{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T13:38:56Z","timestamp":1783431536387,"version":"3.54.6"},"posted":{"date-parts":[[2025,8,15]]},"group-title":"Genetic and Genomic Medicine","reference-count":152,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,8,15]],"date-time":"2025-08-15T00:00:00Z","timestamp":1755216000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,8,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Polycystic ovary syndrome (PCOS) is a complex, multi-system, heritable endocrinopathy that is a common cause of anovulatory infertility in reproductive-aged women. While insulin resistance (IR) is not a diagnostic feature, it is widespread in women with PCOS, and often more severe than in women of similar age and BMI. Conversely, women with rare Mendelian disorders of IR also present with features of PCOS. We hypothesize that PCOS is driven by underlying IR, which can be evaluated through a genetic approach. We curated and stratified 310 genes related to three mechanisms of IR using molecular and clinical criteria. We evaluated protein-altering genetic variation in 102 insulin signaling genes, 29 obesity genes, and 22 dyslipidemia genes from whole-exome sequencing data from 675 PCOS patients. 40 insulin signaling genes, 12 obesity genes, and 10 dyslipidemia genes were significantly enriched for protein-altering variation in PCOS cases compared to healthy population controls. Variants in these 62 significantly enriched genes affected 51% of PCOS cases in our study cohort. The 15 highest ranked genes were selected for follow-up:\n                  <jats:italic>LMNA, LEPR, KCNJ11, BSCL2, ACACA, NTRK2, GCK, ABCC8, SLC2A2, POMC, MC4R, TBC1D4, INSR, NR0B2,<\/jats:italic>\n                  and\n                  <jats:italic>GCKR<\/jats:italic>\n                  . 50% of variants identified in these 15 genes were pathogenic, 35% were likely pathogenic, and only 15% were variants of uncertain significance. These findings support IR as a central pathway in PCOS. Furthermore, this study demonstrates that a candidate pathway approach with sufficient pre-processing can successfully identify functionally relevant variants and genes underlying complex traits.\n                <\/jats:p>","DOI":"10.1101\/2025.08.13.25333592","type":"posted-content","created":{"date-parts":[[2025,8,15]],"date-time":"2025-08-15T19:10:15Z","timestamp":1755285015000},"source":"Crossref","is-referenced-by-count":1,"title":["Pathogenic variation in insulin resistance genes is common in polycystic ovary syndrome (PCOS): a strategy for causal gene discovery using whole-exome sequencing (WES) in complex traits"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0350-1666","authenticated-orcid":false,"given":"Rosemary","family":"Bauer","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6257-2272","authenticated-orcid":false,"given":"Chloe","family":"Parker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zulma","family":"Cardona Matos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4617-3981","authenticated-orcid":false,"given":"M. Geoffrey","family":"Hayes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8485-2953","authenticated-orcid":false,"given":"Allen R.","family":"Kunselman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9927-7584","authenticated-orcid":false,"given":"Richard S.","family":"Legro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8219-5504","authenticated-orcid":false,"given":"Corrine K.","family":"Welt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6994-7110","authenticated-orcid":false,"given":"Margrit","family":"Urbanek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025081809101157000_2025.08.13.25333592v1.1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2013-2350"},{"key":"2025081809101157000_2025.08.13.25333592v1.2","doi-asserted-by":"publisher","DOI":"10.1093\/humrep\/deh098"},{"key":"2025081809101157000_2025.08.13.25333592v1.3","doi-asserted-by":"publisher","DOI":"10.1016\/j.fertnstert.2008.06.035"},{"key":"2025081809101157000_2025.08.13.25333592v1.4","doi-asserted-by":"publisher","DOI":"10.1210\/er.2011-1034"},{"key":"2025081809101157000_2025.08.13.25333592v1.5","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2005-1494"},{"issue":"3","key":"2025081809101157000_2025.08.13.25333592v1.6","doi-asserted-by":"crossref","first-page":"478","DOI":"10.1016\/S0015-0282(16)57412-3","article-title":"A twin study of polycystic ovary syndrome","volume":"63","year":"1995","journal-title":"Fertil Steril"},{"issue":"1","key":"2025081809101157000_2025.08.13.25333592v1.7","doi-asserted-by":"crossref","first-page":"7502","DOI":"10.1038\/ncomms8502","article-title":"Genome-wide association of polycystic ovary syndrome implicates alterations in gonadotropin secretion in European ancestry populations","volume":"6","year":"2015","journal-title":"Nat Comm"},{"key":"2025081809101157000_2025.08.13.25333592v1.8","doi-asserted-by":"crossref","unstructured":"Tian Y , et al. PCOS-GWAS Susceptibility Variants in THADA, INSR, TOX3, and DENND1A Are Associated With Metabolic Syndrome or Insulin Resistance in Women With PCOS. Front Endocrinol (Lausanne). 