{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,18]],"date-time":"2026-07-18T06:01:59Z","timestamp":1784354519863,"version":"3.55.0"},"reference-count":28,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,6,18]],"date-time":"2025-06-18T00:00:00Z","timestamp":1750204800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:p>Congenital hypogonadotropic hypogonadism (CHH) is a rare endocrine disorder characterized by gonadal dysfunction attributed to impaired gonadotropin secretion. CHH is associated with approximately 60 genes including <jats:italic>FGFR1<\/jats:italic>. Nevertheless, the nucleotide variants of these genes are only related to less than half of the cases. Herein, we report a case of CHH caused by a novel mechanism. A 6-year-old boy presented with hypomasculinized genitalia, hyposmia, and syndactyly. Endocrine examinations showed impaired gonadotropin secretion. Short-read next-generation sequencing (NGS) identified the absence of mutations in the major causative genes for CHH. However, it detected an accumulation of discordant and split reads in a genomic region within the <jats:italic>FGFR1<\/jats:italic> gene. Array-based comparative genomic hybridization did not detect copy-number abnormalities. Targeted long-read NGS and Sanger sequencing identified a <jats:italic>de novo<\/jats:italic> 333-bp insertion in exon 9 of the <jats:italic>FGFR1<\/jats:italic> gene. A similarity search revealed that the insertion was an Alu element. This insertion caused a frameshift and resulted in premature termination (p. His409fsTer31). Further, it had several hallmarks of retrotransposition such as target site duplication, an endonuclease cleavage site-like motif, and a poly-A tail. The study results broadened the genetic basis of CHH that considered retrotransposon insertions. Importantly, this case emphasizes the need for additional genomic analyses in patients with CHH who had negative results on short-read NGS and array-based comparative genomic hybridization.<\/jats:p>","DOI":"10.3389\/fendo.2025.1565316","type":"journal-article","created":{"date-parts":[[2025,6,18]],"date-time":"2025-06-18T04:16:35Z","timestamp":1750220195000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["De novo retrotransposon insertion into the FGFR1 gene in a boy with congenital hypogonadotropic hypogonadism: a case report"],"prefix":"10.3389","volume":"16","author":[{"given":"Kentaro","family":"Sawano","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keisuke","family":"Nagasaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erina","family":"Suzuki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasuko","family":"Ogiwara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ikuko","family":"Kageyama","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maki","family":"Fukami","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoko","family":"Kuroki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,6,18]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"669","DOI":"10.1210\/er.2018-00116","article-title":"Clinical management of congenital hypogonadotropic hypogonadism","volume":"40","author":"Young","year":"2019","journal-title":"Endocr Rev"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(91)90193-3","article-title":"The candidate gene for the X-linked Kallmann syndrome encodes a protein related to adhesion molecules","volume":"67","author":"Legouis","year":"1991","journal-title":"Cell"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1038\/353529a0","article-title":"A gene deleted in Kallmann\u2019s syndrome shares homology with neural cell adhesion and axonal path-finding molecules","volume":"353","author":"Franco","year":"1991","journal-title":"Nature"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMcp1109290","article-title":"Clinical practice. Delayed puberty","volume":"366","author":"Palmert","year":"2012","journal-title":"N Engl J Med"},{"key":"B5","doi-asserted-by":"publisher","first-page":"283","DOI":"10.1016\/j.ecl.2017.01.010","article-title":"Molecular and genetic aspects of congenital isolated hypogonadotropic hypogonadism","volume":"46","author":"Lima Amato","year":"2017","journal-title":"Endocrinol Metab Clin North Am"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1007\/s00439-020-02148-0","article-title":"Molecular genetic diagnostics of hypogonadotropic hypogonadism: from panel design towards result interpretation in clinical practice","volume":"140","author":"Butz","year":"2021","journal-title":"Hum Genet"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1038\/s41431-022-01261-0","article-title":"Panel testing for the molecular genetic diagnosis of congenital hypogonadotropic hypogonadism - a clinical perspective","volume":"31","author":"Al Sayed","year":"2023","journal-title":"Eur J Hum Genet"},{"key":"B8","doi-asserted-by":"publisher","first-page":"1130","DOI":"10.1016\/j.fertnstert.2014.06.017","article-title":"Genome-wide copy number analysis and systematic mutation screening in 58 patients with hypogonadotropic hypogonadism","volume":"102","author":"Izumi","year":"2014","journal-title":"Fertil Steril"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1186\/s13100-016-0065-9","article-title":"Roles for retrotransposon insertions in human