{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,30]],"date-time":"2026-01-30T02:01:45Z","timestamp":1769738505505,"version":"3.49.0"},"reference-count":40,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,1,11]],"date-time":"2021-01-11T00:00:00Z","timestamp":1610323200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Genet."],"abstract":"<jats:p>Glycogen storage diseases (GSDs) are the heterogeneous group of disorders caused by mutations in at least 30 different genes. Different types of GSDs, especially liver GSDs, take overlapping symptoms and can be clinically indistinguishable. This survey evaluated the use of whole-exome sequencing (WES) for the genetic analysis of the liver GSD-suspected patients in three unrelated families. An in-house filtering pipeline was used to assess rare pathogenic variants in GSD-associated genes, autosomal recessive\/mendelian disorder genes (carrier status for genetic counseling subjects), and the ACMG\u2019s list of 59 actionable genes. For the interpretation of the causative variants and the incidental\/secondary findings, ACMG guidelines were applied. Additionally, we have explored PharmGKB class IA\/IB pharmacogenetic variants. The segregation analysis was performed using Sanger sequencing for the novel causative variants. Bioinformatics analysis of the exome data in three individuals revealed three novel homozygous causative variants in the GSD-associated genes. The first variant, c.298_307delATGATCAACC in PYGL gene has related to HERS disease (GSD VI). Both variants of c.1043dupT and c.613-1G &amp;gt; C in SLC2A2 gene have been associated with Fanconi-Bickel syndrome (GSDXI). Eight pathogenic\/likely pathogenic medical actionable findings in Mendelian disease genes and 10 pharmacogenetic variants with underlying drug response phenotypes have been identified. No known\/expected pathogenic variants were detected in the ACMG\u2019s list of 59 actionable genes. The logical filtering steps can help in finding other medical actionable secondary\/incidental findings as well as effectively identifying the causative variants in heterogeneous conditions such as GSDs. Three novel variants related to GSD genes recognized in liver GSD-suspected patients with early infantile and childhood-age onset.<\/jats:p>","DOI":"10.3389\/fgene.2020.601566","type":"journal-article","created":{"date-parts":[[2021,1,13]],"date-time":"2021-01-13T01:59:28Z","timestamp":1610503168000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":10,"title":["Whole-Exome Sequencing Uncovers Novel Causative Variants and Additional Findings in Three Patients Affected by Glycogen Storage Disease Type VI and Fanconi\u2212Bickel Syndrome"],"prefix":"10.3389","volume":"11","author":[{"given":"Maryam","family":"Eghbali","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kiyana Sadat","family":"Fatemi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shadab","family":"Salehpour","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maryam","family":"Abiri","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hassan","family":"Saei","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Saeed","family":"Talebi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nasrin Alipour","family":"Olyaei","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vahid Reza","family":"Yassaee","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mohammad Hossein","family":"Modarressi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2021,1,11]]},"reference":[{"key":"B1","doi-asserted-by":"crossref","DOI":"10.1002\/0471142905.hg0720s76","article-title":"Predicting functional effect of human missense mutations using PolyPhen-2.","author":"Adzhubei","year":"2013","journal-title":"Curr. Protoc. Hum. Genet."},{"key":"B2","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1007\/s00431-019-03499-1","article-title":"Glycogen storage disease type VI: clinical course and molecular background.","volume":"179","author":"Aeppli","year":"2020","journal-title":"Eur. J. Pediatr."},{"key":"B3","doi-asserted-by":"publisher","first-page":"785","DOI":"10.1086\/301790","article-title":"Mutations in the liver glycogen phosphorylase gene (Pygl) underlying glycogenosis type VI (Hers disease).","volume":"62","author":"Burwinkel","year":"1998","journal-title":"Am. J. Hum. Genet."},{"key":"B4","doi-asserted-by":"publisher","first-page":"865","DOI":"10.1093\/hmg\/7.5.865","article-title":"Identification of a mutation in liver glycogen phosphorylase in glycogen storage disease type VI.","volume":"7","author":"Chang","year":"1998","journal-title":"Hum. Mol. Genet."},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1001025","article-title":"Identifying a high fraction of the human genome to be under selective constraint using GERP++.","volume":"6","author":"Davydov","year":"2010","journal-title":"PLoS Comput. Biol."