{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T07:06:31Z","timestamp":1770793591868,"version":"3.50.0"},"reference-count":44,"publisher":"The Endocrine Society","issue":"10","license":[{"start":{"date-parts":[[2023,4,3]],"date-time":"2023-04-03T00:00:00Z","timestamp":1680480000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Grants-in-Aid for Scientific Research","doi-asserted-by":"publisher","award":["JP20H00539"],"award-info":[{"award-number":["JP20H00539"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,9,18]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Context<\/jats:title>\n                  <jats:p>We have previously reported that a specific \u201cAGATC\u201d haplotype in a &amp;gt;34 kb tight linkage disequilibrium (LD) block within ESR1 is strongly associated with cryptorchidism and hypospadias in Japanese boys.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Objective<\/jats:title>\n                  <jats:p>We aimed to determine the true susceptibility factor for cryptorchidism and hypospadias linked to the \u201cAGATC\u201d haplotype.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>We performed various molecular studies in hitherto unreported 230 Italian boys (80 with cryptorchidism and 150 with normal genitalia) and previously reported and newly recruited 415 Japanese boys (149 with cryptorchidism, 141 with hypospadias, and 125 with normal genitalia). We also performed ESR1 expression analyses using breast cancer\u2013derived MCF-7 cells.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Haplotype analysis revealed the LD block and positive association of the \u201cAGATC\u201d haplotype with cryptorchidism in Italian boys. Whole genome sequencing identified an identical 2249-bp microdeletion (\u0394ESR1) generated by a microhomology-mediated replication error in both Japanese and Italian boys with the specific haplotype. \u0394ESR1 was found to be strongly associated with cryptorchidism and hypospadias by Cochran-Armitage trend test and was revealed to show nearly absolute LD with the \u201cAGATC\u201d haplotype. ESR1 expression was upregulated in MCF-7 cells with a homozygous deletion encompassing \u0394ESR1 and those with a homozygous deletion involving a CTCF-binding site within \u0394ESR1.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>The results reveal that \u0394ESR1, which has been registered as \u201cDEL_6_75504\u201d in gnomAD SVs v2.1, is the true susceptibility factor for cryptorchidism and hypospadias. It appears that \u0394ESR1 was produced in a single ancestral founder of modern humans and has been maintained within the genome of multiple ethnic groups by selection.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1210\/clinem\/dgad187","type":"journal-article","created":{"date-parts":[[2023,4,3]],"date-time":"2023-04-03T11:58:36Z","timestamp":1680523116000},"page":"2550-2560","source":"Crossref","is-referenced-by-count":2,"title":["Microdeletion at <i>ESR1<\/i> Intron 6 (DEL_6_75504) Is a Susceptibility Factor for Cryptorchidism and Hypospadias"],"prefix":"10.1210","volume":"108","author":[{"given":"Yohei","family":"Masunaga","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Hamamatsu University School of Medicine , Hamamatsu 431-3192 , Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yasuko","family":"Fujisawa","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Hamamatsu University School of Medicine , Hamamatsu 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