{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T16:35:01Z","timestamp":1792427701222,"version":"4.5.0"},"reference-count":73,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2024,9,16]],"date-time":"2024-09-16T00:00:00Z","timestamp":1726444800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,9,16]],"date-time":"2024-09-16T00:00:00Z","timestamp":1726444800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Biol Sex Differ"],"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Purpose<\/jats:title>\n                <jats:p>46,XY disorders of sex development (46,XY DSD) are characterized by incomplete masculinization of genitalia with reduced androgenization. Accurate clinical management remains challenging, especially based solely on physical examination. Targeted next-generation sequencing (NGS) with known pathogenic genes provides a powerful tool for diagnosis efficiency. This study aims to identify the prevalent genetic variants by targeted NGS technology and investigate the diagnostic rate in a large cohort of 46,XY DSD patients, with most of them presenting atypical phenotypes.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>Two different DSD panels were developed for sequencing purposes, targeting a cohort of 402 patients diagnosed with 46,XY DSD, who were recruited from the Department of Urology at Children\u2019s Hospital, Zhejiang University School of Medicine (Hangzhou, China). The detailed clinical characteristics were evaluated, and peripheral blood was collected for targeted panels to find the patients\u2019 variants. The clinical significance of these variants was annotated according to American College of Medical Genetics and Genomics (ACMG) guidelines.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>A total of 108 variants across 42 genes were found in 107 patients, including 46 pathogenic or likely pathogenic variants, with 45.7%(21\/46) being novel. Among these genes, <jats:italic>SRD5A2<\/jats:italic>, <jats:italic>AR<\/jats:italic>, <jats:italic>FGFR1<\/jats:italic>, <jats:italic>LHCGR<\/jats:italic>, <jats:italic>NR5A1<\/jats:italic>, <jats:italic>CHD7<\/jats:italic> were the most frequently observed. Besides, we also detected some uncommon causative genes like <jats:italic>SOS1<\/jats:italic>, and <jats:italic>GNAS<\/jats:italic>. Oligogenic variants were also identified in 9 patients, including several combinations <jats:italic>PROKR2\/FGFR1\/CYP11B1<\/jats:italic>,<jats:italic> PROKR2\/ATRX<\/jats:italic>,<jats:italic> PROKR2\/AR<\/jats:italic>,<jats:italic> FGFR1\/LHCGR\/POR<\/jats:italic>,<jats:italic> FGFR1\/NR5A1<\/jats:italic>,<jats:italic> GATA4\/NR5A1<\/jats:italic>,<jats:italic> WNT4\/AR<\/jats:italic>,<jats:italic> MAP3K1\/FOXL2<\/jats:italic>,<jats:italic> WNT4\/AR<\/jats:italic>,<jats:italic> and SOS1\/FOXL2<\/jats:italic>.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusion<\/jats:title>\n                <jats:p>The overall genetic diagnostic rate was 11.2%(45\/402), with an additional 15.4% (62\/402) having variants of uncertain significance. Additionally, trio\/duo patients had a higher genetic diagnostic rate (13.4%) compared to singletons (8.6%), with a higher proportion of singletons (15.1%) presenting variants of uncertain significance. In conclusion, targeted gene panels identified pathogenic variants in a Chinese 46,XY DSD cohort, expanding the genetic understanding and providing evidence for known pathogenic genes\u2019 involvement.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s13293-024-00648-6","type":"journal-article","created":{"date-parts":[[2024,9,16]],"date-time":"2024-09-16T10:02:12Z","timestamp":1726480932000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Application and insights of targeted next-generation sequencing in a large cohort of 46,XY disorders of sex development in Chinese"],"prefix":"10.1186","volume":"15","author":[{"given":"Hongyu","family":"Chen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guangjie","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fengxia","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linfeng","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yijun","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziyi","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiang","family":"Yan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lan","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,9,16]]},"reference":[{"key":"648_CR1","doi-asserted-by":"publisher","first-page":"7554","DOI":"10.1136\/adc.2006.098319","volume":"91","author":"IA Hughes","year":"2006","unstructured":"Hughes IA, Houk C, Ahmed SF, Lee PA, Group LC, Group EC. Consensus statement on management of intersex disorders. Arch Dis Child. 