{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:21:29Z","timestamp":1790814089692,"version":"4.1.0"},"reference-count":99,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,12,22]],"date-time":"2021-12-22T00:00:00Z","timestamp":1640131200000},"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. Cell Dev. Biol."],"abstract":"<jats:p>Many common developmental disorders are thought to arise from a complex set of genetic and environmental risk factors. These factors interact with each other to affect the strength and duration of key developmental signaling pathways, thereby increasing the possibility that they fail to achieve the thresholds required for normal embryonic patterning. One such disorder, holoprosencephaly (HPE), serves as a useful model system in understanding various forms of multifactorial etiology. Genomic analysis of HPE cases, epidemiology, and mechanistic studies of animal models have illuminated multiple potential ways that risk factors interact to produce adverse developmental outcomes. Among these are: 1) interactions between driver and modifier genes; 2) oligogenic inheritance, wherein each parent provides predisposing variants in one or multiple distinct loci; 3) interactions between genetic susceptibilities and environmental risk factors that may be insufficient on their own; and 4) interactions of multiple genetic variants with multiple non-genetic risk factors. These studies combine to provide concepts that illuminate HPE and are also applicable to additional disorders with complex etiology, including neural tube defects, congenital heart defects, and oro-facial clefting.<\/jats:p>","DOI":"10.3389\/fcell.2021.795194","type":"journal-article","created":{"date-parts":[[2021,12,22]],"date-time":"2021-12-22T08:48:20Z","timestamp":1640162900000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":20,"title":["Concepts in Multifactorial Etiology of Developmental Disorders: Gene-Gene and Gene-Environment Interactions in Holoprosencephaly"],"prefix":"10.3389","volume":"9","author":[{"given":"Hsiao-Fan","family":"Lo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingi","family":"Hong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert S.","family":"Krauss","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,12,22]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"973","DOI":"10.1002\/ar.23791","article-title":"Clinical and Demographic Evaluation of a Holoprosencephaly Cohort from the Kyoto Collection of Human Embryos","volume":"301","author":"Abe","year":"2018","journal-title":"Anat. Rec."},{"key":"B2","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1186\/s12940-020-00611-z","article-title":"Prenatal Exposure to Pesticides and Risk for Holoprosencephaly: a Case-Control Study","volume":"19","author":"Addissie","year":"2020","journal-title":"Environ. Health"},{"key":"B3","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1002\/bdr2.1834","article-title":"Identifying Environmental Risk Factors and Gene-Environment Interactions in Holoprosencephaly","volume":"113","author":"Addissie","year":"2021","journal-title":"Birth Defects Res."},{"key":"B4","doi-asserted-by":"publisher","first-page":"224","DOI":"10.1002\/bdra.20447","article-title":"Fetal Ethanol Exposure Activates Protein Kinase a and impairsShh Expression in Prechordal Mesendoderm Cells in the Pathogenesis of Holoprosencephaly","volume":"82","author":"Aoto","year":"2008","journal-title":"Birth Defect Res. A."},{"key":"B5","doi-asserted-by":"publisher","first-page":"231","DOI":"10.1016\/j.ajhg.2011.07.001","article-title":"Mutations in CDON, Encoding a Hedgehog Receptor, Result in Holoprosencephaly and Defective Interactions with Other Hedgehog Receptors","volume":"89","author":"Bae","year":"2011","journal-title":"Am. J. Hum. Genet."