2020;11.","DOI":"10.3389\/fendo.2020.00274"},{"key":"2025081809101157000_2025.08.13.25333592v1.9","doi-asserted-by":"publisher","DOI":"10.1038\/nature08494"},{"key":"2025081809101157000_2025.08.13.25333592v1.10","doi-asserted-by":"crossref","unstructured":"Andrews SJ , et al. The complex genetic architecture of Alzheimer\u2019s disease: novel insights and future directions. eBioMedicine. 2023;90.","DOI":"10.1016\/j.ebiom.2023.104511"},{"key":"2025081809101157000_2025.08.13.25333592v1.11","doi-asserted-by":"publisher","DOI":"10.1016\/S2213-2600(21)00510-5"},{"key":"2025081809101157000_2025.08.13.25333592v1.12","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22147297"},{"issue":"1","key":"2025081809101157000_2025.08.13.25333592v1.13","first-page":"1","article-title":"Familial hypercholesterolaemia","volume":"3","year":"2017","journal-title":"Nat Rev Dis Primers"},{"key":"2025081809101157000_2025.08.13.25333592v1.14","first-page":"1","article-title":"The epidemiology, molecular pathogenesis, diagnosis, and treatment of maturity-onset diabetes of the young (MODY)","volume":"6","year":"2020","journal-title":"Clin Diabetes Endocrinol"},{"key":"2025081809101157000_2025.08.13.25333592v1.15","doi-asserted-by":"crossref","unstructured":"Crespo RP , et al. High-throughput Sequencing to Identify Monogenic Etiologies in a Preselected Polycystic Ovary Syndrome Cohort. J Endocr Soc. 2022;6(9).","DOI":"10.1210\/jendso\/bvac106"},{"key":"2025081809101157000_2025.08.13.25333592v1.16","doi-asserted-by":"crossref","unstructured":"Bauer R , et al. Rare Variation in LMNA Underlies Polycystic Ovary Syndrome Pathogenesis in 2 Independent Cohorts. J Clin Endocrinol Metab. 2024:dgae761.","DOI":"10.1210\/clinem\/dgae761"},{"key":"2025081809101157000_2025.08.13.25333592v1.17","doi-asserted-by":"crossref","unstructured":"Gorsic LK , et al. Pathogenic Anti-Mullerian Hormone Variants in Polycystic Ovary Syndrome. J Clin Endocrinol Metab. 2017.","DOI":"10.1210\/jc.2017-00612"},{"key":"2025081809101157000_2025.08.13.25333592v1.18","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2018-02178"},{"key":"2025081809101157000_2025.08.13.25333592v1.19","doi-asserted-by":"publisher","DOI":"10.1016\/S1043-2760(03)00142-5"},{"key":"2025081809101157000_2025.08.13.25333592v1.20","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2007-2521"},{"key":"2025081809101157000_2025.08.13.25333592v1.21","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.115.307344"},{"key":"2025081809101157000_2025.08.13.25333592v1.22","doi-asserted-by":"publisher","DOI":"10.7326\/M21-4109"},{"key":"2025081809101157000_2025.08.13.25333592v1.23","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00063.2017"},{"key":"2025081809101157000_2025.08.13.25333592v1.24","doi-asserted-by":"publisher","DOI":"10.1210\/er.2010-0020"},{"key":"2025081809101157000_2025.08.13.25333592v1.25","doi-asserted-by":"publisher","DOI":"10.1038\/sj.ejhg.5201802"},{"key":"2025081809101157000_2025.08.13.25333592v1.26","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2265.2012.04389.x"},{"key":"2025081809101157000_2025.08.13.25333592v1.27","doi-asserted-by":"publisher","DOI":"10.1016\/j.gene.2013.05.074"},{"issue":"1","key":"2025081809101157000_2025.08.13.25333592v1.28","doi-asserted-by":"crossref","first-page":"2279565","DOI":"10.1080\/09513590.2023.2279565","article-title":"Association between leptin receptor polymorphisms and polycystic ovary syndrome risk: a meta-analysis based on 11 studies","volume":"39","year":"2023","journal-title":"Gynecol Endocrinol"},{"issue":"20","key":"2025081809101157000_2025.08.13.25333592v1.29","doi-asserted-by":"crossref","first-page":"3214","DOI":"10.3390\/diagnostics13203214","article-title":"Examining the Genetic Role of rs8192675 Variant in Saudi Women Diagnosed with Polycystic Ovary Syndrome","volume":"13","year":"2023","journal-title":"Diagnostics"},{"key":"2025081809101157000_2025.08.13.25333592v1.30","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2006-1191"},{"key":"2025081809101157000_2025.08.13.25333592v1.31","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2006-1327"},{"key":"2025081809101157000_2025.08.13.25333592v1.32","doi-asserted-by":"publisher","DOI":"10.1016\/j.cct.2011.12.005"},{"key":"2025081809101157000_2025.08.13.25333592v1.33","doi-asserted-by":"publisher","DOI":"10.1016\/j.fertnstert.2013.08.056"},{"key":"2025081809101157000_2025.08.13.25333592v1.34","doi-asserted-by":"publisher","DOI":"10.1016\/j.fertnstert.2003.10.004"},{"key":"2025081809101157000_2025.08.13.25333592v1.35","doi-asserted-by":"publisher","DOI":"10.4161\/fly.19695"},{"key":"2025081809101157000_2025.08.13.25333592v1.36","doi-asserted-by":"crossref","unstructured":"Cingolani P , et al. Using Drosophila melanogaster as a model for genotoxic chemical mutational studies with a new program, SnpSift. Front Genet. 