2006;91:7554\u201363. https:\/\/doi.org\/10.1136\/adc.2006.098319.","journal-title":"Arch Dis Child"},{"key":"648_CR2","doi-asserted-by":"publisher","first-page":"783","DOI":"10.1016\/j.juro.2013.09.058","volume":"191","author":"AS Nordenvall","year":"2014","unstructured":"Nordenvall AS, Frisen L, Nordenstrom A, Lichtenstein P, Nordenskjold A. Population based nationwide study of hypospadias in Sweden, 1973 to 2009: incidence and risk factors. J Urol. 2014;191:3:783\u20139. https:\/\/doi.org\/10.1016\/j.juro.2013.09.058.","journal-title":"J Urol"},{"key":"648_CR3","doi-asserted-by":"publisher","first-page":"1547","DOI":"10.1210\/er.2019-00049","volume":"40","author":"AB Wisniewski","year":"2019","unstructured":"Wisniewski AB, Batista RL, Costa EMF, Finlayson C, Sircili MHP, Denes FT, et al. Management of 46,XY Differences\/Disorders of Sex Development (DSD) throughout life. Endocr Rev. 2019;40:6:1547\u201372. https:\/\/doi.org\/10.1210\/er.2019-00049.","journal-title":"Endocr Rev"},{"key":"648_CR4","doi-asserted-by":"publisher","first-page":"2228","DOI":"10.1038\/s41443-021-00422-x","volume":"33","author":"U Lampalzer","year":"2021","unstructured":"Lampalzer U, Briken P, Schweizer K. Psychosocial care and support in the field of intersex\/diverse sex development (dsd): counselling experiences, localisation and needed improvements. Int J Impot Res. 2021;33:2228\u201342. https:\/\/doi.org\/10.1038\/s41443-021-00422-x.","journal-title":"Int J Impot Res"},{"key":"648_CR5","doi-asserted-by":"publisher","first-page":"856128","DOI":"10.3389\/fped.2022.856128","volume":"10","author":"L Lu","year":"2022","unstructured":"Lu L, Luo F, Wang X. Gonadal tumor risk in pediatric and adolescent phenotypic females with disorders of sex development and Y chromosomal constitution with different genetic etiologies. Front Pediatr. 2022;10:856128. https:\/\/doi.org\/10.3389\/fped.2022.856128.","journal-title":"Front Pediatr"},{"key":"648_CR6","doi-asserted-by":"publisher","unstructured":"Mendonca BB, Domenice S, Arnhold IJ, Costa EM. 46,XY disorders of sex development (DSD). Clin Endocrinol (Oxf). 2009;70. https:\/\/doi.org\/10.1111\/j.1365-2265.2008.03392.x. :2:173\u2009\u2013\u200987.","DOI":"10.1111\/j.1365-2265.2008.03392.x"},{"key":"648_CR7","doi-asserted-by":"publisher","first-page":"2221","DOI":"10.1016\/j.beem.2010.08.013","volume":"25","author":"RA Rey","year":"2011","unstructured":"Rey RA, Grinspon RP. Normal male sexual differentiation and aetiology of disorders of sex development. Best Pract Res Clin Endocrinol Metab. 2011;25:2221\u201338. https:\/\/doi.org\/10.1016\/j.beem.2010.08.013.","journal-title":"Best Pract Res Clin Endocrinol Metab"},{"key":"648_CR8","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1038\/nrendo.2012.235","volume":"9","author":"M Ono","year":"2013","unstructured":"Ono M, Harley VR. Disorders of sex development: new genes, new concepts. Nat Rev Endocrinol. 2013;9:2:79\u201391. https:\/\/doi.org\/10.1038\/nrendo.2012.235.","journal-title":"Nat Rev Endocrinol"},{"key":"648_CR9","doi-asserted-by":"publisher","first-page":"588","DOI":"10.1038\/s41576-021-00365-5","volume":"22","author":"EC Delot","year":"2021","unstructured":"Delot EC, Vilain E. Towards improved genetic diagnosis of human differences of sex development. Nat Rev Genet. 