{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T13:23:45Z","timestamp":1788528225185,"version":"build-2803163510"},"reference-count":39,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"6","license":[{"start":{"date-parts":[[2025,11,1]],"date-time":"2025-11-01T00:00:00Z","timestamp":1761955200000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-sa\/4.0"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2025,11]]},"abstract":"<jats:title>\n                    A\n                    <jats:sc>BSTRACT<\/jats:sc>\n                  <\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background:<\/jats:title>\n                    <jats:p>Anorectal malformations (ARM) and hypospadias are common congenital anomalies that occasionally co-occur, suggesting shared developmental pathways. Despite their clinical significance, the genetic etiology of combined ARM-hypospadias remains poorly understood.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective:<\/jats:title>\n                    <jats:p>The objective of this study was to identify genetic variants underlying concurrent ARM and hypospadias using whole exome sequencing and elucidate the molecular mechanisms driving their co-occurrence.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Materials and Methods:<\/jats:title>\n                    <jats:p>Six boys with concurrent ARM and hypospadias underwent whole exome sequencing. Variants were filtered using stringent bioinformatic criteria (Minor Allele Frequency (MAF) &lt;0.05, Combined Annotation Dependent Depletion (CADD) &gt;20) and analyzed for pathogenicity using multiple prediction tools. Gene enrichment analysis, protein\u2013protein interaction networks, and tissue expression profiles were evaluated. All patients had normal 46, XY karyotypes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>\n                      Five patients harbored a recurrent heterozygous missense variant in\n                      <jats:italic toggle=\"yes\">ESRRA<\/jats:italic>\n                      (c.1162C&gt;T; p.Leu388Phe), whereas the sixth patient carried a Hemizygous\n                      <jats:italic toggle=\"yes\">STARD8<\/jats:italic>\n                      variant (c.2950C&gt;T; p.Leu984Phe).\n                      <jats:italic toggle=\"yes\">ESRRA<\/jats:italic>\n                      encodes an orphan nuclear receptor regulating steroidogenesis, whereas\n                      <jats:italic toggle=\"yes\">STARD8<\/jats:italic>\n                      modulates Rho GTPase signaling and cytoskeletal dynamics. Pathway analysis revealed\n                      <jats:italic toggle=\"yes\">ESRRA<\/jats:italic>\n                      enrichment in steroid hormone biosynthesis and oestrogen signaling, whereas\n                      <jats:italic toggle=\"yes\">STARD8<\/jats:italic>\n                      was enriched in epithelial morphogenesis and cell adhesion pathways. String analysis confirmed\n                      <jats:italic toggle=\"yes\">ESRRA<\/jats:italic>\n                      \u2019s predicted transcriptional regulation of\n                      <jats:italic toggle=\"yes\">STARD8<\/jats:italic>\n                      . Both genes showed peak expression during critical urogenital development windows (8-14 weeks).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion:<\/jats:title>\n                    <jats:p>\n                      This study suggests a potential\n                      <jats:italic toggle=\"yes\">ESRRA\u2013STARD8<\/jats:italic>\n                      regulatory pathway contributing to the pathogenesis of concurrent ARM and hypospadias. The convergence of hormonal dysregulation (via\n                      <jats:italic toggle=\"yes\">ESRRA<\/jats:italic>\n                      ) and structural defects (via\n                      <jats:italic toggle=\"yes\">STARD8<\/jats:italic>\n                      ) provides a unified molecular mechanism for these complex malformations. These findings have immediate implications for genetic screening, counseling, and potentially personalized surgical management of affected children.