2012;3:35.","DOI":"10.3389\/fgene.2012.00035"},{"key":"2025081809101157000_2025.08.13.25333592v1.37","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2308-7"},{"key":"2025081809101157000_2025.08.13.25333592v1.38","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2016.08.016"},{"issue":"D1","key":"2025081809101157000_2025.08.13.25333592v1.39","first-page":"D789","article-title":"OMIM.org: Online Mendelian Inheritance in Man (OMIM\u00ae), an online catalog of human genes and genetic disorders","volume":"43","year":"2014","journal-title":"Nucleic Acids Res"},{"key":"2025081809101157000_2025.08.13.25333592v1.40","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-024-07050-7"},{"key":"2025081809101157000_2025.08.13.25333592v1.41","doi-asserted-by":"publisher","DOI":"10.1126\/science.1260419"},{"key":"2025081809101157000_2025.08.13.25333592v1.42","doi-asserted-by":"publisher","DOI":"10.1101\/gr.176601"},{"key":"2025081809101157000_2025.08.13.25333592v1.43","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2015.30"},{"issue":"8","key":"2025081809101157000_2025.08.13.25333592v1.44","doi-asserted-by":"crossref","first-page":"1562","DOI":"10.3390\/genes14081562","article-title":"The Spectrum of the Heterozygous Egect in Biallelic Mendelian Diseases\u2014The Symptomatic Heterozygote Issue","volume":"14","year":"2023","journal-title":"Genes"},{"key":"2025081809101157000_2025.08.13.25333592v1.45","unstructured":"Barber T , et al. Association between polymorphisms within the SUR1\/Kir6. 2 gene region and polycystic ovary syndrome: a case-control study. Endocr Abstr. 2006;11."},{"issue":"9","key":"2025081809101157000_2025.08.13.25333592v1.46","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1002\/mrd.22505","article-title":"Acetyl CoA carboxylase inactivation and meiotic maturation in mouse oocytes","volume":"82","year":"2015","journal-title":"Mol Reprod Dev"},{"key":"2025081809101157000_2025.08.13.25333592v1.47","doi-asserted-by":"publisher","DOI":"10.1095\/biolreprod.106.055749"},{"key":"2025081809101157000_2025.08.13.25333592v1.48","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-3476(79)80087-6"},{"issue":"2","key":"2025081809101157000_2025.08.13.25333592v1.49","first-page":"317","article-title":"Congenital generalized lipodystrophy in an Indian patient with a novel mutation in BSCL2 gene","volume":"31","year":"2008","journal-title":"J Inherit Metab Dis"},{"issue":"1","key":"2025081809101157000_2025.08.13.25333592v1.50","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1007\/s11033-016-4080-1","article-title":"Association between copy-number variation on metabolic phenotypes and HDL-C levels in patients with polycystic ovary syndrome","volume":"44","year":"2017","journal-title":"Mol Biol Rep"},{"key":"2025081809101157000_2025.08.13.25333592v1.51","doi-asserted-by":"publisher","DOI":"10.1016\/j.fertnstert.2005.12.073"},{"issue":"5","key":"2025081809101157000_2025.08.13.25333592v1.52","doi-asserted-by":"crossref","first-page":"1213","DOI":"10.1016\/j.fertnstert.2007.05.026","article-title":"A novel single nucleotide polymorphism of INSR gene for polycystic ovary syndrome","volume":"89","year":"2008","journal-title":"Fertil Steril"},{"issue":"2","key":"2025081809101157000_2025.08.13.25333592v1.53","doi-asserted-by":"crossref","first-page":"2403","DOI":"10.3390\/ijms16022403","article-title":"The Association between Polymorphism of INSR and Polycystic Ovary Syndrome: A Meta-Analysis","volume":"16","year":"2015","journal-title":"Int J Mol Sci"},{"issue":"7","key":"2025081809101157000_2025.08.13.25333592v1.54","first-page":"499","article-title":"INSR gene variation is associated with decreased insulin sensitivity in Iraqi women with PCOs","volume":"12","author":"M TM","year":"2014","journal-title":"Iran J Reprod Med"},{"issue":"4","key":"2025081809101157000_2025.08.13.25333592v1.55","first-page":"470","article-title":"Investigation of the FSHR, CYP11, and INSR Mutations and Polymorphisms in Iranian Infertile Women with Polycystic Ovary Syndrome (PCOS)","volume":"9","year":"2021","journal-title":"Rep Biochem Mol Biol"},{"issue":"1","key":"2025081809101157000_2025.08.13.25333592v1.56","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1007\/s12041-017-0749-z","article-title":"Single-nucleotide polymorphism of INS, INSR, IRS1, IRS2, PPAR-G and CAPN10 genes in the pathogenesis of polycystic ovary syndrome","volume":"96","year":"2017","journal-title":"J Genet"},{"key":"2025081809101157000_2025.08.13.25333592v1.57","doi-asserted-by":"publisher","DOI":"10.1016\/S0015-0282(02)04241-3"},{"issue":"9","key":"2025081809101157000_2025.08.13.25333592v1.58","first-page":"582","article-title":"[Correlation between single nucleotide polymorphism of insulin receptor gene with polycystic ovary syndrome]","volume":"39","year":"2004","journal-title":"Zhonghua fu chan ke za zhi"},{"key":"2025081809101157000_2025.08.13.25333592v1.59","doi-asserted-by":"publisher","DOI":"10.1530\/EJE-08-0932"},{"key":"2025081809101157000_2025.08.13.25333592v1.60","doi-asserted-by":"publisher","DOI":"10.1007\/s10815-009-9308-8"},{"key":"2025081809101157000_2025.08.13.25333592v1.61","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2009.10.013"},{"key":"2025081809101157000_2025.08.13.25333592v1.62","doi-asserted-by":"publisher","DOI":"10.1016\/j.fertnstert.2011.01.015"},{"key":"2025081809101157000_2025.08.13.25333592v1.63","doi-asserted-by":"publisher","DOI":"10.1080\/09513590802196379"},{"issue":"4","key":"2025081809101157000_2025.08.13.25333592v1.64","doi-asserted-by":"crossref","first-page":"299","DOI":"10.2217\/pme-2017-0016","article-title":"LEPR Gene Polymorphism and Plasma Soluble Leptin Receptor Levels are Associated with Polycystic Ovary Syndrome in Han Chinese Women","volume":"14","year":"2017","journal-title":"Per Med"},{"issue":"1","key":"2025081809101157000_2025.08.13.25333592v1.65","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1159\/000500996","article-title":"Associations of Leptin Receptor and Peroxisome Proliferator-Activated Receptor Gamma Polymorphisms with Polycystic Ovary Syndrome: A Meta-Analysis","volume":"75","year":"2019","journal-title":"Ann Nutr Metab"},{"issue":"2","key":"2025081809101157000_2025.08.13.25333592v1.66","first-page":"120","article-title":"Prospective role of leptin receptor gene and its polymorphisms on the onset of polycystic ovarian syndrome","volume":"20","year":"2024","journal-title":"Curr Womens Health Rev"},{"issue":"1","key":"2025081809101157000_2025.08.13.25333592v1.67","first-page":"20","article-title":"Genotype-Phenotype correlations of Leptin receptor gene in Polycystic ovarian disease (PCOS)","volume":"4","year":"2018","journal-title":"IOSR J Biotechnol Biochem"},{"key":"2025081809101157000_2025.08.13.25333592v1.68","doi-asserted-by":"crossref","unstructured":"Dallel M , et al. Contrasting association of Leptin receptor polymorphisms and haplotypes with polycystic ovary syndrome in Bahraini and Tunisian women: a case\u2013 control study. Biosci Rep. 2021;41(1).","DOI":"10.1042\/BSR20202726"},{"issue":"4","key":"2025081809101157000_2025.08.13.25333592v1.69","doi-asserted-by":"crossref","first-page":"149","DOI":"10.30699\/jogcr.5.4.149","article-title":"Reduction of Soluble Leptin Receptor Levels in Women with Unexplained Infertility and the Egect of Leptin Receptor Gln223Arg Polymorphism on its Serum Level","volume":"5","year":"2020","journal-title":"J Gynaecol Obstet Cancer Res"},{"issue":"6","key":"2025081809101157000_2025.08.13.25333592v1.70","first-page":"550","article-title":"Familial partial lipodystrophy as digerential diagnosis of polycystic ovary syndrome","volume":"66","year":"2015","journal-title":"Endokrynol Pol"},{"key":"2025081809101157000_2025.08.13.25333592v1.71","doi-asserted-by":"publisher","DOI":"10.1530\/EJE-08-0272"},{"key":"2025081809101157000_2025.08.13.25333592v1.72","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2008-2704"},{"key":"2025081809101157000_2025.08.13.25333592v1.73","doi-asserted-by":"crossref","unstructured":"Maciel GAR , et al. LMNA Gene Variations in PCOS: A Persistent Genetic Clue. J Clin Endocrinol Metab. 