2021;22:9:588\u2013602. https:\/\/doi.org\/10.1038\/s41576-021-00365-5.","journal-title":"Nat Rev Genet"},{"key":"648_CR10","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1093\/bmb\/ldt008","volume":"106","author":"SF Ahmed","year":"2013","unstructured":"Ahmed SF, Bashamboo A, Lucas-Herald A, McElreavey K. Understanding the genetic aetiology in patients with XY DSD. Br Med Bull. 2013;106:67\u201389. https:\/\/doi.org\/10.1093\/bmb\/ldt008.","journal-title":"Br Med Bull"},{"key":"648_CR11","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1016\/j.jmoldx.2023.02.001","volume":"25","author":"X Luo","year":"2023","unstructured":"Luo X, Wang R, Sun Y, Qiu W, Lu D, Wang Y, et al. Deep intronic PAH variants explain missing heritability in Hyperphenylalaninemia. J Mol Diagn. 2023;25:5. https:\/\/doi.org\/10.1016\/j.jmoldx.2023.02.001.","journal-title":"J Mol Diagn"},{"key":"648_CR12","doi-asserted-by":"publisher","first-page":"i17884","DOI":"10.1093\/bioinformatics\/bty560","volume":"34","author":"S Chen","year":"2018","unstructured":"Chen S, Zhou Y, Chen Y, Gu J. Fastp: an ultra-fast all-in-one FASTQ preprocessor. Bioinformatics. 2018;34:i17884\u201390. https:\/\/doi.org\/10.1093\/bioinformatics\/bty560.","journal-title":"Bioinformatics"},{"key":"648_CR13","doi-asserted-by":"publisher","first-page":"1754","DOI":"10.1093\/bioinformatics\/btp324","volume":"25","author":"H Li","year":"2009","unstructured":"Li H, Durbin R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics. 2009;25:14:1754\u201360. https:\/\/doi.org\/10.1093\/bioinformatics\/btp324.","journal-title":"Bioinformatics"},{"key":"648_CR14","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1093\/bioinformatics\/btp352","volume":"25","author":"H Li","year":"2009","unstructured":"Li H, Handsaker B, Wysoker A, Fennell T, Ruan J, Homer N, et al. The sequence Alignment\/Map format and SAMtools. Bioinformatics. 2009;25:16. https:\/\/doi.org\/10.1093\/bioinformatics\/btp352.","journal-title":"Bioinformatics"},{"key":"648_CR15","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1002\/0471250953.bi1110s43","volume":"43","author":"GA Van der Auwera","year":"2013","unstructured":"Van der Auwera GA, Carneiro MO, Hartl C, Poplin R, Del Angel G, Levy-Moonshine A, et al. From FastQ data to high confidence variant calls: the Genome Analysis Toolkit best practices pipeline. Curr Protoc Bioinf. 2013;43:11. https:\/\/doi.org\/10.1002\/0471250953.bi1110s43.","journal-title":"Curr Protoc Bioinf"},{"key":"648_CR16","doi-asserted-by":"publisher","first-page":"16e164","DOI":"10.1093\/nar\/gkq603","volume":"38","author":"K Wang","year":"2010","unstructured":"Wang K, Li M, Hakonarson H. ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res. 2010;38:16e164. https:\/\/doi.org\/10.1093\/nar\/gkq603.","journal-title":"Nucleic Acids Res"},{"key":"648_CR17","doi-asserted-by":"publisher","first-page":"5405","DOI":"10.1038\/gim.2015.30","volume":"17","author":"S Richards","year":"2015","unstructured":"Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:5405\u201324. https:\/\/doi.org\/10.1038\/gim.2015.30.","journal-title":"Genet Med"},{"key":"648_CR18","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1093\/bioinformatics\/bty897","volume":"35","author":"C Kopanos","year":"2019","unstructured":"Kopanos C, Tsiolkas V, Kouris A, Chapple CE, Albarca Aguilera M, Meyer R, et al. VarSome: the human genomic variant search engine. Bioinformatics. 2019;35:11. https:\/\/doi.org\/10.1093\/bioinformatics\/bty897.","journal-title":"Bioinformatics"},{"key":"648_CR19","doi-asserted-by":"publisher","first-page":"3265","DOI":"10.1007\/s00439-018-1879-y","volume":"137","author":"H Wang","year":"2018","unstructured":"Wang H, Zhang L, Wang N, Zhu H, Han B, Sun F, et al. Next-generation sequencing reveals genetic landscape in 46, XY disorders of sexual development patients with variable phenotypes. Hum Genet. 2018;137:3265\u201377. https:\/\/doi.org\/10.1007\/s00439-018-1879-y.","journal-title":"Hum Genet"},{"issue":"1","key":"648_CR20","doi-asserted-by":"publisher","first-page":"69","DOI":"10.4103\/aja.aja_36_20","volume":"23","author":"BQ Yu","year":"2021","unstructured":"Yu BQ, Liu ZX, Gao YJ, Wang X, Mao JF, Nie M, et al. Prevalence of gene mutations in a Chinese 46,XY disorders of sex development cohort detected by targeted next-generation sequencing. Asian J Androl. 