},{"key":"B6","doi-asserted-by":"publisher","first-page":"2045","DOI":"10.1111\/acer.14430","article-title":"Patterns of Prenatal Alcohol Exposure and Alcohol\u2010Related Dysmorphic Features","volume":"44","author":"Bandoli","year":"2020","journal-title":"Alcohol. Clin. Exp. Res."},{"key":"B7","doi-asserted-by":"publisher","first-page":"dev191064","DOI":"10.1242\/dev.191064","article-title":"Gene-environment Interactions: Aligning Birth Defects Research with Complex Etiology","volume":"147","author":"Beames","year":"2020","journal-title":"Development"},{"key":"B8","doi-asserted-by":"publisher","first-page":"185","DOI":"10.1006\/dbio.1998.8995","article-title":"Ethanol Impairs Migration of the Prechordal Plate in the Zebrafish Embryo","volume":"201","author":"Blader","year":"1998","journal-title":"Develop. Biol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"162","DOI":"10.1002\/ar.10110","article-title":"Midline Corpus Callosum Is a Neuroanatomical Focus of Fetal Alcohol Damage","volume":"269","author":"Bookstein","year":"2002","journal-title":"Anat. Rec."},{"key":"B10","doi-asserted-by":"publisher","first-page":"595","DOI":"10.1039\/c5np00153f","article-title":"I Only Have Eye for Ewe: the Discovery of Cyclopamine and Development of Hedgehog Pathway-Targeting Drugs","volume":"33","author":"Chen","year":"2016","journal-title":"Nat. Prod. Rep."},{"key":"B11","doi-asserted-by":"publisher","first-page":"2743","DOI":"10.1101\/gad.1025302","article-title":"Inhibition of Hedgehog Signaling by Direct Binding of Cyclopamine to Smoothened","volume":"16","author":"Chen","year":"2002","journal-title":"Genes Dev."},{"key":"B12","doi-asserted-by":"publisher","first-page":"485","DOI":"10.1172\/jci200419596","article-title":"Temporal Perturbations in Sonic Hedgehog Signaling Elicit the Spectrum of Holoprosencephaly Phenotypes","volume":"114","author":"Cordero","year":"2004","journal-title":"J. Clin. Invest."},{"key":"B13","doi-asserted-by":"publisher","first-page":"771","DOI":"10.1001\/archneur.1993.00540070083022","article-title":"Midline Cerebral Dysgenesis, Dysfunction of the Hypothalamic-Pituitary Axis, and Fetal Alcohol Effects","volume":"50","author":"Coulter","year":"1993","journal-title":"Arch. Neurol."},{"key":"B14","doi-asserted-by":"publisher","first-page":"320","DOI":"10.1002\/(sici)1096-8628(20000214)90::4<320:aid-ajmg11>3.0.co;2-8","article-title":"Risk Factors for Cytogenetically normal Holoprosencephaly in California: a Population-Based Case-Control Study","volume":"90","author":"Croen","year":"2000","journal-title":"Am. J. Med. Genet."},{"key":"B15","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1542\/peds.34.2.256","article-title":"The Face Predicts the Brain: Diagnostic Significance of Median Facial Anomalies for Holoprosencephaly (Arhinencephaly)","volume":"34","author":"DeMyer","year":"1964","journal-title":"Pediatrics"},{"key":"B16","doi-asserted-by":"publisher","first-page":"1238","DOI":"10.1111\/j.1530-0277.2009.00949.x","article-title":"Ethanol Teratogenesis in Five Inbred Strains of Mice","volume":"33","author":"Downing","year":"2009","journal-title":"Alcohol. Clin. Exp. Res."},{"key":"B17","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1136\/jmedgenet-2020-107237","article-title":"Mutations in Phospholipase C Eta-1 (PLCH1) Are Associated with Holoprosencephaly","author":"Drissi","year":"2021","journal-title":"J. Med. Genet."},{"key":"B18","doi-asserted-by":"publisher","first-page":"1329","DOI":"10.1002\/humu.23038","article-title":"Mutational Spectrum in Holoprosencephaly Shows that FGF Is a New Major Signaling Pathway","volume":"37","author":"Dubourg","year":"2016","journal-title":"Hum. Mutat."},{"key":"B19","doi-asserted-by":"publisher","first-page":"258","DOI":"10.1002\/ajmg.c.31619","article-title":"Recent Advances in Understanding Inheritance of Holoprosencephaly","volume":"178","author":"Dubourg","year":"2018","journal-title":"Am. J. Med. Genet."