEH). Here we report nine individuals with NEDBEH who carry partial deletions or deleterious sequence variants in RERE. These variants were found to be de novo in all cases in which parental samples were available. An analysis of data from individuals with NEDBEH suggests that point mutations affecting the Atrophin-1 domain of RERE are associated with an increased risk of structural eye defects, congenital heart defects, renal anomalies and sensorineural hearing loss when compared to loss-of-function variants that are likely to lead to haploinsufficiency...
January 13, 2018: Human Mutation
Takako Yamamoto, Chiemi Takenaka, Yusuke Yoda, Yasuhiro Oshima, Kenichi Kagawa, Hiroshi Miyajima, Tetsuji Sasaki, Shin Kawamata
Embryonic Stem Cells (ESC) possesses two distinct features; self-renewal and the potential to differentiate. Here we show the differentiation potential and growth rate of ESC correlates positively with the expression level of the gene encoding chromodomain helicase DNA binding protein 7 (CHD7). When ESCs are maintained in feeder-free conditions and single cell seeding, ESC KhES-1 having 4520 copies or more of CHD7 in 5 ng total RNA show differentiation potential, but this is lost when the CHD7 copy number is reduced in KhES-1 to less than 696 by alternative culture conditions...
January 10, 2018: Scientific Reports
Catherine Bélanger, Félix-Antoine Bérubé-Simard, Elizabeth Leduc, Guillaume Bernas, Philippe M Campeau, Seema R Lalani, Donna M Martin, Stephanie Bielas, Amanda Moccia, Anshika Srivastava, David W Silversides, Nicolas Pilon
CHARGE syndrome-which stands for coloboma of the eye, heart defects, atresia of choanae, retardation of growth/development, genital abnormalities, and ear anomalies-is a severe developmental disorder with wide phenotypic variability, caused mainly by mutations in CHD7 (chromodomain helicase DNA-binding protein 7), known to encode a chromatin remodeler. The genetic lesions responsible for CHD7 mutation-negative cases are unknown, at least in part because the pathogenic mechanisms underlying CHARGE syndrome remain poorly defined...
January 8, 2018: Proceedings of the National Academy of Sciences of the United States of America
Jung Ran Choi, Sang-Baek Koh, Seong Yong Park, Hye Run Kim, Hyojin Lee, Dae Ryong Kang
Background: Lung cancer is the leading cause of cancer-related death worldwide, for which smoking is considered as the primary risk factor. The present study was conducted to determine whether genetic alterations induced by radon exposure are associated with the susceptible risk of lung cancer in never smokers. Methods: To accurately identify mutations within individual tumors, next generation sequencing was conduct for 19 pairs of lung cancer tissue. The associations of germline and somatic variations with radon exposure were visualized using OncoPrint and heatmap graphs...
December 2017: Journal of Cancer Prevention
Amanda Moccia, Anshika Srivastava, Jennifer M Skidmore, John A Bernat, Marsha Wheeler, Jessica X Chong, Deborah Nickerson, Michael Bamshad, Margaret A Hefner, Donna M Martin, Stephanie L Bielas
PurposeCHARGE syndrome is an autosomal-dominant, multiple congenital anomaly condition characterized by vision and hearing loss, congenital heart disease, and malformations of craniofacial and other structures. Pathogenic variants in CHD7, encoding adenosine triphosphate-dependent chromodomain helicase DNA binding protein 7, are present in the majority of affected individuals. However, no causal variant can be found in 5-30% (depending on the cohort) of individuals with a clinical diagnosis of CHARGE syndrome...
January 4, 2018: Genetics in Medicine: Official Journal of the American College of Medical Genetics
A Kemal Topaloğlu
Traditionally, idiopathic hypogonadotropic hypogonadism (IHH) is divided into two major categories: Kallmann syndrome (KS) and normosmic IHH (nIHH). To date, inactivating variants in more than 50 genes have been reported to cause IHH. These mutations are estimated to account for up to 50% of all apparently hereditary cases. Identification of further causative gene mutations is expected to be more feasible with the increasing use of whole exome/genome sequencing. Presence of more than one IHH-associated mutant gene in a given patient/pedigree (oligogenic inheritance) is seen in 10-20% of all IHH cases...
December 30, 2017: Journal of Clinical Research in Pediatric Endocrinology
Manuel H Aguiar-Oliveira, Caridad Davalos, Viviane C Campos, Luiz A Oliveira Neto, Cindi G Marinho, Carla R P Oliveira
Several acquired or congenital hypothalamic abnormalities may cause growth failure (GF). We described two of these congenital abnormalities. First, a case of CHARGE syndrome, an epigenetic disorder mostly caused by heterozygous mutations in the gene encoding CHD7, a chromatin remodeling protein, causing several malformations, some life-threatening, with additional secondary hypothalamus-hypophyseal dysfunction, including GF. Second, a cohort of individuals with genetic isolated severe GH deficiency (IGHD), due to a homozygous mutation in the GH-releasing hormone (GHRH) receptor gene described in Itabaianinha County, in northeast Brazil...