2021;23(1):69\u201373. https:\/\/doi.org\/10.4103\/aja.aja_36_20.","journal-title":"Asian J Androl"},{"key":"648_CR21","doi-asserted-by":"publisher","first-page":"131","DOI":"10.1002\/ped4.12111","volume":"3","author":"B Zhang","year":"2019","unstructured":"Zhang B, Song Y, Li W, Gong C. Variant analysis of the chromodomain helicase DNA-binding protein 7 in pediatric disorders of sex development. Pediatr Investig. 2019;3:131\u20138. https:\/\/doi.org\/10.1002\/ped4.12111.","journal-title":"Pediatr Investig"},{"key":"648_CR22","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1097\/MOP.0000000000000644","volume":"30","author":"M Alimussina","year":"2018","unstructured":"Alimussina M, Diver LA, McGowan R, Ahmed SF. Genetic testing of XY newborns with a suspected disorder of sex development. Curr Opin Pediatr. 2018;30:4. https:\/\/doi.org\/10.1097\/MOP.0000000000000644.","journal-title":"Curr Opin Pediatr"},{"key":"648_CR23","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1053\/j.semperi.2017.03.016","volume":"41","author":"SA Yatsenko","year":"2017","unstructured":"Yatsenko SA, Witchel SF. Genetic approach to ambiguous genitalia and disorders of sex development: what clinicians need to know. Semin Perinatol. 2017;41:4. https:\/\/doi.org\/10.1053\/j.semperi.2017.03.016.","journal-title":"Semin Perinatol"},{"key":"648_CR24","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1159\/000314536","volume":"4","author":"J Pleskacova","year":"2010","unstructured":"Pleskacova J, Hersmus R, Oosterhuis JW, Setyawati BA, Faradz SM, Cools M, et al. Tumor risk in disorders of sex development. Sex Dev. 2010;4:4\u20135. https:\/\/doi.org\/10.1159\/000314536.","journal-title":"Sex Dev"},{"key":"648_CR25","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1038\/nrg3051","volume":"12","author":"ZE Sauna","year":"2011","unstructured":"Sauna ZE, Kimchi-Sarfaty C. Understanding the contribution of synonymous mutations to human disease. Nat Rev Genet. 2011;12:10. https:\/\/doi.org\/10.1038\/nrg3051.","journal-title":"Nat Rev Genet"},{"key":"648_CR26","doi-asserted-by":"publisher","first-page":"83","DOI":"10.2147\/TACG.S198178","volume":"13","author":"RL Batista","year":"2020","unstructured":"Batista RL, Mendonca BB. Integrative and Analytical Review of the 5-Alpha-reductase type 2 Deficiency Worldwide. Appl Clin Genet. 2020;13:83\u201396. https:\/\/doi.org\/10.2147\/TACG.S198178.","journal-title":"Appl Clin Genet"},{"key":"648_CR27","doi-asserted-by":"publisher","first-page":"1789514","DOI":"10.1155\/2020\/1789514","volume":"2020","author":"B Han","year":"2020","unstructured":"Han B, Cheng T, Zhu H, Yu J, Zhu WJ, Song HD, et al. Genetic analysis of 25 patients with 5alpha-Reductase Deficiency in Chinese Population. Biomed Res Int. 2020;2020:1789514. https:\/\/doi.org\/10.1155\/2020\/1789514.","journal-title":"Biomed Res Int"},{"key":"648_CR28","doi-asserted-by":"publisher","first-page":"10685","DOI":"10.1136\/jmedgenet-2018-105915","volume":"56","author":"B Gui","year":"2019","unstructured":"Gui B, Song Y, Su Z, Luo FH, Chen L, Wang X, et al. New insights into 5alpha-reductase type 2 deficiency based on a multi-centre study: regional distribution and genotype-phenotype profiling of SRD5A2 in 190 Chinese patients. J Med Genet. 2019;56:10685\u201392. https:\/\/doi.org\/10.1136\/jmedgenet-2018-105915.","journal-title":"J Med Genet"},{"key":"648_CR29","doi-asserted-by":"publisher","DOI":"10.1007\/s12098-024-05144-8","author":"R Palui","year":"2024","unstructured":"Palui R, Ravichandran L, Kamalanathan S, Chapla A, Sahoo J, Narayanan N, et al. Clinical, hormonal, and genetic spectrum of 46 XY disorders of sexual development (DSD) patients. Indian J Pediatr. 2024. https:\/\/doi.org\/10.1007\/s12098-024-05144-8.","journal-title":"Indian J Pediatr"},{"key":"648_CR30","doi-asserted-by":"publisher","first-page":"2153","DOI":"10.4274\/jcrpe.galenos.2022.2021-9-19","volume":"14","author":"N Akcan","year":"2022","unstructured":"Akcan N, Uyguner O, Bas F, Altunoglu U, Toksoy G, Karaman B, et al. Mutations in AR or SRD5A2 genes: clinical findings, endocrine pitfalls, and genetic features of children with 46,XY DSD. J Clin Res Pediatr Endocrinol. 