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.4103\/jiaps.jiaps_144_25","type":"journal-article","created":{"date-parts":[[2025,11,1]],"date-time":"2025-11-01T07:00:14Z","timestamp":1761980414000},"page":"719-727","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":1,"title":["Convergent Genetic Architecture in Concurrent Anorectal Malformations and Hypospadias: The ESRRA-STARD8 Axis as a Key Regulator of Urogenital Development"],"prefix":"10.4103","volume":"30","author":[{"given":"Chandramouli","family":"Goswami","sequence":"first","affiliation":[{"name":"Department of Paediatric Surgery, All India Institute of Medical Sciences, New Delhi, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jyoti","family":"Sharma","sequence":"additional","affiliation":[{"name":"Department of Paediatric Surgery, All India Institute of Medical Sciences, New Delhi, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rahila","family":"Sardar","sequence":"additional","affiliation":[{"name":"CEO, Vgenomics, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dinesh","family":"Gupta","sequence":"additional","affiliation":[{"name":"Translational Bioinformatics, International Centre for Genetic Engineering and Biotechnology, New Delhi, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sourabh","family":"Kumar","sequence":"additional","affiliation":[{"name":"Department of Paediatric Surgery, All India Institute of Medical Sciences, New Delhi, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vishesh","family":"Jain","sequence":"additional","affiliation":[{"name":"Department of Paediatric Surgery, All India Institute of Medical Sciences, New Delhi, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anjan Kumar","family":"Dhua","sequence":"additional","affiliation":[{"name":"Department of Paediatric Surgery, All India Institute of Medical Sciences, New Delhi, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Devendra Kumar","family":"Yadav","sequence":"additional","affiliation":[{"name":"Department of Paediatric Surgery, All India Institute of Medical Sciences, New Delhi, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harpreet","family":"Singh","sequence":"additional","affiliation":[{"name":"Indian Council of Medical Research, New Delhi, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Prabudh","family":"Goel","sequence":"additional","affiliation":[{"name":"Department of Paediatric Surgery, All India Institute of Medical Sciences, New Delhi, India"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2025,11,1]]},"reference":[{"key":"R1-20260904","doi-asserted-by":"crossref","first-page":"831","DOI":"10.1542\/peds.100.5.831","article-title":"Hypospadias trends in two US surveillance systems","volume":"100","author":"Paulozzi","year":"1997","journal-title":"Pediatrics"},{"key":"R2-20260904","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1111\/j.1365-3016.1990.tb00650.x","article-title":"An epidemiological study of congenital anorectal malformations:15 Danish birth cohorts followed for 7 years","volume":"4","author":"Christensen","year":"1990","journal-title":"Paediatr Perinat Epidemiol"},{"key":"R3-20260904","first-page":"231","article-title":"Incidence, frequency of types, and etiology of anorectal malformations","volume":"24","author":"Smith","year":"1988","journal-title":"Birth Defects Orig Artic Ser"},{"key":"R4-20260904","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1002\/ajmg.1320250619","article-title":"Imperforate anus in 700,000 consecutive liveborn infants","volume":"2","author":"Spouge","year":"1986","journal-title":"Am J Med Genet Suppl"},{"key":"R5-20260904","doi-asserted-by":"crossref","first-page":"64.e1","DOI":"10.1016\/j.jpurol.2020.11.015","article-title":"Patterns of co-occurring birth defects among infants with hypospadias","volume":"17","author":"Ludorf","year":"2021","journal-title":"J Pediatr Urol"},{"key":"R6-20260904","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1093\/humupd\/dms002","article-title":"Aetiology of hypospadias:A systematic review of genes and environment","volume":"18","author":"van","year":"2012","journal-title":"Hum Reprod Update"},{"key":"R7-20260904","doi-asserted-by":"crossref","first-page":"371","DOI":"10.3390\/analytica3030025","article-title":"Performance of spectrophotometric and fluorometric DNA quantification methods","volume":"3","author":"Bruijns","year":"2022","journal-title":"Analytica"},{"key":"R8-20260904","doi-asserted-by":"crossref","first-page":"582","DOI":"10.1186\/s12864-022-08825-w","article-title":"Performance comparison of Agilent new sureselect all exon v8 probes with v7 probes for exome sequencing","volume":"23","author":"Belova","year":"2022","journal-title":"BMC Genomics"},{"key":"R9-20260904","doi-asserted-by":"crossref","first-page":"3137","DOI":"10.1093\/bioinformatics\/btx373","article-title":"FQC Dashboard:Integrates FastQC results into a web-based, interactive, and extensible FASTQ quality control