},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkp215","article-title":"Human splicing finder: an online bioinformatics tool to predict splicing signals.","volume":"37","author":"Desmet","year":"2009","journal-title":"Nucleic Acids Res."},{"key":"B7","first-page":"359","article-title":"Chronic aminoaciduria (amino acid diabetes or nephrotic-glucosuric dwarfism) in glycogen storage and cystine disease.","volume":"4","author":"Fanconi","year":"1949","journal-title":"Helv. Paediatr Acta"},{"key":"B8","doi-asserted-by":"publisher","first-page":"565","DOI":"10.1038\/gim.2013.73","article-title":"ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing.","volume":"15","author":"Green","year":"2013","journal-title":"Genet. Med."},{"key":"B9","doi-asserted-by":"publisher","first-page":"327","DOI":"10.1038\/ng1197-327","article-title":"Early diabetes and abnormal postnatal pancreatic islet development in mice lacking Glut-2.","volume":"17","author":"Guillam","year":"1997","journal-title":"Nat. Genet."},{"key":"B10","doi-asserted-by":"publisher","first-page":"1512","DOI":"10.1056\/nejmra012240","article-title":"Genomic medicine\u2014a primer.","volume":"347","author":"Guttmacher","year":"2002","journal-title":"N. Eng. J. Med."},{"key":"B11","doi-asserted-by":"publisher","first-page":"782","DOI":"10.1160\/th05-10-0678","article-title":"The influence of sequence variations in factor VII, \u03b3-glutamyl carboxylase and vitamin K epoxide reductase complex genes on warfarin dose requirement.","volume":"95","author":"Herman","year":"2006","journal-title":"Thromb. Haemost."},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2019.00240","article-title":"Actionable pharmacogenetic variation in the Slovenian genomic database.","volume":"10","author":"Ho\u010devar","year":"2019","journal-title":"Front. Pharmacol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"249","DOI":"10.1038\/gim.2016.190","article-title":"Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2016 update (ACMG SF v2. 0): a policy statement of the American College of Medical Genetics and Genomics.","volume":"19","author":"Kalia","year":"2017","journal-title":"Genet. Med."},{"key":"B14","doi-asserted-by":"publisher","first-page":"310","DOI":"10.1038\/ng.2892","article-title":"A general framework for estimating the relative pathogenicity of human genetic variants.","volume":"46","author":"Kircher","year":"2014","journal-title":"Nat. Genet."},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2014.128","article-title":"Diagnosis and management of glycogen storage disease type I: a practice guideline of the American College of Medical Genetics and Genomics.","volume":"16","author":"Kishnani","year":"2014","journal-title":"Genet. Med."},{"key":"B16","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1097\/GIM.0b013e3181e655b6","article-title":"Glycogen storage disease type III diagnosis and management guidelines.","volume":"12","author":"Kishnani","year":"2010","journal-title":"Genet. Med."},{"key":"B17","doi-asserted-by":"publisher","first-page":"1978","DOI":"10.1093\/bioinformatics\/bty897","article-title":"VarSome: the human genomic variant search engine.","volume":"35","author":"Kopanos","year":"2019","journal-title":"Bioinformatics"},{"key":"B18","doi-asserted-by":"publisher","first-page":"461","DOI":"10.1242\/jcs.181008","article-title":"Nonsense-mediated mRNA decay in humans at a glance.","volume":"129","author":"Kurosaki","year":"2016","journal-title":"J. Cell Sci."},{"key":"B19","doi-asserted-by":"crossref","DOI":"10.1007\/978-3-642-15720-2_6","article-title":"The glycogen storage diseases and related disorders","author":"Laforet","year":"2012","journal-title":"Inborn Metabolic Diseases"},{"key":"B20","doi-asserted-by":"publisher","first-page":"589","DOI":"10.1093\/bioinformatics\/btp698","article-title":"Fast and accurate long-read alignment with Burrows\u2013Wheeler transform.","volume":"26","author":"Li","year":"2010","journal-title":"Bioinformatics"},{"key":"B21","doi-asserted-by":"publisher","first-page":"2078","DOI":"10.1093\/bioinformatics\/btp352","article-title":"The sequence alignment\/map format and SAMtools.","volume":"25","author":"Li","year":"2009","journal-title":"Bioinformatics"},{"key":"B22","doi-asserted-by":"publisher","first-page":"267","DOI":"10.1016\/j.ajhg.2017.01.004","article-title":"InterVar: clinical interpretation of genetic variants by the 2015 ACMG-AMP guidelines.","volume":"100","author":"Li","year":"2017","journal-title":"Am. J. Hum. Genet."},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1186\/s12881-020-01010-4","article-title":"Novel Pygl mutations in Chinese children leading to glycogen storage disease type VI: two case reports.","volume":"21","author":"Luo","year":"2020","journal-title":"BMC Med. Genet."},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/16.3.1215","article-title":"A simple salting out procedure for extracting DNA from human nucleated cells.","volume":"16","author":"Mwer","year":"1988","journal-title":"Nucleic Acids Res."