{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T05:58:51Z","timestamp":1783490331917,"version":"3.55.0"},"reference-count":17,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2017,7,20]],"date-time":"2017-07-20T00:00:00Z","timestamp":1500508800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Mayo Clinic Center for Individualized Medicine (CIM)"},{"name":"CIM Investigative and Functional Genomics Program"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molec Gen &amp; Gen Med"],"published-print":{"date-parts":[[2017,11]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>The <jats:italic><jats:styled-content style=\"fixed-case\">CYP<\/jats:styled-content>11A1<\/jats:italic> gene encodes the cytochrome P450 side\u2010chain cleavage enzyme, which is essential for steroid formation. Recessive variants in this gene can lead to impairment of sexual differentiation caused by a complete or partial loss of steroid hormone production. The phenotypic spectrum in affected 46<jats:styled-content style=\"fixed-case\">XY<\/jats:styled-content> males may vary from surgically repairable defects including cryptorchidism and hypospadias to complete feminization of external gonads, accompanied by symptoms of adrenal dysfunction.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Whole\u2010exome sequencing (<jats:styled-content style=\"fixed-case\">WES<\/jats:styled-content>) of a 12\u2010year\u2010old male proband and his parents was performed after a protracted diagnostic odyssey failed to uncover the cause of his primary adrenal insufficiency. Of note, the proband had early symptomatology and corrective surgery for hypospadias, raising suspicion for a disorder of steroidogenesis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p><jats:styled-content style=\"fixed-case\">WES<\/jats:styled-content> identified compound heterozygous variants in <jats:italic><jats:styled-content style=\"fixed-case\">CYP<\/jats:styled-content>11A1<\/jats:italic> including a novel canonical splice site variant (c.425+1G&gt;A) and a previously reported p.E314K variant, which were consistent with a diagnosis of congenital adrenal insufficiency with partial 46<jats:styled-content style=\"fixed-case\">XY<\/jats:styled-content> sex reversal.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Congenital adrenal insufficiency with 46<jats:styled-content style=\"fixed-case\">XY<\/jats:styled-content> sex reversal is a rare disorder that is characterized by dysregulation of steroid hormone synthesis, leading to adrenal and gonadal dysfunction. In this report, we describe a patient with adrenal insufficiency, hypospadias, and skin hyperpigmentation who was found to have a novel c.425+1G&gt;A variant in <jats:italic>trans<\/jats:italic> with the p.E314K variant in <jats:italic><jats:styled-content style=\"fixed-case\">CYP<\/jats:styled-content>11A1<\/jats:italic>. We performed structural analyses to examine the effect of the p.E314K variant on protein function and show that it falls in the core of the protein may disrupt cholesterol binding in the active site.<\/jats:p><\/jats:sec>","DOI":"10.1002\/mgg3.322","type":"journal-article","created":{"date-parts":[[2017,7,20]],"date-time":"2017-07-20T06:02:47Z","timestamp":1500530567000},"page":"781-787","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["A novel splice site variant in <i><scp>CYP<\/scp>11A1<\/i> in <i>trans<\/i> with the p.E314K variant in a male patient with congenital adrenal insufficiency"],"prefix":"10.1002","volume":"5","author":[{"given":"Montserrat","family":"Lara\u2010Velazquez","sequence":"first","affiliation":[{"name":"Department of Neurosurgery Mayo Clinic Jacksonville Florida"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Perdomo\u2010Pantoja","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery Johns Hopkins University Baltimore Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0658-1275","authenticated-orcid":false,"given":"Patrick R.","family":"Blackburn","sequence":"additional","affiliation":[{"name":"Center for Individualized Medicine Mayo Clinic Jacksonville Florida"},{"name":"Department of Health Sciences Research Mayo Clinic Jacksonville Florida"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8189-4189","authenticated-orcid":false,"given":"Jennifer M.","family":"Gass","sequence":"additional","affiliation":[{"name":"Center for Individualized Medicine Mayo Clinic Jacksonville Florida"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas R.","family":"Caulfield","sequence":"additional","affiliation":[{"name":"Department of Neuroscience Mayo Clinic Jacksonville Florida"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8515-744X","authenticated-orcid":false,"given":"Paldeep S.","family":"Atwal","sequence":"additional","affiliation":[{"name":"Center for Individualized Medicine Mayo Clinic Jacksonville Florida"},{"name":"Department of Clinical Genomics Mayo Clinic Jacksonville Florida"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2017,7,20]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2015.00113"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1159\/000321215"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2004-1059"},{"key":"e_1_2_10_5_1","doi-asserted-by":"crossref","first-page":"3808","DOI":"10.1210\/jcem.87.8.8763","article-title":"Compound heterozygous mutations in the cholesterol side\u2010chain cleavage enzyme gene (CYP11A) cause congenital adrenal insufficiency in humans","volume":"87","author":"Katsumata N.","year":"2002","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12020-015-0715-6"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jsbmb.2016.03.009"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1210\/er.2010-0013"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1097\/MED.0b013e328338f608"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2011-1277"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1530\/EJE-12-0450"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1515\/jpem-2015-0255"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jsbmb.2014.11.010"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1210\/jcem.86.8.7748"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2012-2828"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jsbmb.2015.05.013"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12519-016-0018-x"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0749-0704(05)70150-0"}],"container-title":["Molecular Genetics &amp; Genomic Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fmgg3.322","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/mgg3.322","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,17]],"date-time":"2023-09-17T07:22:38Z","timestamp":1694935358000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/mgg3.322"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,7,20]]},"references-count":17,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2017,11]]}},"alternative-id":["10.1002\/mgg3.322"],"URL":"https:\/\/doi.org\/10.1002\/mgg3.322","archive":["Portico"],"relation":{},"ISSN":["2324-9269","2324-9269"],"issn-type":[{"value":"2324-9269","type":"print"},{"value":"2324-9269","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,7,20]]},"assertion":[{"value":"2017-05-24","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2017-06-25","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2017-07-20","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}