},{"key":"B20","doi-asserted-by":"publisher","first-page":"1122","DOI":"10.1093\/hmg\/ddq556","article-title":"NOTCH, a New Signaling Pathway Implicated in Holoprosencephaly","volume":"20","author":"Dup\u00e9","year":"2010","journal-title":"Hum. Mol. Genet."},{"key":"B21","doi-asserted-by":"publisher","first-page":"dev189076","DOI":"10.1242\/dev.189076","article-title":"The Hedgehog Co-receptor BOC Differentially Regulates SHH Signaling during Craniofacial Development","volume":"147","author":"Echevarr\u00eda-Andino","year":"2020","journal-title":"Development"},{"key":"B22","doi-asserted-by":"publisher","first-page":"1988","DOI":"10.1111\/acer.14427","article-title":"Multifactorial Genetic and Environmental Hedgehog Pathway Disruption Sensitizes Embryos to Alcohol\u2010Induced Craniofacial Defects","volume":"44","author":"Everson","year":"2020","journal-title":"Alcohol. Clin. Exp. Res."},{"key":"B23","doi-asserted-by":"publisher","first-page":"107006","DOI":"10.1289\/ehp5260","article-title":"Developmental Toxicity Assessment of Piperonyl Butoxide Exposure Targeting Sonic Hedgehog Signaling and Forebrain and Face Morphogenesis in the Mouse: An In Vitro and In Vivo Study","volume":"127","author":"Everson","year":"2019","journal-title":"Environ. Health Perspect."},{"key":"B24","doi-asserted-by":"publisher","first-page":"413","DOI":"10.1111\/j.1399-0004.2008.00994.x","article-title":"The Ups and downs of Holoprosencephaly: Dorsal versus Ventral Patterning Forces","volume":"73","author":"Fernandes","year":"2008","journal-title":"Clin. Genet."},{"key":"B25","doi-asserted-by":"publisher","first-page":"659612","DOI":"10.3389\/fgene.2021.659612","article-title":"Gene Environment Interactions in the Etiology of Neural Tube Defects","volume":"12","author":"Finnell","year":"2021","journal-title":"Front. Genet."},{"key":"B26","doi-asserted-by":"publisher","first-page":"16057","DOI":"10.1038\/s41598-019-52336-w","article-title":"Cannabinoids Exacerbate Alcohol Teratogenesis by a CB1-Hedgehog Interaction","volume":"9","author":"Fish","year":"2019","journal-title":"Sci. Rep."},{"key":"B27","doi-asserted-by":"publisher","first-page":"1934","DOI":"10.12688\/f1000research.16190.1","article-title":"Positive and Negative Regulation of Shh Signalling in Vertebrate Retinal Development","volume":"7","author":"Gallardo","year":"2018","journal-title":"F1000Research"},{"key":"B28","doi-asserted-by":"publisher","first-page":"236","DOI":"10.1016\/j.devcel.2008.07.003","article-title":"Haploinsufficiency of Six3 Fails to Activate Sonic Hedgehog Expression in the Ventral Forebrain and Causes Holoprosencephaly","volume":"15","author":"Geng","year":"2008","journal-title":"Develop. Cel"},{"key":"B29","doi-asserted-by":"publisher","first-page":"e377","DOI":"10.1002\/wdev.377","article-title":"Signaling in the Primary Cilium through the Lens of the Hedgehog Pathway","volume":"9","author":"Gigante","year":"2020","journal-title":"WIREs Dev. Biol."},{"key":"B30","doi-asserted-by":"publisher","first-page":"2243","DOI":"10.1002\/ajmg.a.61759","article-title":"Ocular Measurements in Fetal Alcohol Spectrum Disorders","volume":"182","author":"Gomez","year":"2020","journal-title":"Am. J. Med. Genet."},{"key":"B31","doi-asserted-by":"publisher","first-page":"626","DOI":"10.1002\/dvdy.41","article-title":"A Forebrain Undivided: Unleashing Model Organisms to Solve the Mysteries of Holoprosencephaly","volume":"248","author":"Grinblat","year":"2019","journal-title":"Dev. Dyn."