2025:dgaf072.","DOI":"10.1210\/clinem\/dgaf072"},{"key":"2025081809101157000_2025.08.13.25333592v1.74","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0016390"},{"issue":"1","key":"2025081809101157000_2025.08.13.25333592v1.75","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1186\/1471-2350-11-12","article-title":"Large egects on body mass index and insulin resistance of fat mass and obesity associated gene (FTO) variants in patients with polycystic ovary syndrome (PCOS)","volume":"11","year":"2010","journal-title":"BMC Med Genet"},{"issue":"1","key":"2025081809101157000_2025.08.13.25333592v1.76","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1186\/s13048-024-01567-1","article-title":"The melanocortin receptor genes are linked to and associated with the risk of polycystic ovary syndrome in Italian families","volume":"17","year":"2024","journal-title":"J Ovarian Res"},{"key":"2025081809101157000_2025.08.13.25333592v1.77","doi-asserted-by":"publisher","DOI":"10.1186\/s12881-019-0876-x"},{"issue":"3","key":"2025081809101157000_2025.08.13.25333592v1.78","doi-asserted-by":"crossref","first-page":"136","DOI":"10.3109\/19396368.2014.889774","article-title":"Digerential genes in adipocytes induced from polycystic and non-polycystic ovary syndrome-derived human embryonic stem cells","volume":"60","year":"2014","journal-title":"Syst Biol Reprod Med"},{"key":"2025081809101157000_2025.08.13.25333592v1.79","doi-asserted-by":"crossref","unstructured":"Li C , et al. In utero bisphenol A exposure disturbs germ cell cyst breakdown through the PI3k\/Akt signaling pathway and BDNF expression. Ecotoxicol Environ Saf. 2023;259:115031.","DOI":"10.1016\/j.ecoenv.2023.115031"},{"issue":"12","key":"2025081809101157000_2025.08.13.25333592v1.80","doi-asserted-by":"crossref","first-page":"1904","DOI":"10.1071\/RD15131","article-title":"Egects of brain-derived neurotrophic factor on oocyte maturation and embryonic development in a rat model of polycystic ovary syndrome","volume":"28","year":"2016","journal-title":"Reprod Fertil Dev"},{"issue":"19","key":"2025081809101157000_2025.08.13.25333592v1.81","doi-asserted-by":"crossref","first-page":"5584","DOI":"10.3390\/jcm11195584","article-title":"Moderate Aerobic Exercise Regulates Follicular Dysfunction by Initiating Brain-Derived Neurotrophic Factor (BDNF)-Mediated Anti-Apoptotic Signaling Pathways in Polycystic Ovary Syndrome","volume":"11","year":"2022","journal-title":"J Clin Med"},{"issue":"8","key":"2025081809101157000_2025.08.13.25333592v1.82","doi-asserted-by":"crossref","first-page":"1609","DOI":"10.3390\/genes14081609","article-title":"Identification of Novel Intronic SNPs in Transporter Genes Associated with Metformin Side Egects","volume":"14","year":"2023","journal-title":"Genes"},{"key":"2025081809101157000_2025.08.13.25333592v1.83","doi-asserted-by":"publisher","DOI":"10.2337\/db07-0706"},{"issue":"3","key":"2025081809101157000_2025.08.13.25333592v1.84","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1515\/jpem-2018-0389","article-title":"A rare case of congenital hyperinsulinism (CHI) due to dual genetic aetiology involving HNF4A and ABCC8","volume":"32","year":"2019","journal-title":"J Pediatr Endocrinol Metab"},{"issue":"10","key":"2025081809101157000_2025.08.13.25333592v1.85","doi-asserted-by":"crossref","first-page":"e002087","DOI":"10.1161\/CIRCGEN.118.002087","article-title":"Loss-of-Function ABCC8 Mutations in Pulmonary Arterial Hypertension","volume":"11","year":"2018","journal-title":"Circ Genom Precis Med"},{"issue":"1","key":"2025081809101157000_2025.08.13.25333592v1.86","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1111\/pedi.12931","article-title":"Next generation sequencing targeted gene panel in Greek MODY patients increases diagnostic accuracy","volume":"21","year":"2020","journal-title":"Pediatr Diabetes"},{"key":"2025081809101157000_2025.08.13.25333592v1.87","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.2009.075416"},{"key":"2025081809101157000_2025.08.13.25333592v1.88","doi-asserted-by":"publisher","DOI":"10.1172\/JCI35414"},{"key":"2025081809101157000_2025.08.13.25333592v1.89","doi-asserted-by":"publisher","DOI":"10.1530\/EJE-16-0027"},{"issue":"9","key":"2025081809101157000_2025.08.13.25333592v1.90","doi-asserted-by":"crossref","first-page":"847","DOI":"10.3390\/metabo12090847","article-title":"Glucocorticoid-Induced Hyperinsulinism in a Preterm Neonate with Inherited ABCC8 Variant","volume":"12","year":"2022","journal-title":"Metabolites"},{"issue":"2","key":"2025081809101157000_2025.08.13.25333592v1.91","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1002\/humu.9401","article-title":"Mutation spectra of ABCC8 gene in Spanish patients with Hyperinsulinism of Infancy (HI)","volume":"27","year":"2006","journal-title":"Hum Mutat"},{"issue":"01","key":"2025081809101157000_2025.08.13.25333592v1.92","doi-asserted-by":"crossref","first-page":"e80","DOI":"10.1055\/s-0041-1726462","article-title":"Reintroduction of Diazoxide after Diagnosis of Pulmonary Hypertension in a Patient with Transient Hyperinsulinism","volume":"11","year":"2021","journal-title":"J Child