2022;14:2153\u201371. https:\/\/doi.org\/10.4274\/jcrpe.galenos.2022.2021-9-19.","journal-title":"J Clin Res Pediatr Endocrinol"},{"key":"648_CR31","doi-asserted-by":"publisher","first-page":"394","DOI":"10.1055\/s-0035-1545274","volume":"47","author":"IA Hughes","year":"2015","unstructured":"Hughes IA. Consequences of the Chicago DSD Consensus: a personal perspective. Horm Metab Res. 2015;47:5:394\u2013400. https:\/\/doi.org\/10.1055\/s-0035-1545274.","journal-title":"Horm Metab Res"},{"key":"648_CR32","doi-asserted-by":"publisher","first-page":"64","DOI":"10.1097\/00005792-199603000-00003","volume":"75","author":"BB Mendonca","year":"1996","unstructured":"Mendonca BB, Inacio M, Costa EM, Arnhold IJ, Silva FA, Nicolau W, et al. Male pseudohermaphroditism due to steroid 5alpha-reductase 2 deficiency. Diagnosis, psychological evaluation, and management. Med (Baltim). 1996;75:2:64\u201376. https:\/\/doi.org\/10.1097\/00005792-199603000-00003.","journal-title":"Med (Baltim)"},{"key":"648_CR33","first-page":"3","volume":"37","author":"RA Davey","year":"2016","unstructured":"Davey RA, Grossmann M. Androgen receptor structure, function and Biology: from bench to Bedside. Clin Biochem Rev. 2016;37:1:3\u201315. https:\/\/www.ncbi.nlm.nih.gov\/pubmed\/27057074.","journal-title":"Clin Biochem Rev"},{"key":"648_CR34","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1073\/pnas.89.14.6319","volume":"89","author":"JR Newmark","year":"1992","unstructured":"Newmark JR, Hardy DO, Tonb DC, Carter BS, Epstein JI, Isaacs WB, et al. Androgen receptor gene mutations in human prostate cancer. Proc Natl Acad Sci U S A. 1992;89:14. https:\/\/doi.org\/10.1073\/pnas.89.14.6319.","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"2","key":"648_CR35","doi-asserted-by":"publisher","first-page":"162","DOI":"10.4103\/aja.aja_36_19","volume":"22","author":"SD Lv","year":"2020","unstructured":"Lv SD, Wang HY, Yu XP, Zhai QL, Wu YB, Wei Q, et al. Integrative molecular characterization of Chinese prostate cancer specimens. Asian J Androl. 2020;22(2):162\u20138. https:\/\/doi.org\/10.4103\/aja.aja_36_19.","journal-title":"Asian J Androl"},{"key":"648_CR36","doi-asserted-by":"publisher","unstructured":"Torquato S, Pallavajjala A, Goldstein A, Toro PV, Silberstein JL, Lee J, et al. Genetic alterations detected in cell-free DNA are Associated with Enzalutamide and Abiraterone Resistance in Castration-resistant prostate Cancer. JCO Precis Oncol. 2019;3. https:\/\/doi.org\/10.1200\/PO.18.00227.","DOI":"10.1200\/PO.18.00227"},{"key":"648_CR37","doi-asserted-by":"publisher","first-page":"7","DOI":"10.3390\/ijerph16071268","volume":"16","author":"L Lanciotti","year":"2019","unstructured":"Lanciotti L, Cofini M, Leonardi A, Bertozzi M, Penta L, Esposito S. Different clinical presentations and management in complete androgen insensitivity syndrome (CAIS). Int J Environ Res Public Health. 2019;16:7. https:\/\/doi.org\/10.3390\/ijerph16071268.","journal-title":"Int J Environ Res Public Health"},{"key":"648_CR38","doi-asserted-by":"publisher","first-page":"1285508","DOI":"10.3389\/fonc.2023.1285508","volume":"13","author":"J Yang","year":"2023","unstructured":"Yang J, Zhao S, Su J, Liu S, Wu Z, Ma W, et al. Comprehensive genomic profiling reveals prognostic signatures and insights into the molecular landscape of colorectal cancer. Front Oncol. 2023;13:1285508. https:\/\/doi.org\/10.3389\/fonc.2023.1285508.","journal-title":"Front Oncol"},{"key":"648_CR39","doi-asserted-by":"publisher","first-page":"3310","DOI":"10.1210\/jc.2006-0218","volume":"91","author":"C Bouvattier","year":"2006","unstructured":"Bouvattier C, Mignot B, Lefevre H, Morel Y, Bougneres P. Impaired sexual activity in male adults with partial androgen insensitivity. J Clin Endocrinol Metab. 2006;91:9:3310\u20135. https:\/\/doi.org\/10.1210\/jc.2006-0218.","journal-title":"J Clin Endocrinol Metab"},{"key":"648_CR40","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1111\/and.12763","volume":"49","author":"L Su","year":"2017","unstructured":"Su L, Cheng J, Yin X, Liu G, Lu Z, Sheng H, et al. Clinical and molecular characteristics in 15 patients with androgen receptor gene mutations from South China. Andrologia. 