},{"key":"B32","doi-asserted-by":"publisher","first-page":"3777","DOI":"10.1242\/dev.01935","article-title":"Cerebral Hypoplasia and Craniofacial Defects in Mice Lacking Heparan Sulfate Ndst1 Gene Function","volume":"132","author":"Grobe","year":"2005","journal-title":"Development"},{"key":"B33","doi-asserted-by":"publisher","first-page":"e3183","DOI":"10.1210\/clinem\/dgaa249","article-title":"Disrupted Hypothalamo-Pituitary Axis in Association with Reduced SHH Underlies the Pathogenesis of NOTCH-Deficiency","volume":"105","author":"Hamdi-Roz\u00e9","year":"2020","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"B34","doi-asserted-by":"publisher","first-page":"1307","DOI":"10.1242\/dmm.026328","article-title":"Gli2 Gene-Environment Interactions Contribute to the Etiological Complexity of Holoprosencephaly: Evidence from a Mouse Model","volume":"9","author":"Heyne","year":"2016","journal-title":"Dis. Model. Mech."},{"key":"B35","doi-asserted-by":"publisher","first-page":"e60351","DOI":"10.7554\/eLife.60351","article-title":"Cdon Mutation and Fetal Alcohol Converge on Nodal Signaling in a Mouse Model of Holoprosencephaly","volume":"9","author":"Hong","year":"2020","journal-title":"eLife"},{"key":"B36","doi-asserted-by":"publisher","first-page":"e1002999","DOI":"10.1371\/journal.pgen.1002999","article-title":"Cdon Mutation and Fetal Ethanol Exposure Synergize to Produce Midline Signaling Defects and Holoprosencephaly Spectrum Disorders in Mice","volume":"8","author":"Hong","year":"2012","journal-title":"PLOS Genet."},{"key":"B37","doi-asserted-by":"publisher","first-page":"140","DOI":"10.1002\/ajmg.c.31611","article-title":"Modeling the Complex Etiology of Holoprosencephaly in Mice","volume":"178","author":"Hong","year":"2018","journal-title":"Am. J. Med. Genet."},{"key":"B38","doi-asserted-by":"publisher","first-page":"1464","DOI":"10.1002\/humu.23286","article-title":"BOC Is a Modifier Gene in Holoprosencephaly","volume":"38","author":"Hong","year":"2017","journal-title":"Hum. Mutat."},{"key":"B39","doi-asserted-by":"publisher","first-page":"e20154256","DOI":"10.1542\/peds.2015-4256","article-title":"Updated Clinical Guidelines for Diagnosing Fetal Alcohol Spectrum Disorders","volume":"138","author":"Hoyme","year":"2016","journal-title":"Pediatrics"},{"key":"B40","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1542\/peds.2004-0259","article-title":"A Practical Clinical Approach to Diagnosis of Fetal Alcohol Spectrum Disorders: Clarification of the 1996 Institute of Medicine Criteria","volume":"115","author":"Hoyme","year":"2005","journal-title":"Pediatrics"},{"key":"B41","doi-asserted-by":"publisher","first-page":"1348","DOI":"10.1038\/ng.230","article-title":"Regulation of a Remote Shh Forebrain Enhancer by the Six3 Homeoprotein","volume":"40","author":"Jeong","year":"2008","journal-title":"Nat. Genet."},{"key":"B42","doi-asserted-by":"publisher","first-page":"329","DOI":"10.1002\/(sici)1096-8628(19960202)61:4<329::aid-ajmg6>3.0.co;2-p","article-title":"Fetal Alcohol Syndrome: Craniofacial and central Nervous System Manifestations","volume":"61","author":"Johnson","year":"1996","journal-title":"Am. J. Med. Genet."},{"key":"B43","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1007\/s00439-014-1487-4","article-title":"STIL Mutation Causes Autosomal Recessive Microcephalic Lobar Holoprosencephaly","volume":"134","author":"Kakar","year":"2015","journal-title":"Hum. Genet."},{"key":"B44","doi-asserted-by":"publisher","first-page":"3415","DOI":"10.1073\/pnas.1416463112","article-title":"Endocannabinoids Are Conserved Inhibitors of the Hedgehog Pathway","volume":"112","author":"Khaliullina","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"B45","doi-asserted-by":"publisher","first-page":"e89448","DOI":"10.1371\/journal.pone.0089448","article-title":"The Teratogenic Effects of Prenatal Ethanol Exposure Are Exacerbated by Sonic Hedgehog or GLI2 Haploinsufficiency in the Mouse","volume":"9","author":"Kietzman","year":"2014","journal-title":"PLOS ONE"},{"key":"B46","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1093\/brain\/awy290","article-title":"Integrated Clinical and Omics Approach to Rare Diseases: Novel Genes and Oligogenic Inheritance in Holoprosencephaly","volume":"142","author":"Kim","year":"2018","journal-title":"Brain"},{"key":"B47","doi-asserted-by":"publisher","first-page":"10","DOI":"10.3389\/fcvm.2021.653244","article-title":"Genetic and Cellular Interaction during Cardiovascular Development Implicated in Congenital Heart Diseases","volume":"8","author":"Kodo","year":"2021","journal-title":"Front. Cardiovasc. Med."