December 20, 2017: Growth Hormone & IGF Research
Sara Badodi, Adrian Dubuc, Xinyu Zhang, Gabriel Rosser, Mariane Da Cunha Jaeger, Michelle M Kameda-Smith, Anca Sorana Morrissy, Paul Guilhamon, Philipp Suetterlin, Xiao-Nan Li, Loredana Guglielmi, Ashirwad Merve, Hamza Farooq, Mathieu Lupien, Sheila K Singh, M Albert Basson, Michael D Taylor, Silvia Marino
We describe molecular convergence between BMI1 and CHD7 in the initiation of medulloblastoma. Identified in a functional genomic screen in mouse models, a BMI1High ;CHD7Low expression signature within medulloblastoma characterizes patients with poor overall survival. We show that BMI1-mediated repression of the ERK1/2 pathway leads to increased proliferation and tumor burden in primary human MB cells and in a xenograft model, respectively. We provide evidence that repression of the ERK inhibitor DUSP4 by BMI1 is dependent on a more accessible chromatin configuration in G4 MB cells with low CHD7 expression...
December 5, 2017: Cell Reports
Fang Kong, Donna M Martin
BACKGROUND: Atopic disorders have been reported in CHARGE syndrome, but the prevalence and underlying mechanisms are not known. METHODS: We performed a retrospective study of atopic disorders in 23 individuals with CHARGE syndrome, and reviewed other published reports of atopic disorders in CHARGE syndrome. We assayed for enrichment of atopic disorders in CHARGE syndrome based on gender and presence of a CHD7 pathogenic variant. RESULTS: In our cohort, 65% (15/23) of individuals with CHARGE syndrome were found to have a pathogenic CHD7 variant...
November 27, 2017: European Journal of Medical Genetics
Hironobu Okuno, Francois Renault Mihara, Shigeki Ohta, Kimiko Fukuda, Kenji Kurosawa, Wado Akamatsu, Tsukasa Sanosaka, Jun Kohyama, Kanehiro Hayashi, Kazunori Nakajima, Takao Takahashi, Joanna Wysocka, Kenjiro Kosaki, Hideyuki Okano
CHARGE syndrome is caused by heterozygous mutations in the chromatin remodeler, CHD7, and is characterized by a set of malformations that, on clinical grounds, were historically postulated to arise from defects in neural crest formation during embryogenesis. To better delineate neural crest defects in CHARGE syndrome, we generated induced pluripotent stem cells (iPSCs) from two patients with typical syndrome manifestations, and characterized neural crest cells differentiated in vitro from these iPSCs (iPSC-NCCs)...
November 28, 2017: ELife
Marine Legendre, Véronique Abadie, Tania Attié-Bitach, Nicole Philip, Tiffany Busa, Dominique Bonneau, Estelle Colin, Hélène Dollfus, Didier Lacombe, Annick Toutain, Sophie Blesson, Sophie Julia, Dominique Martin-Coignard, David Geneviève, Bruno Leheup, Sylvie Odent, Pierre-Simon Jouk, Sandra Mercier, Laurence Faivre, Catherine Vincent-Delorme, Christine Francannet, Sophie Naudion, Michèle Mathieu-Dramard, Marie-Ange Delrue, Alice Goldenberg, Delphine Héron, Philippe Parent, Renaud Touraine, Valérie Layet, Damien Sanlaville, Chloé Quélin, Sébastien Moutton, Mélanie Fradin, Aurélia Jacquette, Sabine Sigaudy, Lucile Pinson, Pierre Sarda, Anne-Marie Guerrot, Massimiliano Rossi, Alice Masurel-Paulet, Salima El Chehadeh, Xavier Piguel, Montserrat Rodriguez-Ballesteros, Stéphanie Ragot, Stanislas Lyonnet, Frédéric Bilan, Brigitte Gilbert-Dussardier
CHARGE syndrome (CS) is a genetic disorder whose first description included Coloboma, Heart disease, Atresia of choanae, Retarded growth and development, Genital hypoplasia, and Ear anomalies and deafness, most often caused by a genetic mutation in the CHD7 gene. Two features were then added: semicircular canal anomalies and arhinencephaly/olfactory bulb agenesis, with classification of typical, partial, or atypical forms on the basis of major and minor clinical criteria. The detection rate of a pathogenic variant in the CHD7 gene varies from 67% to 90%...
December 2017: American Journal of Medical Genetics. Part C, Seminars in Medical Genetics
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