2017;49:10. https:\/\/doi.org\/10.1111\/and.12763.","journal-title":"Andrologia"},{"key":"648_CR41","doi-asserted-by":"publisher","first-page":"4e61824","DOI":"10.1371\/journal.pone.0061824","volume":"8","author":"N Kalfa","year":"2013","unstructured":"Kalfa N, Philibert P, Werner R, Audran F, Bashamboo A, Lehors H, et al. Minor hypospadias: the tip of the iceberg of the partial androgen insensitivity syndrome. PLoS ONE. 2013;8:4e61824. https:\/\/doi.org\/10.1371\/journal.pone.0061824.","journal-title":"PLoS ONE"},{"key":"648_CR42","doi-asserted-by":"publisher","first-page":"4507","DOI":"10.1016\/j.eururo.2020.12.036","volume":"79","author":"V Ea","year":"2021","unstructured":"Ea V, Bergougnoux A, Philibert P, Servant-Fauconnet N, Faure A, Breaud J, et al. How far should we explore Hypospadias? Next-generation sequencing Applied to a large cohort of Hypospadiac patients. Eur Urol. 2021;79:4507\u201315. https:\/\/doi.org\/10.1016\/j.eururo.2020.12.036.","journal-title":"Eur Urol"},{"key":"648_CR43","doi-asserted-by":"publisher","first-page":"15702","DOI":"10.1038\/s41467-021-25846-3","volume":"12","author":"NC Reddy","year":"2021","unstructured":"Reddy NC, Majidi SP, Kong L, Nemera M, Ferguson CJ, Moore M, et al. CHARGE syndrome protein CHD7 regulates epigenomic activation of enhancers in granule cell precursors and gyrification of the cerebellum. Nat Commun. 2021;12:15702. https:\/\/doi.org\/10.1038\/s41467-021-25846-3.","journal-title":"Nat Commun"},{"key":"648_CR44","doi-asserted-by":"publisher","first-page":"397","DOI":"10.1002\/ajmg.c.31592","volume":"175","author":"C van Ravenswaaij-Arts","year":"2017","unstructured":"van Ravenswaaij-Arts C, Martin DM. New insights and advances in CHARGE syndrome: diagnosis, etiologies, treatments, and research discoveries. Am J Med Genet C Semin Med Genet. 2017;175:4:397\u2013406. https:\/\/doi.org\/10.1002\/ajmg.c.31592.","journal-title":"Am J Med Genet C Semin Med Genet"},{"key":"648_CR45","doi-asserted-by":"publisher","first-page":"9","DOI":"10.21037\/tau-23-225","volume":"12","author":"Y Wang","year":"2023","unstructured":"Wang Y, Jiang W, Xia X. Clinical and molecular features of 40 Chinese patients with idiopathic hypogonadotropic hypogonadism. Transl Androl Urol. 2023;12:9. https:\/\/doi.org\/10.21037\/tau-23-225.","journal-title":"Transl Androl Urol"},{"key":"648_CR46","doi-asserted-by":"publisher","first-page":"8e827","DOI":"10.1002\/mgg3.827","volume":"7","author":"W Zhang","year":"2019","unstructured":"Zhang W, Shi J, Zhang C, Jiang X, Wang J, Wang W, et al. Identification of gene variants in 130 Han Chinese patients with hypospadias by targeted next-generation sequencing. Mol Genet Genomic Med. 2019;7:8e827. https:\/\/doi.org\/10.1002\/mgg3.827.","journal-title":"Mol Genet Genomic Med"},{"key":"648_CR47","doi-asserted-by":"publisher","first-page":"1149","DOI":"10.1002\/humu.22086","volume":"33","author":"N Janssen","year":"2012","unstructured":"Janssen N, Bergman JE, Swertz MA, Tranebjaerg L, Lodahl M, Schoots J, et al. Mutation update on the CHD7 gene involved in CHARGE syndrome. Hum Mutat. 2012;33:8:1149\u201360. https:\/\/doi.org\/10.1002\/humu.22086.","journal-title":"Hum Mutat"},{"key":"648_CR48","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1111\/j.1399-0004.2012.01884.x","volume":"83","author":"E Husu","year":"2013","unstructured":"Husu E, Hove HD, Farholt S, Bille M, Tranebjaerg L, Vogel I, et al. Phenotype in 18 Danish subjects with genetically verified CHARGE syndrome. Clin Genet. 2013;83:2. https:\/\/doi.org\/10.1111\/j.1399-0004.2012.01884.x.","journal-title":"Clin Genet"},{"key":"648_CR49","doi-asserted-by":"publisher","first-page":"31622","DOI":"10.1038\/srep31622","volume":"6","author":"G Bademci","year":"2016","unstructured":"Bademci G, Cengiz FB, Foster Ii J, Duman D, Sennaroglu L, Diaz-Horta O, et al. Variations in multiple syndromic deafness genes mimic non-syndromic hearing loss. Sci Rep. 2016;6:31622. https:\/\/doi.org\/10.1038\/srep31622.","journal-title":"Sci Rep"},{"key":"648_CR50","doi-asserted-by":"publisher","first-page":"E102138","DOI":"10.1210\/jc.2014-2110","volume":"99","author":"S Marcos","year":"2014","unstructured":"Marcos S, Sarfati J, Leroy C, Fouveaut C, Parent P, Metz C, et al. The prevalence of CHD7 missense versus truncating mutations is higher in patients with Kallmann syndrome than in typical CHARGE patients. J Clin Endocrinol Metab. 