},{"key":"B48","doi-asserted-by":"publisher","first-page":"204","DOI":"10.1016\/j.sbi.2019.05.015","article-title":"Structures of Vertebrate Patched and Smoothened Reveal Intimate Links between Cholesterol and Hedgehog Signalling","volume":"57","author":"Kowatsch","year":"2019","journal-title":"Curr. Opin. Struct. Biol."},{"key":"B49","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1017\/s1462399407000440","article-title":"Holoprosencephaly: New Models, New Insights","volume":"9","author":"Krauss","year":"2007","journal-title":"Expert Rev. Mol. Med."},{"key":"B50","doi-asserted-by":"publisher","first-page":"569","DOI":"10.1016\/bs.ctdb.2015.12.010","article-title":"Gene-Environment Interactions and the Etiology of Birth Defects","volume":"116","author":"Krauss","year":"2016","journal-title":"Curr. Top. Dev. Biol."},{"key":"B51","doi-asserted-by":"publisher","first-page":"2631","DOI":"10.1093\/brain\/awz210","article-title":"Cohesin Complex-Associated Holoprosencephaly","volume":"142","author":"Kruszka","year":"","journal-title":"Brain"},{"key":"B52","doi-asserted-by":"publisher","first-page":"990","DOI":"10.1016\/j.ajhg.2019.03.017","article-title":"A CCR4-NOT Transcription Complex, Subunit 1, CNOT1, Variant Associated with Holoprosencephaly","volume":"104","author":"Kruszka","year":"","journal-title":"Am. J. Hum. Genet."},{"key":"B53","doi-asserted-by":"publisher","first-page":"229","DOI":"10.1002\/ajmg.c.31620","article-title":"Syndromes Associated with Holoprosencephaly","volume":"178","author":"Kruszka","year":"2018","journal-title":"Am. J. Med. Genet."},{"key":"B54","doi-asserted-by":"publisher","first-page":"389","DOI":"10.1136\/jmg.2008.063818","article-title":"Clinical Spectrum of SIX3-Associated Mutations in Holoprosencephaly: Correlation between Genotype, Phenotype and Function","volume":"46","author":"Lacbawan","year":"2009","journal-title":"J. Med. Genet."},{"key":"B55","doi-asserted-by":"publisher","first-page":"585","DOI":"10.1002\/bdra.20479","article-title":"Frequency of Holoprosencephaly in the International Clearinghouse Birth Defects Surveillance Systems: Searching for Population Variations","volume":"82","author":"Leoncini","year":"2008","journal-title":"Birth Defect Res. A."},{"key":"B56","doi-asserted-by":"publisher","first-page":"2319","DOI":"10.1002\/dvdy.22366","article-title":"Loss of Procollagen IIA from the Anterior Mesendoderm Disrupts the Development of Mouse Embryonic Forebrain","volume":"239","author":"Leung","year":"2010","journal-title":"Dev. Dyn."},{"key":"B57","doi-asserted-by":"publisher","first-page":"1161","DOI":"10.2105\/ajph.73.10.1161","article-title":"The Association of Marijuana Use with Outcome of Pregnancy","volume":"73","author":"Linn","year":"1983","journal-title":"Am. J. Public Health"},{"key":"B58","doi-asserted-by":"publisher","first-page":"dev199585","DOI":"10.1242\/dev.199585","article-title":"\u03949-Tetrahydrocannabinol Inhibits Hedgehog-dependent Patterning during Development","volume":"148","author":"Lo","year":"2021","journal-title":"Development"},{"key":"B59","doi-asserted-by":"publisher","first-page":"299","DOI":"10.1016\/bs.ctdb.2015.09.001","article-title":"Facial Morphogenesis","volume":"115","author":"Marcucio","year":"2015","journal-title":"Curr. Top. Dev. Biol."},{"key":"B60","doi-asserted-by":"publisher","first-page":"592271","DOI":"10.3389\/fcell.2020.592271","article-title":"Non-syndromic Cleft Palate: An Overview on Human Genetic and Environmental Risk Factors","volume":"8","author":"Martinelli","year":"2020","journal-title":"Front. Cel Dev. Biol."