tool","volume":"33","author":"Brown","year":"2017","journal-title":"Bioinformatics"},{"key":"R10-20260904","doi-asserted-by":"crossref","first-page":"2114","DOI":"10.1093\/bioinformatics\/btu170","article-title":"Trimmomatic:A flexible trimmer for Illumina sequence data","volume":"30","author":"Bolger","year":"2014","journal-title":"Bioinformatics"},{"key":"R11-20260904","doi-asserted-by":"crossref","first-page":"2404","DOI":"10.1093\/bioinformatics\/btac137","article-title":"BWA-MEME:BWA-MEM emulated with a machine learning approach","volume":"38","author":"Jung","year":"2022","journal-title":"Bioinformatics"},{"issue":"Suppl 7","key":"R12-20260904","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1186\/s12859-016-1097-3","article-title":"Evaluating the necessity of PCR duplicate removal from next-generation sequencing data and a comparison of approaches","volume":"17","author":"Ebbert","year":"2016","journal-title":"BMC Bioinformatics"},{"key":"R13-20260904","doi-asserted-by":"crossref","first-page":"11331","DOI":"10.1038\/s41598-022-15563-2","article-title":"The evaluation of Bcftools mpileup and GATK HaplotypeCaller for variant calling in non-human species","volume":"12","author":"Lefouili","year":"2022","journal-title":"Sci Rep"},{"key":"R14-20260904","doi-asserted-by":"crossref","first-page":"e164","DOI":"10.1093\/nar\/gkq603","article-title":"ANNOVAR:Functional annotation of genetic variants from high-throughput sequencing data","volume":"38","author":"Wang","year":"2010","journal-title":"Nucleic Acids Res"},{"key":"R15-20260904","doi-asserted-by":"crossref","first-page":"1012","DOI":"10.1002\/humu.24309","article-title":"Variant interpretation using population databases:Lessons from gnomAD","volume":"43","author":"Gudmundsson","year":"2022","journal-title":"Hum Mutat"},{"key":"R16-20260904","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1016\/j.neuroimage.2015.06.092","article-title":"SIFT2:Enabling dense quantitative assessment of brain white matter connectivity using streamlines tractography","volume":"119","author":"Smith","year":"2015","journal-title":"Neuroimage"},{"key":"R17-20260904","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":"R18-20260904","doi-asserted-by":"crossref","first-page":"877","DOI":"10.1016\/j.ajhg.2016.08.016","article-title":"REVEL:An ensemble method for predicting the pathogenicity of rare missense variants","volume":"99","author":"Ioannidis","year":"2016","journal-title":"Am J Hum Genet"},{"key":"R19-20260904","doi-asserted-by":"crossref","first-page":"btac830","DOI":"10.1093\/bioinformatics\/btac830","article-title":"igv.js:An embeddable JavaScript implementation of the Integrative Genomics Viewer (IGV)","volume":"39","author":"Robinson","year":"2023","journal-title":"Bioinformatics"},{"key":"R20-20260904","doi-asserted-by":"crossref","first-page":"W191","DOI":"10.1093\/nar\/gkz369","article-title":"g:Profiler:A web server for functional enrichment analysis and conversions of gene lists (2019 update)","volume":"47","author":"Raudvere","year":"2019","journal-title":"Nucleic Acids Res"},{"key":"R21-20260904","doi-asserted-by":"crossref","first-page":"W90","DOI":"10.1093\/nar\/gkw377","article-title":"Enrichr:A comprehensive gene set enrichment analysis web server 2016 update","volume":"44","author":"Kuleshov","year":"2016","journal-title":"Nucleic Acids Res"},{"key":"R22-20260904","doi-asserted-by":"crossref","first-page":"P3","DOI":"10.1186\/gb-2003-4-5-p3","article-title":"DAVID:Database for annotation, visualization, and integrated discovery","volume":"4","author":"Dennis","year":"2003","journal-title":"Genome Biol"},{"key":"R23-20260904","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1093\/nar\/28.1.27","article-title":"KEGG:Kyoto encyclopedia of genes and genomes","volume":"28","author":"Kanehisa","year":"2000","journal-title":"Nucleic Acids Res"},{"key":"R24-20260904","doi-asserted-by":"crossref","first-page":"D687","DOI":"10.1093\/nar\/gkab1028","article-title":"The reactome pathway knowledgebase 2022","volume":"50","author":"Gillespie","year":"2022","journal-title":"Nucleic Acids Res"},{"key":"R25-20260904","doi-asserted-by":"crossref","first-page":"D330","DOI":"10.1093\/nar\/gky1055","article-title":"The gene ontology resource:20 years and still going strong","volume":"47","year":"2019","journal-title":"Nucleic Acids Res"},{"key":"R26-20260904","doi-asserted-by":"crossref","first-page":"1318","DOI":"10.1126\/science.aaz1776","article-title":"The GTEx consortium atlas of genetic regulatory effects across human