Sci"},{"key":"2025081809101157000_2025.08.13.25333592v1.93","doi-asserted-by":"publisher","DOI":"10.2337\/diabetes.55.01.06.db05-1128"},{"key":"2025081809101157000_2025.08.13.25333592v1.94","doi-asserted-by":"publisher","DOI":"10.5152\/balkanmedj.2021.20155"},{"key":"2025081809101157000_2025.08.13.25333592v1.95","doi-asserted-by":"publisher","DOI":"10.1515\/jpem-2018-0184"},{"key":"2025081809101157000_2025.08.13.25333592v1.96","doi-asserted-by":"publisher","DOI":"10.2337\/dc11-1469"},{"key":"2025081809101157000_2025.08.13.25333592v1.97","doi-asserted-by":"publisher","DOI":"10.2337\/db17-0029"},{"key":"2025081809101157000_2025.08.13.25333592v1.98","doi-asserted-by":"publisher","DOI":"10.1002\/humu.23995"},{"key":"2025081809101157000_2025.08.13.25333592v1.99","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-020-72089-1"},{"issue":"3","key":"2025081809101157000_2025.08.13.25333592v1.100","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1016\/j.ymgme.2014.12.304","article-title":"Molecular genetic testing of patients with monogenic diabetes and hyperinsulinism","volume":"114","year":"2015","journal-title":"Mol Genet Metab"},{"issue":"5","key":"2025081809101157000_2025.08.13.25333592v1.101","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1111\/ahg.12070","article-title":"Novel ABCC8 (SUR1) gene mutations in Asian Indian children with congenital hyperinsulinemic hypoglycemia","volume":"78","year":"2014","journal-title":"Ann Hum Genet"},{"issue":"2","key":"2025081809101157000_2025.08.13.25333592v1.102","first-page":"93","article-title":"Congenital hyperinsulinism in Gran Canaria","volume":"95","year":"2021","journal-title":"Canary Isles. An Pediatr (Engl Ed)"},{"issue":"5","key":"2025081809101157000_2025.08.13.25333592v1.103","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1007\/s00592-018-01283-5","article-title":"Genetic characterization of suspected MODY patients in Tunisia by targeted next-generation sequencing","volume":"56","year":"2019","journal-title":"Acta Diabetol"},{"issue":"8","key":"2025081809101157000_2025.08.13.25333592v1.104","first-page":"901","article-title":"[Novel MFN2, BSCL2 and LRSAM1 variants in a cohort of Chinese patients with Charcot-Marie-Tooth disease]","volume":"61","year":"2022","journal-title":"Zhonghua Nei Ke Za Zhi"},{"key":"2025081809101157000_2025.08.13.25333592v1.105","doi-asserted-by":"crossref","unstructured":"Jiang F , et al. Functional characterization of a novel heterozygous mutation in the glucokinase gene that causes mody2 in Chinese pedigrees. Front Endocrinol (Lausanne). 2021;12:803992.","DOI":"10.3389\/fendo.2021.803992"},{"key":"2025081809101157000_2025.08.13.25333592v1.106","doi-asserted-by":"publisher","DOI":"10.1016\/j.gene.2017.10.057"},{"issue":"6","key":"2025081809101157000_2025.08.13.25333592v1.107","doi-asserted-by":"crossref","first-page":"e38906","DOI":"10.1371\/journal.pone.0038906","article-title":"Glucokinase (GCK) Mutations and Their Characterization in MODY2 Children of Southern Italy","volume":"7","year":"2012","journal-title":"PLoS One"},{"issue":"3","key":"2025081809101157000_2025.08.13.25333592v1.108","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1111\/jdi.13957","article-title":"Targeted gene panel analysis of Japanese patients with maturity-onset diabetes of the young-like diabetes mellitus: Roles of inactivating variants in the ABCC8 and insulin resistance genes","volume":"14","year":"2023","journal-title":"J Diabetes Investig"},{"issue":"1","key":"2025081809101157000_2025.08.13.25333592v1.109","first-page":"130","article-title":"The Genetic Spectrum of Maturity-Onset Diabetes of the Young (MODY) in Qatar, a Population-Based Study","volume":"24","year":"2023","journal-title":"Int J Mol Sci"},{"issue":"7","key":"2025081809101157000_2025.08.13.25333592v1.110","doi-asserted-by":"crossref","first-page":"1164","DOI":"10.1111\/pedi.12714","article-title":"Genetic basis of early-onset, maturity-onset diabetes of the young-like diabetes in Japan and features of patients without mutations in the major MODY genes: dominance of maternal inheritance","volume":"19","year":"2018","journal-title":"Pediatr Diabetes"},{"issue":"6","key":"2025081809101157000_2025.08.13.25333592v1.111","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1136\/adc.78.6.552","article-title":"Genetic testing for maturity onset diabetes of the young in childhood hyperglycaemia","volume":"78","year":"1998","journal-title":"Arch Dis Child"},{"key":"2025081809101157000_2025.08.13.25333592v1.112","doi-asserted-by":"publisher","DOI":"10.2337\/dc14-1788"},{"issue":"1","key":"2025081809101157000_2025.08.13.25333592v1.113","first-page":"7216339","article-title":"Identification of Novel GCK and HNF4\u03b1 Gene Variants in Japanese Pediatric Patients with Onset of Diabetes before 17 Years of