Low Frequency of Pathogenic Allelic Variants in the 46,XY Differences of Sex Development (DSD)-Related Genes in Small for Gestational Age Children with Hypospadias
作者： Barbara L. Braga , Nathalia L. Gomes , Mirian Yumie Nishi , Bruna Lucheze Freire , Rafael Loch Batista
DOI: 10.1101/748277
关键词:
摘要: Abstract Background Hypospadias is a congenital disorder of male genital formation where the urinary opening not on head penis and genetic factors play an important role in incidence this early developmental defect 46,XY individuals, both isolated syndromic forms. Children born small for gestational age (SGA) present high frequency hypospadias undetermined etiology, ranging from 15 to 30%, but detection hypospadias’ etiology remains low. Patients methods cohort DSD patients, we identified 25 SGA children with medium or proximal hypospadias; four them associated characteristics. DNA samples subjects were studied by massively parallel targeted sequencing (MPTS) using panel. MLPA was used molecular diagnosis two clinical phenotype Silver Russel syndrome. Results Loss methylation (11p15 LOM) at ICR1 out children. The other patient had 3M syndrome novel likely-pathogenic variants compound heterozygous state found CUL7 gene. last subject Mulibrey nanism and, homozygous variant TRIM37 confirmed mother. Among non-syndromic seven rare uncertain significance six DSD-related genes identified: DHX37 GATA4 WWOX variants, respectively; three WT1, IGF1R, BMP8B genes. Conclusion Pathogenic hypospadias, suggesting that multi-factorial causes, unknown unidentified environmental (epigenetic defects), may be involved condition.
sci-hub.st 参考文章(17)
Laurence S. Baskin, Michele B. Ebbers, Hypospadias: anatomy, etiology, and technique. Journal of Pediatric Surgery. ,vol. 41, pp. 463- 472 ,(2006) , 10.1016/J.JPEDSURG.2005.11.059
Nicolas Kalfa, Pascal Philibert, Charles Sultan, Is hypospadias a genetic, endocrine or environmental disease, or still an unexplained malformation? International Journal of Andrology. ,vol. 32, pp. 187- 197 ,(2009) , 10.1111/J.1365-2605.2008.00899.X
P. A. Lee, S. D. Chernausek, A. C. S. Hokken-Koelega, P. Czernichow, , International Small for Gestational Age Advisory Board Consensus Development Conference Statement: Management of Short Children Born Small for Gestational Age, April 24-October 1, 2001 Pediatrics. ,vol. 111, pp. 1253- 1261 ,(2003) , 10.1542/PEDS.111.6.1253
T. Eggermann, D. Gonzalez, S. Spengler, M. Arslan-Kirchner, G. Binder, N. Schonherr, Broad Clinical Spectrum in Silver-Russell Syndrome and Consequences for Genetic Testing in Growth Retardation Pediatrics. ,vol. 123, ,(2009) , 10.1542/PEDS.2008-3228
AzizN RichardsS, ACMG Laboratory Quality Assurance Committee, None, Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genetics in Medicine. ,vol. 17, pp. 405- 424 ,(2015) , 10.1038/GIM.2015.30
Jeanne M. Manson, Michael C. Carr, Molecular epidemiology of hypospadias: review of genetic and environmental risk factors. Birth Defects Research Part A-clinical and Molecular Teratology. ,vol. 67, pp. 825- 836 ,(2003) , 10.1002/BDRA.10084
, A global reference for human genetic variation. Nature. ,vol. 526, pp. 68- 74 ,(2015) , 10.1038/NATURE15393