tissues","volume":"369","year":"2020","journal-title":"Science"},{"key":"R27-20260904","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1111\/j.1365-2796.2011.02427.x","article-title":"The human protein atlas as a proteomic resource for biomarker discovery","volume":"270","author":"Pont\u00e9n","year":"2011","journal-title":"J Intern Med"},{"key":"R28-20260904","doi-asserted-by":"crossref","first-page":"D447","DOI":"10.1093\/nar\/gku1003","article-title":"STRING v10:Protein-protein interaction networks, integrated over the tree of life","volume":"43","author":"Szklarczyk","year":"2015","journal-title":"Nucleic Acids Res"},{"key":"R29-20260904","doi-asserted-by":"crossref","first-page":"D529","DOI":"10.1093\/nar\/gky1079","article-title":"The BioGRID interaction database:2019 update","volume":"47","author":"Oughtred","year":"2019","journal-title":"Nucleic Acids Res"},{"key":"R30-20260904","doi-asserted-by":"crossref","first-page":"baq020","DOI":"10.1093\/database\/baq020","article-title":"GeneCards Version 3:The human gene integrator","volume":"2010","author":"Safran","year":"2010","journal-title":"Database (Oxford)"},{"key":"R31-20260904","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1038\/aps.2014.121","article-title":"The multiple universes of estrogen-related receptor ? and ? in metabolic control and related diseases","volume":"36","author":"Audet-Walsh","year":"2015","journal-title":"Acta Pharmacol Sin"},{"key":"R32-20260904","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1038\/s41585-018-0008-y","article-title":"Regulation of masculinization:Androgen signalling for external genitalia development","volume":"15","author":"Matsushita","year":"2018","journal-title":"Nat Rev Urol"},{"key":"R33-20260904","doi-asserted-by":"crossref","first-page":"100802","DOI":"10.1016\/j.xcrm.2022.100802","article-title":"Estrogen-related receptor alpha drives mitochondrial biogenesis and resistance to neoadjuvant chemoradiation in esophageal cancer","volume":"3","author":"Dings","year":"2022","journal-title":"Cell Rep Med"},{"key":"R34-20260904","doi-asserted-by":"crossref","first-page":"1386","DOI":"10.1242\/jcs.163857","article-title":"The Rho-specific GAP protein DLC3 coordinates endocytic membrane trafficking","volume":"128","author":"Braun","year":"2015","journal-title":"J Cell Sci"},{"key":"R35-20260904","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1159\/000537877","article-title":"Mutations in STARD8 (DLC3) may cause 46, XY gonadal dysgenesis","volume":"17","author":"Sirokha","year":"2023","journal-title":"Sex Dev"},{"key":"R36-20260904","doi-asserted-by":"crossref","first-page":"3148","DOI":"10.3390\/biomedicines10123148","article-title":"Large-scale functional assessment of genes involved in rare diseases with intellectual disabilities unravels unique developmental and behaviour profiles in mouse models","volume":"10","author":"Meziane","year":"2022","journal-title":"Biomedicines"},{"issue":"Suppl 1","key":"R37-20260904","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1159\/000066197","article-title":"The future of targeted therapy:Combining novel agents","volume":"63","author":"Gianni","year":"2002","journal-title":"Oncology"},{"key":"R38-20260904","doi-asserted-by":"crossref","first-page":"1617","DOI":"10.1111\/j.1476-5381.2011.01551.x","article-title":"Pharmacological modulation of chemokine receptor function","volume":"165","author":"Scholten","year":"2012","journal-title":"Br J Pharmacol"},{"key":"R39-20260904","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1146\/annurev.biochem.74.050304.091637","article-title":"Gene therapy:Twenty-first century medicine","volume":"74","author":"Verma","year":"2005","journal-title":"Annu Rev Biochem"}],"container-title":["Journal of Indian Association of Pediatric Surgeons"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ovid.com\/10.4103\/jiaps.jiaps_144_25","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T13:00:49Z","timestamp":1788526849000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ovid.com\/10.4103\/jiaps.jiaps_144_25"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11]]},"references-count":39,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2025]]}},"URL":"https:\/\/doi.org\/10.4103\/jiaps.jiaps_144_25","relation":{},"ISSN":["0971-9261","1998-3891"],"issn-type":[{"value":"0971-9261","type":"print"},{"value":"1998-3891","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11]]},"assertion":[{"value":"2025-05-15","name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-08-19","name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}}]}}