},{"key":"B25","doi-asserted-by":"crossref","first-page":"642","DOI":"10.1097\/FPC.0b013e32833433b6","article-title":"VKORC1 pharmacogenomics summary.","volume":"20","author":"Owen","year":"2010","journal-title":"Pharmacogenet. Genomics"},{"key":"B26","doi-asserted-by":"publisher","first-page":"761","DOI":"10.1093\/bioinformatics\/btu703","article-title":"DANN: a deep learning approach for annotating the pathogenicity of genetic variants.","volume":"31","author":"Quang","year":"2015","journal-title":"Bioinformatics"},{"key":"B27","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1038\/jhg.2013.114","article-title":"The promise of whole-exome sequencing in medical genetics.","volume":"59","author":"Rabbani","year":"2014","journal-title":"J. Hum. Genet."},{"key":"B28","doi-asserted-by":"publisher","first-page":"423","DOI":"10.1038\/clpt.2014.125","article-title":"The clinical pharmacogenetics implementation consortium guideline for SLCO1B1 and simvastatin-induced myopathy: 2014 update.","volume":"96","author":"Ramsey","year":"2014","journal-title":"Clin. Pharmacol. Ther."},{"key":"B29","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"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.","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. Med."},{"key":"B30","doi-asserted-by":"publisher","first-page":"171","DOI":"10.1016\/j.ymgme.2014.09.005","article-title":"The natural history of glycogen storage disease types VI and IX: long-term outcome from the largest metabolic center in Canada.","volume":"113","author":"Roscher","year":"2014","journal-title":"Mol. Genet. Metab."},{"key":"B31","doi-asserted-by":"publisher","first-page":"586","DOI":"10.1203\/00006450-200011000-00005","article-title":"Mutation analysis of the GLUT2 gene in patients with Fanconi-Bickel syndrome.","volume":"48","author":"Sakamoto","year":"2000","journal-title":"Pediatr. Res."},{"key":"B32","doi-asserted-by":"publisher","first-page":"213","DOI":"10.2174\/1566524024605743","article-title":"Fanconi-bickel syndrome-a congenital defect of facilitative glucose transport.","volume":"2","author":"Santer","year":"2002","journal-title":"Curr. Mol. Med."},{"key":"B33","doi-asserted-by":"publisher","first-page":"361","DOI":"10.1038\/nmeth.2890","article-title":"MutationTaster2: mutation prediction for the deep-sequencing age.","volume":"11","author":"Schwarz","year":"2014","journal-title":"Nat. Methods"},{"key":"B34","doi-asserted-by":"publisher","first-page":"434","DOI":"10.24953\/turkjped.2017.04.010","article-title":"Impaired glucose tolerance in fanconi-bickel syndrome: eight patients with two novel mutations.","volume":"59","author":"\u015eeker-Y\u0131lmaz","year":"2017","journal-title":"Turkish J. Pediatr."},{"key":"B35","first-page":"7","article-title":"Effect of whole exome sequencing in diagnosis of inborn errors of metabolism and neurogenetic disorders.","volume":"12","author":"Shakiba","year":"2018","journal-title":"Iran. J. Child Neurol."},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21176286","article-title":"Fanconi\u2013bickel syndrome: a review of the mechanisms that lead to dysglycaemia.","volume":"21","author":"Sharari","year":"2020","journal-title":"Int. J. Mol. Sci."},{"key":"B37","doi-asserted-by":"crossref","first-page":"W452","DOI":"10.1093\/nar\/gks539","article-title":"SIFT web server: predicting effects of amino acid substitutions on proteins.","volume":"40","author":"Sim","year":"2012","journal-title":"Nucleic Acids Res."},{"key":"B38","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/nprot.2015.123","article-title":"SIFT missense predictions for genomes.","volume":"11","author":"Vaser","year":"2016","journal-title":"Nat. Protoc."},{"key":"B39","doi-asserted-by":"publisher","first-page":"262","DOI":"10.1038\/sj.tpj.6500313","article-title":"Common VKORC1 and GGCX polymorphisms associated with warfarin dose.","volume":"5","author":"Wadelius","year":"2005","journal-title":"Pharmacogenomics J."},{"key":"B40","doi-asserted-by":"publisher","first-page":"795","DOI":"10.1038\/gim.2012.41","article-title":"Characterization and pathogenesis of anemia in glycogen storage disease type Ia and Ib.","volume":"14","author":"Wang","year":"2012","journal-title":"Genet. Med."}],"container-title":["Frontiers in Genetics"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2020.601566\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,1,13]],"date-time":"2021-01-13T21:56:06Z","timestamp":1610574966000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2020.601566\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,1,11]]},"references-count":40,"alternative-id":["10.3389\/fgene.2020.601566"],"URL":"https:\/\/doi.org\/10.3389\/fgene.2020.601566","relation":{},"ISSN":["1664-8021"],"issn-type":[{"value":"1664-8021","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,1,11]]},"article-number":"601566"}}