Age","volume":"2021","year":"2021","journal-title":"J Diabetes Res"},{"issue":"4","key":"2025081809101157000_2025.08.13.25333592v1.114","doi-asserted-by":"crossref","first-page":"538","DOI":"10.1111\/j.1365-2265.2007.02921.x","article-title":"Mutations in GCK and HNF-1\u03b1 explain the majority of cases with clinical diagnosis of MODY in Spain","volume":"67","year":"2007","journal-title":"Clin Endocrinol (Oxf)"},{"issue":"3","key":"2025081809101157000_2025.08.13.25333592v1.115","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1111\/j.1399-0004.2011.01656.x","article-title":"Novel glucokinase mutations in patients with monogenic diabetes \u2013 clinical outline of GCK-MD and potential for founder egect in Slavic population","volume":"81","year":"2012","journal-title":"Clin Genet"},{"issue":"5","key":"2025081809101157000_2025.08.13.25333592v1.116","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1530\/EC-20-0074","article-title":"MODY2 in Asia: analysis of GCK mutations and clinical characteristics","volume":"9","year":"2020","journal-title":"Endocr Connect"},{"key":"2025081809101157000_2025.08.13.25333592v1.117","doi-asserted-by":"crossref","unstructured":"Zhou Q , et al. Molecular and Clinical Profiles of Pediatric Monogenic Diabetes Subtypes: Comprehensive Genetic Analysis of 138 Patients. J Clin Endocrinol Metab. 2024.","DOI":"10.1210\/clinem\/dgae779"},{"key":"2025081809101157000_2025.08.13.25333592v1.118","doi-asserted-by":"publisher","DOI":"10.1111\/j.1399-5448.2008.00399.x"},{"key":"2025081809101157000_2025.08.13.25333592v1.119","doi-asserted-by":"publisher","DOI":"10.1111\/j.1399-5448.2010.00646.x"},{"key":"2025081809101157000_2025.08.13.25333592v1.120","doi-asserted-by":"publisher","DOI":"10.1172\/JCI46425"},{"key":"2025081809101157000_2025.08.13.25333592v1.121","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1016\/j.ebiom.2018.11.001","article-title":"Intensive genetic analysis for Chinese patients with very high triglyceride levels: Relations of mutations to triglyceride levels and acute pancreatitis","volume":"38","year":"2018","journal-title":"eBioMedicine"},{"key":"2025081809101157000_2025.08.13.25333592v1.122","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/j.cca.2018.10.041","article-title":"Clinical whole exome sequencing in severe hypertriglyceridemia","volume":"488","year":"2019","journal-title":"Clin Chim Acta"},{"issue":"12","key":"2025081809101157000_2025.08.13.25333592v1.123","doi-asserted-by":"crossref","first-page":"1264","DOI":"10.5551\/jat.51540","article-title":"Variants of Lipid-Related Genes in Adult Japanese Patients with Severe Hypertriglyceridemia","volume":"27","year":"2020","journal-title":"J Atheroscler Thromb"},{"issue":"11","key":"2025081809101157000_2025.08.13.25333592v1.124","doi-asserted-by":"crossref","first-page":"3884","DOI":"10.1210\/jc.2016-2179","article-title":"Type 1 Hyperlipoproteinemia Due to Compound Heterozygous Rare Variants in GCKR","volume":"101","year":"2016","journal-title":"J Clin Endocrinol Metab"},{"key":"2025081809101157000_2025.08.13.25333592v1.125","doi-asserted-by":"publisher","DOI":"10.2337\/diab.40.6.777"},{"issue":"1","key":"2025081809101157000_2025.08.13.25333592v1.126","first-page":"8826174","article-title":"Genotyping of ABCC8, KCNJ11, and HADH in Iranian Infants with Congenital Hyperinsulinism","volume":"2021","year":"2021","journal-title":"Case Rep Endocrinol"},{"key":"2025081809101157000_2025.08.13.25333592v1.127","doi-asserted-by":"publisher","DOI":"10.1210\/clinem\/dgab404"},{"key":"2025081809101157000_2025.08.13.25333592v1.128","unstructured":"Hakim A. A Genomic Approach To Idiopathic Liver Disease In Adults. 2019."},{"issue":"5","key":"2025081809101157000_2025.08.13.25333592v1.129","doi-asserted-by":"crossref","first-page":"514","DOI":"10.1159\/000531529","article-title":"The Narrative of a Patient with Leptin Receptor Deficiency: Personalized Medicine for a Rare Genetic Obesity Disorder","volume":"16","year":"2023","journal-title":"Obes Facts"},{"key":"2025081809101157000_2025.08.13.25333592v1.130","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa063988"},{"issue":"4","key":"2025081809101157000_2025.08.13.25333592v1.131","first-page":"1099","article-title":"Regional Body Fat Changes and Metabolic Complications in Children With, Lipodystrophy-Causing LMNA Variants","volume":"104","year":"2018","journal-title":"J Clin Endocrinol Metab"},{"key":"2025081809101157000_2025.08.13.25333592v1.132","doi-asserted-by":"crossref","unstructured":"Vasandani C , et al. Phenotypic Digerences Among Familial Partial Lipodystrophy Due to LMNA or PPARG Variants. J Endocr Soc. 