},{"key":"B61","doi-asserted-by":"publisher","first-page":"4883","DOI":"10.1158\/1078-0432.ccr-11-2509","article-title":"Molecular Pathways: The Hedgehog Signaling Pathway in Cancer: Figure 1","volume":"18","author":"McMillan","year":"2012","journal-title":"Clin. Cancer Res."},{"key":"B62","doi-asserted-by":"publisher","first-page":"dev199307","DOI":"10.1242\/dev.199307","article-title":"Identification of Disease-Relevant Modulators of the SHH Pathway in the Developing Brain","volume":"148","author":"Mecklenburg","year":"2021","journal-title":"Development"},{"key":"B63","doi-asserted-by":"publisher","first-page":"62","DOI":"10.1002\/ajmg.c.30244","article-title":"Risk Factors for Non-syndromic Holoprosencephaly in the National Birth Defects Prevention Study","author":"Miller","year":"2010","journal-title":"Am. J. Med. Genet."},{"key":"B64","doi-asserted-by":"publisher","first-page":"566","DOI":"10.1097\/nen.0b013e3180986e1b","article-title":"The Morphogen Signaling Network in Forebrain Development and Holoprosencephaly","volume":"66","author":"Monuki","year":"2007","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"B65","doi-asserted-by":"publisher","first-page":"e0117418","DOI":"10.1371\/journal.pone.0117418","article-title":"Homozygous STIL Mutation Causes Holoprosencephaly and Microcephaly in Two Siblings","volume":"10","author":"Mouden","year":"2015","journal-title":"PLoS One"},{"key":"B66","first-page":"6203","article-title":"Holoprosencephaly","volume-title":"The Metabolic & Molecular Bases of Inherited Disease","author":"Muenke","year":"2001"},{"key":"B67","doi-asserted-by":"publisher","first-page":"477","DOI":"10.1002\/ajmg.1320290302","article-title":"Facial Midline Defect in the Fetal Alcohol Syndrome. Embryogenetic Considerations in Two Clinical Cases","volume":"29","author":"Neri","year":"1988","journal-title":"Am. J. Med. Genet."},{"key":"B68","doi-asserted-by":"publisher","first-page":"2756","DOI":"10.1002\/ajmg.a.62186","article-title":"Hedgehog Acyl\u2010transferase\u2010related Multiple Congenital Anomalies: Report of an Additional Family and Delineation of the Syndrome","volume":"185","author":"Pande","year":"2021","journal-title":"Am. J. Med. Genet."},{"key":"B69","doi-asserted-by":"publisher","first-page":"145","DOI":"10.1146\/annurev-cellbio-100616-060847","article-title":"Sending and Receiving Hedgehog Signals","volume":"33","author":"Petrov","year":"2017","journal-title":"Annu. Rev. Cel Dev. Biol."},{"key":"B70","doi-asserted-by":"publisher","first-page":"397","DOI":"10.1016\/j.tibs.2020.01.006","article-title":"Mechanistic Insights into the Generation and Transduction of Hedgehog Signaling","volume":"45","author":"Qi","year":"2020","journal-title":"Trends Biochem. Sci."},{"key":"B71","doi-asserted-by":"publisher","first-page":"1303","DOI":"10.1038\/s41589-020-00678-2","article-title":"Cholesterol Access in Cellular Membranes Controls Hedgehog Signaling","volume":"16","author":"Radhakrishnan","year":"2020","journal-title":"Nat. Chem. Biol."},{"key":"B72","doi-asserted-by":"publisher","first-page":"1085","DOI":"10.1177\/0009922819861281","article-title":"Cannabis Teratology Explains Current Patterns of Coloradan Congenital Defects: The Contribution of Increased Cannabinoid Exposure to Rising Teratological Trends","volume":"58","author":"Reece","year":"2019","journal-title":"Clin. Pediatr. (Phila)"},{"key":"B73","doi-asserted-by":"publisher","first-page":"539","DOI":"10.1186\/s12887-020-02431-z","article-title":"Contemporary Epidemiology of Rising Atrial Septal Defect Trends across USA 1991-2016: a Combined Ecological Geospatiotemporal and Causal Inferential Study","volume":"20","author":"Reece","year":"2020","journal-title":"BMC Pediatr."