2014;99:E102138\u201343. https:\/\/doi.org\/10.1210\/jc.2014-2110.","journal-title":"J Clin Endocrinol Metab"},{"key":"648_CR51","doi-asserted-by":"publisher","first-page":"17953","DOI":"10.1073\/pnas.1417438111","volume":"111","author":"R Balasubramanian","year":"2014","unstructured":"Balasubramanian R, Choi JH, Francescatto L, Willer J, Horton ER, Asimacopoulos EP, et al. Functionally compromised CHD7 alleles in patients with isolated GnRH deficiency. Proc Natl Acad Sci U S A. 2014;111:50:17953\u20138. https:\/\/doi.org\/10.1073\/pnas.1417438111.","journal-title":"Proc Natl Acad Sci U S A"},{"key":"648_CR52","doi-asserted-by":"publisher","first-page":"124","DOI":"10.1016\/j.metabol.2017.10.012","volume":"86","author":"MI Stamou","year":"2018","unstructured":"Stamou MI, Georgopoulos NA. Kallmann syndrome: phenotype and genotype of hypogonadotropic hypogonadism. Metabolism. 2018;86:124\u201334. https:\/\/doi.org\/10.1016\/j.metabol.2017.10.012.","journal-title":"Metabolism"},{"key":"648_CR53","doi-asserted-by":"publisher","first-page":"97","DOI":"10.3389\/fendo.2019.00097","volume":"10","author":"DS Swee","year":"2019","unstructured":"Swee DS, Quinton R. Congenital Hypogonadotrophic Hypogonadism: Minipuberty and the case for neonatal diagnosis. Front Endocrinol (Lausanne). 2019;10:97. https:\/\/doi.org\/10.3389\/fendo.2019.00097.","journal-title":"Front Endocrinol (Lausanne)"},{"key":"648_CR54","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1016\/j.mce.2017.01.037","volume":"444","author":"JH Kim","year":"2017","unstructured":"Kim JH, Kang E, Heo SH, Kim GH, Jang JH, Cho EH, et al. Diagnostic yield of targeted gene panel sequencing to identify the genetic etiology of disorders of sex development. Mol Cell Endocrinol. 2017;444:19\u201325. https:\/\/doi.org\/10.1016\/j.mce.2017.01.037.","journal-title":"Mol Cell Endocrinol"},{"key":"648_CR55","doi-asserted-by":"publisher","first-page":"1503","DOI":"10.1210\/jc.2013-3690","volume":"99","author":"H Ostrer","year":"2014","unstructured":"Ostrer H. Disorders of sex development (DSDs): an update. J Clin Endocrinol Metab. 2014;99:5:1503\u20139. https:\/\/doi.org\/10.1210\/jc.2013-3690.","journal-title":"J Clin Endocrinol Metab"},{"key":"648_CR56","doi-asserted-by":"publisher","first-page":"1243","DOI":"10.1186\/s13059-016-1105-y","volume":"17","author":"S Eggers","year":"2016","unstructured":"Eggers S, Sadedin S, van den Bergen JA, Robevska G, Ohnesorg T, Hewitt J, et al. Disorders of sex development: insights from targeted gene sequencing of a large international patient cohort. Genome Biol. 2016;17:1243. https:\/\/doi.org\/10.1186\/s13059-016-1105-y.","journal-title":"Genome Biol"},{"key":"648_CR57","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1002\/dvg.23333","volume":"57","author":"Z Zhao","year":"2019","unstructured":"Zhao Z, Zhan Y, Chen W, Ma X, Sheng W, Huang G. Functional analysis of rare variants of GATA4 identified in Chinese patients with congenital heart defect. Genesis. 2019;57:11\u20132. https:\/\/doi.org\/10.1002\/dvg.23333.","journal-title":"Genesis"},{"key":"648_CR58","doi-asserted-by":"publisher","first-page":"4566","DOI":"10.1016\/j.cell.2011.01.013","volume":"144","author":"GB Deutsch","year":"2011","unstructured":"Deutsch GB, Zielonka EM, Coutandin D, Weber TA, Schafer B, Hannewald J, et al. DNA damage in oocytes induces a switch of the quality control factor TAp63alpha from dimer to tetramer. Cell. 2011;144:4566\u201376. https:\/\/doi.org\/10.1016\/j.cell.2011.01.013.","journal-title":"Cell"},{"key":"648_CR59","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1128\/MCB.01223-13","volume":"34","author":"DA Kim","year":"2014","unstructured":"Kim DA, Suh EK. Defying DNA double-strand break-induced death during prophase I meiosis by temporal TAp63alpha phosphorylation