disease","volume":"7","author":"Hancks","year":"2016","journal-title":"Mobile DNA"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2018-00482","article-title":"Sex differences in reproductive hormones during mini-puberty in infants with normal and disordered sex development","volume":"103","author":"Johannsen","year":"2018","journal-title":"J Clin Endocrinol Metab"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.17458\/per.vol17.2020.tsm.NeonatalinfantintervalsArgentina","article-title":"Neonatal and infant reference intervals for FSH, LH, Testosterone, Estradiol, Cortisol and DHEA-S by electrochemiluminescence in Argentina","volume":"17","author":"Tarifa","year":"2020","journal-title":"Pediatr Endocrinol Rev"},{"key":"B12","article-title":"Research group for investigating disorders of the diencephalon and pituitary, supported by the ministry of health, labour and welfare, Japan","year":"2019"},{"key":"B13","volume-title":"Brook\u2019s Clinical pediatric endocrinology","author":"Brown","year":"2005"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1210\/jendso\/bvab056","article-title":"SOX10 mutation screening for 117 patients with Kallmann syndrome","volume":"5","author":"Shima","year":"2021","journal-title":"J Endocr Soc"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.3930","article-title":"Real-time selective sequencing using nanopore technology","volume":"13","author":"Loose","year":"2016","journal-title":"Nat Methods"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-020-00746-x","article-title":"Readfish enables targeted nanopore sequencing of gigabase-sized genomes","volume":"39","author":"Payne","year":"2021","journal-title":"Nat Biotechnol"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.94.5.1872","article-title":"Sequence patterns indicate an enzymatic involvement in integration of mammalian retroposons","volume":"94","author":"Jurka","year":"1997","journal-title":"Proc Natl Acad Sci U S A"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1038\/ng1223","article-title":"LINE-mediated retrotransposition of marked Alu sequences","volume":"35","author":"Dewannieux","year":"2003","journal-title":"Nat Genet"},{"key":"B19","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1159\/000312693","article-title":"FGFR1 mutations in Kallmann syndrome","volume":"39","author":"Villanueva","year":"2010","journal-title":"Front Horm Res"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2014.166","article-title":"Congenital hypogonadotropic hypogonadism with split hand\/foot malformation: a clinical entity with a high frequency of FGFR1 mutations","volume":"17","author":"Villanueva","year":"2015","journal-title":"Genet Med"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2393-9-8","article-title":"The HELLP syndrome: clinical issues and management","volume":"9","author":"Haram","year":"2009","journal-title":"A Review BMC Pregn Childbirth"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.3390\/diagnostics14040352","article-title":"HELLP syndrome and differential diagnosis with other thrombotic microangiopathies in pregnancy","volume":"14","author":"Giannubilo","year":"2024","journal-title":"Diagn (Basel)"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1038\/nrm4063","article-title":"Nonsense-mediated mRNA decay: an intricate machinery that shapes transcriptomes","volume":"16","author":"Lykke-Andersen","year":"2015","journal-title":"Nat Rev Mol Cell Biol"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1093\/nargab\/lqz023","article-title":"Few SINEs of life: Alu elements have little evidence for biological relevance despite elevated translation","volume":"2","author":"Martinez-Gomez","year":"2020","journal-title":"NAR Genom Bioinform"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1093\/molbev\/msg150","article-title":"Recently integrated Alu elements and human genomic diversity","volume":"20","author":"Salem","year":"2003","journal-title":"Mol Biol Evol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1101\/gr.247965.118","article-title":"Pedigree-based estimation of human mobile element retrotransposition rates","volume":"29","author":"Feusier","year":"2019","journal-title":"Genome Res"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1016\/s0168-9525(01)02445-3","article-title":"Transposable elements are found in a large number of human protein-coding genes","volume":"17","author":"Nekrutenko","year":"2001","journal-title":"Trends Genet"},{"key":"B28","doi-asserted-by":"publisher","first-page":"954","DOI":"10.1038\/s42003-023-05322-y","article-title":"Repetitive DNA sequence detection and its role in the human genome","volume":"6","author":"Liao","year":"2023","journal-title":"Commun Biol"}],"container-title":["Frontiers in Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2025.1565316\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,18]],"date-time":"2025-06-18T04:16:37Z","timestamp":1750220197000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2025.1565316\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,18]]},"references-count":28,"alternative-id":["10.3389\/fendo.2025.1565316"],"URL":"https:\/\/doi.org\/10.3389\/fendo.2025.1565316","relation":{},"ISSN":["1664-2392"],"issn-type":[{"value":"1664-2392","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6,18]]},"article-number":"1565316"}}