},{"key":"B74","doi-asserted-by":"publisher","first-page":"128414","DOI":"10.1016\/j.chemosphere.2020.128414","article-title":"Examining the Developmental Toxicity of Piperonyl Butoxide as a Sonic Hedgehog Pathway Inhibitor","volume":"264","author":"Rivera-Gonz\u00e1lez","year":"2021","journal-title":"Chemosphere"},{"key":"B75","doi-asserted-by":"publisher","first-page":"357","DOI":"10.1038\/ng1196-357","article-title":"Mutations in the Human Sonic Hedgehog Gene Cause Holoprosencephaly","volume":"14","author":"Roessler","year":"1996","journal-title":"Nat. Genet."},{"key":"B76","doi-asserted-by":"publisher","first-page":"1416","DOI":"10.1002\/humu.23590","article-title":"Common Genetic Causes of Holoprosencephaly Are Limited to a Small Set of Evolutionarily Conserved Driver Genes of Midline Development Coordinated by TGF-\u03b2, Hedgehog, and FGF Signaling","volume":"39","author":"Roessler","year":"","journal-title":"Hum. Mutat."},{"key":"B77","doi-asserted-by":"publisher","first-page":"165","DOI":"10.1002\/ajmg.c.31615","article-title":"Holoprosencephaly in the Genomics Era","volume":"178","author":"Roessler","year":"","journal-title":"Am. J. Med. Genet."},{"key":"B78","doi-asserted-by":"publisher","first-page":"658","DOI":"10.1016\/j.ymgme.2012.01.005","article-title":"Utilizing Prospective Sequence Analysis of SHH, ZIC2, SIX3 and TGIF in Holoprosencephaly Probands to Describe the Parameters Limiting the Observed Frequency of Mutant Gene\u00d7gene Interactions","volume":"105","author":"Roessler","year":"2012","journal-title":"Mol. Genet. Metab."},{"key":"B79","doi-asserted-by":"publisher","first-page":"dev182154","DOI":"10.1242\/dev.182154","article-title":"Establishing Neuronal Diversity in the Spinal Cord: a Time and a Place","volume":"146","author":"Sagner","year":"2019","journal-title":"Development"},{"key":"B80","doi-asserted-by":"publisher","first-page":"404","DOI":"10.1002\/bdr2.1643","article-title":"Association between Maternal Occupational Exposure to Polycyclic Aromatic Hydrocarbons and Rare Birth Defects of the Face and central Nervous System","volume":"112","author":"Santiago-Col\u00f3n","year":"2020","journal-title":"Birth Defects Res."},{"key":"B81","doi-asserted-by":"publisher","first-page":"728","DOI":"10.1242\/bio.20147989","article-title":"Boc Modifies the Spectrum of Holoprosencephaly in the Absence of Gas1 Function","volume":"3","author":"Seppala","year":"2014","journal-title":"Biol. Open"},{"key":"B82","doi-asserted-by":"publisher","first-page":"246","DOI":"10.1038\/nchembio.1776","article-title":"Regulation of the Oncoprotein Smoothened by Small Molecules","volume":"11","author":"Sharpe","year":"2015","journal-title":"Nat. Chem. Biol."},{"key":"B83","doi-asserted-by":"publisher","first-page":"623","DOI":"10.1002\/bdr2.1888","article-title":"A Life\u2010table Analysis of the Intrauterine Fate of Malformed Human Embryos and Fetuses","volume":"113","author":"Shiota","year":"2021","journal-title":"Birth Defects Res."},{"key":"B84","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1002\/ajmg.c.30248","article-title":"Early Pathogenesis of Holoprosencephaly","author":"Shiota","year":"2010","journal-title":"Am. J. Med. Genet."},{"key":"B85","doi-asserted-by":"publisher","first-page":"473","DOI":"10.1136\/jmedgenet-2012-101008","article-title":"Genotypic and Phenotypic Analysis of 396 Individuals with Mutations inSonic Hedgehog","volume":"49","author":"Solomon","year":"2012","journal-title":"J. Med. Genet."},{"key":"B86","doi-asserted-by":"publisher","first-page":"513","DOI":"10.1136\/jmg.2009.073049","article-title":"Mutations in ZIC2 in Human Holoprosencephaly: Description of a Novel ZIC2 Specific Phenotype and Comprehensive Analysis of 157 Individuals","volume":"47","author":"Solomon","year":"2010","journal-title":"J. Med. Genet."},{"key":"B87","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1111\/cga.12234","article-title":"SIX3 Deletions and Incomplete Penetrance in Families Affected by Holoprosencephaly","volume":"58","author":"Stokes","year":"2018","journal-title":"Congenit. Anom."