Catherine A Brownstein, Alan H Beggs, Nils Homer, Barry Merriman, Timothy W Yu, Katherine C Flannery, Elizabeth T DeChene, Meghan C Towne, Sarah K Savage, Emily N Price, Ingrid A Holm, Lovelace J Luquette, Elaine Lyon, Joseph Majzoub, Peter Neupert, David McCallie Jr, Peter Szolovits, Huntington F Willard, Nancy J Mendelsohn, Renee Temme, Richard S Finkel, Sabrina W Yum, Livija Medne, Shamil R Sunyaev, Ivan Adzhubey, Christopher A Cassa, Paul IW De Bakker, Hatice Duzkale, Piotr Dworzyński, William Fairbrother, Laurent Francioli, Birgit H Funke, Monica A Giovanni, Robert E Handsaker, Kasper Lage, Matthew S Lebo, Monkol Lek, Ignaty Leshchiner, Daniel G MacArthur, Heather M McLaughlin, Michael F Murray, Tune H Pers, Paz P Polak, Soumya Raychaudhuri, Heidi L Rehm, Rachel Soemedi, Nathan O Stitziel, Sara Vestecka, Jochen Supper, Claudia Gugenmus, Bernward Klocke, Alexander Hahn, Max Schubach, Mortiz Menzel, Saskia Biskup, Peter Freisinger, Mario Deng, Martin Braun, Sven Perner, Richard JH Smith, Janeen L Andorf, Jian Huang, Kelli Ryckman, Val C Sheffield, Edwin M Stone, Thomas Bair, E Ann Black-Ziegelbein, Terry A Braun, Benjamin Darbro, Adam P DeLuca, Diana L Kolbe, Todd E Scheetz, Aiden E Shearer, Rama Sompallae, Kai Wang, Alexander G Bassuk, Erik Edens, Katherine Mathews, Steven A Moore, Oleg A Shchelochkov, Pamela Trapane, Aaron Bossler, Colleen A Campbell, Jonathan W Heusel, Anne Kwitek, Tara Maga, Karin Panzer, Thomas Wassink, Douglas Van Daele, Hela Azaiez, Kevin Booth, Nic Meyer, Michael M Segal, Marc S Williams, Gerard Tromp, Peter White, Donald Corsmeier, Sara Fitzgerald-Butt, Gail Herman, Devon Lamb-Thrush, Kim L McBride, David Newsom, Christopher R Pierson, Alexander T Rakowsky, Aleš Maver, Luca Lovrečić, Anja Palandačić, Borut Peterlin, Ali Torkamani, Anna Wedell, Mikael Huss, Andrey Alexeyenko, Jessica M Lindvall, Måns Magnusson, Daniel Nilsson, Henrik Stranneheim, Fulya Taylan, Christian Gilissen, Alexander Hoischen, Bregje Van Bon, Helger Yntema, Marcel Nelen, Weidong Zhang, Jason Sager, Lu Zhang, Kathryn Blair, Deniz Kural, Michael Cariaso, Greg G Lennon, Asif Javed, Saloni Agrawal, Pauline C Ng, Komal S Sandhu, Shuba Krishna, Vamsi Veeramachaneni, Ofer Isakov, Eran Halperin, Eitan Friedman, Noam Shomron, Gustavo Glusman, Jared C Roach, Juan Caballero, Hannah C Cox, Denise Mauldin, Seth A Ament, Lee Rowen, Daniel R Richards, F Anthony San Lucas, Manuel L Gonzalez-Garay, C Thomas Caskey, None, An international effort towards developing standards for best practices in analysis, interpretation and reporting of clinical genome sequencing results in the CLARITY Challenge. Genome Biology. ,vol. 15, pp. 1- 18 ,(2014) , 10.1186/GB-2014-15-3-R53
P. E. Clayton, S. Cianfarani, P. Czernichow, G. Johannsson, R. Rapaport, A. Rogol, Management of the Child Born Small for Gestational Age through to Adulthood: A Consensus Statement of the International Societies of Pediatric Endocrinology and the Growth Hormone Research Society The Journal of Clinical Endocrinology and Metabolism. ,vol. 92, pp. 804- 810 ,(2007) , 10.1210/JC.2006-2017
Sara Bruce, Katariina Hannula-Jouppi, Jari Peltonen, Juha Kere, Marita Lipsanen-Nyman, Clinically Distinct Epigenetic Subgroups in Silver-Russell Syndrome: The Degree of H19 Hypomethylation Associates with Phenotype Severity and Genital and Skeletal Anomalies The Journal of Clinical Endocrinology and Metabolism. ,vol. 94, pp. 579- 587 ,(2009) , 10.1210/JC.2008-1805