{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T14:53:32Z","timestamp":1793199212756,"version":"4.5.0"},"reference-count":92,"publisher":"The Endocrine Society","issue":"8","license":[{"start":{"date-parts":[[2022,5,16]],"date-time":"2022-05-16T00:00:00Z","timestamp":1652659200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/100009633","name":"Eunice Kennedy Shriver National Institute of Child Health and Human Development","doi-asserted-by":"publisher","award":["P50 HD028138"],"award-info":[{"award-number":["P50 HD028138"]}],"id":[{"id":"10.13039\/100009633","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009633","name":"Eunice Kennedy Shriver National Institute of Child Health and Human Development","doi-asserted-by":"publisher","award":["R01 HD096324"],"award-info":[{"award-number":["R01 HD096324"]}],"id":[{"id":"10.13039\/100009633","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009633","name":"Eunice Kennedy Shriver National Institute of Child Health and Human Development","doi-asserted-by":"publisher","award":["R01 HD043341"],"award-info":[{"award-number":["R01 HD043341"]}],"id":[{"id":"10.13039\/100009633","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,7,14]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Context<\/jats:title>\n                  <jats:p>The genetic architecture of isolated hypogonadotropic hypogonadism (IHH) has not been completely defined.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Objective<\/jats:title>\n                  <jats:p>To determine the role of copy number variants (CNVs) in IHH pathogenicity and define their phenotypic spectrum.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Exome sequencing (ES) data in IHH probands (n\u2005=\u20051394) (Kallmann syndrome [IHH with anosmia; KS], n\u2005=\u2005706; normosmic IHH [nIHH], n\u2005=\u2005688) and family members (n\u2005=\u20051092) at the Reproductive Endocrine Unit and the Center for Genomic Medicine of Massachusetts General Hospital were analyzed for CNVs and single nucleotide variants (SNVs)\/indels in 62 known IHH genes. IHH subjects without SNVs\/indels in known genes were considered \u201cunsolved.\u201d Phenotypes associated with CNVs were evaluated through review of patient medical records. A total of 29 CNVs in 13 genes were detected (overall IHH cohort prevalence: ~2%). Almost all (28\/29) CNVs occurred in unsolved IHH cases. While some genes (eg, ANOS1 and FGFR1) frequently harbor both CNVs and SNVs\/indels, the mutational spectrum of others (eg, CHD7) was restricted to SNVs\/indels. Syndromic phenotypes were seen in 83% and 63% of IHH subjects with multigenic and single gene CNVs, respectively.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>CNVs in known genes contribute to ~2% of IHH pathogenesis. Predictably, multigenic contiguous CNVs resulted in syndromic phenotypes. Syndromic phenotypes resulting from single gene CNVs validate pleiotropy of some IHH genes. Genome sequencing approaches are now needed to identify novel genes and\/or other elusive variants (eg, noncoding\/complex structural variants) that may explain the remaining missing etiology of IHH.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1210\/clinem\/dgac300","type":"journal-article","created":{"date-parts":[[2022,5,16]],"date-time":"2022-05-16T08:06:23Z","timestamp":1652688383000},"page":"2228-2242","source":"Crossref","is-referenced-by-count":26,"title":["Prevalence and Phenotypic Effects of Copy Number Variants in Isolated Hypogonadotropic Hypogonadism"],"prefix":"10.1210","volume":"107","author":[{"given":"Maria I","family":"Stamou","sequence":"first","affiliation":[{"name":"Reproductive Endocrine Unit, Massachusetts General Hospital and the Center for Reproductive Medicine , Boston, MA 02141 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harrison","family":"Brand","sequence":"additional","affiliation":[{"name":"Center for Genomic Medicine, Massachusetts General Hospital , Boston, MA 02141 , USA"},{"name":"Department of Neurology, Massachusetts General Hospital and Harvard Medical School , Boston, MA 02141 , USA"},{"name":"Program in Medical and Population Genetics, Broad Institute of MIT and Harvard , Cambridge, MA 02141 , USA"},{"name":"Pediatric Surgical Research Laboratories, Massachusetts General Hospital , Boston, MA 02141 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mei","family":"Wang","sequence":"additional","affiliation":[{"name":"Reproductive Endocrine Unit, Massachusetts General Hospital and the Center for Reproductive Medicine , Boston, MA 02141 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isaac","family":"Wong","sequence":"additional","affiliation":[{"name":"Center for Genomic Medicine, Massachusetts General Hospital , Boston, MA 02141 , USA"},{"name":"Department of Neurology, Massachusetts General Hospital and Harvard Medical School , Boston, MA 02141 , 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