},{"key":"B88","first-page":"309","article-title":"Embryonic Origin of Holoprosencephaly: Interrelationship of the Developing Brain and Face","volume":"1","author":"Sulik","year":"1982","journal-title":"Scan Electron. Microsc."},{"key":"B89","doi-asserted-by":"publisher","first-page":"936","DOI":"10.1126\/science.6795717","article-title":"Fetal Alcohol Syndrome: Embryogenesis in a Mouse Model","volume":"214","author":"Sulik","year":"1981","journal-title":"Science"},{"key":"B90","doi-asserted-by":"publisher","first-page":"151","DOI":"10.1002\/ajmg.c.31614","article-title":"Nongenetic Risk Factors for Holoprosencephaly: An Updated Review of the Epidemiologic Literature","volume":"178","author":"Summers","year":"2018","journal-title":"Am. J. Med. Genet."},{"key":"B91","doi-asserted-by":"publisher","first-page":"1769","DOI":"10.1111\/acer.13820","article-title":"Combined Face-Brain Morphology and Associated Neurocognitive Correlates in Fetal Alcohol Spectrum Disorders","volume":"42","author":"Suttie","year":"2018","journal-title":"Alcohol. Clin. Exp. Res."},{"key":"B92","doi-asserted-by":"publisher","first-page":"266","DOI":"10.1111\/cge.13598","article-title":"Novel Heterozygous Variants in KMT2D Associated with Holoprosencephaly","volume":"96","author":"Tekendo-Ngongang","year":"2019","journal-title":"Clin. Genet."},{"key":"B93","article-title":"Holoprosencephaly Overview","volume-title":"GeneReviews","author":"Tekendo-Ngongang","year":"2020"},{"key":"B94","doi-asserted-by":"publisher","first-page":"517","DOI":"10.1093\/toxsci\/kfs165","article-title":"The Insecticide Synergist Piperonyl Butoxide Inhibits Hedgehog Signaling: Assessing Chemical Risks","volume":"128","author":"Wang","year":"2012","journal-title":"Toxicol. Sci."},{"key":"B95","doi-asserted-by":"publisher","first-page":"231","DOI":"10.1002\/tera.1420270211","article-title":"Some Teratogenic Properties of Ethanol and Acetaldehyde in C57BL\/6J Mice: Implications for the Study of the Fetal Alcohol Syndrome","volume":"27","author":"Webster","year":"1983","journal-title":"Teratology"},{"key":"B96","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1016\/s1534-5807(04)00027-9","article-title":"Early Steps in the Development of the Forebrain","volume":"6","author":"Wilson","year":"2004","journal-title":"Develop. Cel"},{"key":"B97","doi-asserted-by":"publisher","first-page":"3405","DOI":"10.1242\/dev.052340","article-title":"Quantitative Analyses Link Modulation of Sonic Hedgehog Signaling to Continuous Variation in Facial Growth and Shape","volume":"137","author":"Young","year":"2010","journal-title":"Development"},{"key":"B98","doi-asserted-by":"publisher","first-page":"368","DOI":"10.1242\/dmm.005744","article-title":"Bocmodifies the Holoprosencephaly Spectrum ofCdomutant Mice","volume":"4","author":"Zhang","year":"2011","journal-title":"Dis. Model. Mech."},{"key":"B99","doi-asserted-by":"publisher","first-page":"657","DOI":"10.1016\/j.devcel.2006.04.005","article-title":"Cdo Functions at Multiple Points in the Sonic Hedgehog Pathway, and Cdo-Deficient Mice Accurately Model Human Holoprosencephaly","volume":"10","author":"Zhang","year":"2006","journal-title":"Develop. Cel"}],"container-title":["Frontiers in Cell and Developmental Biology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2021.795194\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,12,22]],"date-time":"2021-12-22T08:48:27Z","timestamp":1640162907000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2021.795194\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12,22]]},"references-count":99,"alternative-id":["10.3389\/fcell.2021.795194"],"URL":"https:\/\/doi.org\/10.3389\/fcell.2021.795194","relation":{},"ISSN":["2296-634X"],"issn-type":[{"value":"2296-634X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,12,22]]},"article-number":"795194"}}