2022;6(12).","DOI":"10.1210\/jendso\/bvac155"},{"key":"2025081809101157000_2025.08.13.25333592v1.133","doi-asserted-by":"publisher","DOI":"10.1111\/j.1399-0004.2010.01385.x"},{"issue":"6","key":"2025081809101157000_2025.08.13.25333592v1.134","first-page":"445","article-title":"Progeroid laminopathy with restrictive dermopathy-like features caused by an isodisomic LMNA mutation p. R435C","volume":"5","year":"2013","journal-title":"Aging (Albany NY)"},{"issue":"11","key":"2025081809101157000_2025.08.13.25333592v1.135","first-page":"2387","article-title":"Progeroid syndrome with scleroderma-like skin changes associated with homozygous R435C LMNA mutation","volume":"149","year":"2009","journal-title":"Am J Med Genet A"},{"key":"2025081809101157000_2025.08.13.25333592v1.136","doi-asserted-by":"publisher","DOI":"10.1002\/ana.21417"},{"issue":"10","key":"2025081809101157000_2025.08.13.25333592v1.137","doi-asserted-by":"crossref","first-page":"2452","DOI":"10.1210\/clinem\/dgae210","article-title":"MC4R Variants Modulate \u03b1-MSH and Setmelanotide Induced Cellular Signaling at Multiple Levels","volume":"109","year":"2024","journal-title":"J Clin Endocrinol Metab"},{"key":"2025081809101157000_2025.08.13.25333592v1.138","doi-asserted-by":"publisher","DOI":"10.1196\/annals.1290.006"},{"key":"2025081809101157000_2025.08.13.25333592v1.139","doi-asserted-by":"publisher","DOI":"10.1172\/JCI9238"},{"issue":"3","key":"2025081809101157000_2025.08.13.25333592v1.140","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1007\/BF03178843","article-title":"Obesity and eating behaviour in a three-generation chilean family with carriers of the Thr150Ile mutation in the melanocortin-4 receptor gene","volume":"64","year":"2008","journal-title":"J Physiol Biochem"},{"issue":"1","key":"2025081809101157000_2025.08.13.25333592v1.141","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1159\/000439092","article-title":"Melanocortin-4 receptor gene variation is associated with eating behavior in Chilean adults","volume":"68","year":"2016","journal-title":"Ann Nutr Metab"},{"key":"2025081809101157000_2025.08.13.25333592v1.142","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2265.2007.02788.x"},{"issue":"3","key":"2025081809101157000_2025.08.13.25333592v1.143","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1111\/ahg.12058","article-title":"Novel Variants in the MC4R and LEPR Genes among Severely Obese Children from the Iberian Population","volume":"78","year":"2014","journal-title":"Ann Hum Genet"},{"key":"2025081809101157000_2025.08.13.25333592v1.144","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.98.2.575"},{"key":"2025081809101157000_2025.08.13.25333592v1.145","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2006.01.006"},{"key":"2025081809101157000_2025.08.13.25333592v1.146","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/11.17.1997"},{"key":"2025081809101157000_2025.08.13.25333592v1.147","doi-asserted-by":"publisher","DOI":"10.1038\/sj.ijo.0801485"},{"key":"2025081809101157000_2025.08.13.25333592v1.148","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2008-0954"},{"key":"2025081809101157000_2025.08.13.25333592v1.149","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2017.03.007"},{"issue":"4","key":"2025081809101157000_2025.08.13.25333592v1.150","doi-asserted-by":"crossref","first-page":"104728","DOI":"10.1016\/j.ejmg.2023.104728","article-title":"Next-generation sequencing of 12 obesity genes in a Portuguese cohort of patients with overweight and obesity","volume":"66","year":"2023","journal-title":"Eur J Med Genet"},{"key":"2025081809101157000_2025.08.13.25333592v1.151","doi-asserted-by":"crossref","first-page":"S110","DOI":"10.1016\/j.orcp.2015.10.007","article-title":"Prevalence of POMC R236G mutation in Pakistan","volume":"10","author":"Shabana","year":"2016","journal-title":"Obes Res Clin Pract"},{"key":"2025081809101157000_2025.08.13.25333592v1.152","doi-asserted-by":"crossref","unstructured":"Hosoe J , et al. Clinical usefulness of multigene screening with phenotype-driven bioinformatics analysis for the diagnosis of patients with monogenic diabetes or severe insulin resistance. Diabetes Res Clin Pract. 2020;169:108461.","DOI":"10.1016\/j.diabres.2020.108461"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2025.08.13.25333592","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T20:43:18Z","timestamp":1768509798000},"score":1,"resource":{"primary":{"URL":"http:\/\/medrxiv.org\/lookup\/doi\/10.1101\/2025.08.13.25333592"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,15]]},"references-count":152,"URL":"https:\/\/doi.org\/10.1101\/2025.08.13.25333592","relation":{},"subject":[],"published":{"date-parts":[[2025,8,15]]},"subtype":"preprint"}}