regulation in developing mouse oocytes. Mol Cell Biol. 2014;34:8. https:\/\/doi.org\/10.1128\/MCB.01223-13.","journal-title":"Mol Cell Biol"},{"issue":"3","key":"648_CR60","doi-asserted-by":"publisher","first-page":"146","DOI":"10.1007\/s11914-015-0268-x","volume":"13","author":"S Turan","year":"2015","unstructured":"Turan S, Bastepe M. GNAS Spectrum of disorders. Curr Osteoporos Rep. 2015;13(3):146\u201358. https:\/\/doi.org\/10.1007\/s11914-015-0268-x.","journal-title":"Curr Osteoporos Rep"},{"key":"648_CR61","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1111\/cge.13734","volume":"97","author":"X Chen","year":"2020","unstructured":"Chen X, Meng Y, Tang M, Wang Y, Xie Y, Wan S, et al. A paternally inherited non-sense variant c.424G\u2009>\u2009T (p.G142*) in the first exon of XLalphas in an adult patient with hypophosphatemia and osteopetrosis. Clin Genet. 2020;97:5. https:\/\/doi.org\/10.1111\/cge.13734.","journal-title":"Clin Genet"},{"key":"648_CR62","doi-asserted-by":"publisher","first-page":"E91549","DOI":"10.1210\/jc.2013-1667","volume":"98","author":"N Richard","year":"2013","unstructured":"Richard N, Molin A, Coudray N, Rault-Guillaume P, Juppner H, Kottler ML. Paternal GNAS mutations lead to severe intrauterine growth retardation (IUGR) and provide evidence for a role of XLalphas in fetal development. J Clin Endocrinol Metab. 2013;98:E91549\u201356. https:\/\/doi.org\/10.1210\/jc.2013-1667.","journal-title":"J Clin Endocrinol Metab"},{"key":"648_CR63","doi-asserted-by":"publisher","first-page":"3147","DOI":"10.1159\/000445983","volume":"10","author":"I Mazen","year":"2016","unstructured":"Mazen I, Abdel-Hamid M, Mekkawy M, Bignon-Topalovic J, Boudjenah R, El Gammal M, et al. Identification of NR5A1 mutations and possible digenic inheritance in 46,XY gonadal dysgenesis. Sex Dev. 2016;10:3147\u201351. https:\/\/doi.org\/10.1159\/000445983.","journal-title":"Sex Dev"},{"key":"648_CR64","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1210\/jc.2009-0843","volume":"95","author":"J Sarfati","year":"2010","unstructured":"Sarfati J, Guiochon-Mantel A, Rondard P, Arnulf I, Garcia-Pinero A, Wolczynski S, et al. A comparative phenotypic study of Kallmann syndrome patients carrying monoallelic and biallelic mutations in the prokineticin 2 or prokineticin receptor 2 genes. J Clin Endocrinol Metab. 2010;95:2. https:\/\/doi.org\/10.1210\/jc.2009-0843.","journal-title":"J Clin Endocrinol Metab"},{"key":"648_CR65","doi-asserted-by":"publisher","first-page":"846801","DOI":"10.3389\/fendo.2022.846801","volume":"13","author":"Y Wang","year":"2022","unstructured":"Wang Y, Qin M, Fan L, Gong C. Correlation Analysis of Genotypes and phenotypes in Chinese Male Pediatric patients with congenital hypogonadotropic hypogonadism. Front Endocrinol (Lausanne). 2022;13:846801. https:\/\/doi.org\/10.3389\/fendo.2022.846801.","journal-title":"Front Endocrinol (Lausanne)"},{"key":"648_CR66","doi-asserted-by":"publisher","first-page":"15140","DOI":"10.1073\/pnas.1009622107","volume":"107","author":"GP Sykiotis","year":"2010","unstructured":"Sykiotis GP, Plummer L, Hughes VA, Au M, Durrani S, Nayak-Young S, et al. Oligogenic basis of isolated gonadotropin-releasing hormone deficiency. Proc Natl Acad Sci U S A. 2010;107:34:15140\u20134. https:\/\/doi.org\/10.1073\/pnas.1009622107.","journal-title":"Proc Natl Acad Sci U S A"},{"key":"648_CR67","doi-asserted-by":"publisher","first-page":"746","DOI":"10.3389\/fgene.2019.00746","volume":"10","author":"CE Fluck","year":"2019","unstructured":"Fluck CE, Audi L, Fernandez-Cancio M, Sauter KS, Martinez de LaPiscina I, Castano L, et al. Broad Phenotypes of Disorders\/Differences of Sex Development in MAMLD1 patients through oligogenic disease. Front Genet. 2019;10:746. https:\/\/doi.org\/10.3389\/fgene.2019.00746.","journal-title":"Front Genet"},{"key":"648_CR68","doi-asserted-by":"publisher","unstructured":"YF Xu ea. New insights from unbiased panel and whole-exome sequencing in a large Chinese Cohort with Disorders of Sex Developmen. Eur Soc Endocrinol. 2019; https:\/\/doi.org\/10.1530\/EJE-19-0111..","DOI":"10.1530\/EJE-19-0111."},{"key":"648_CR69","doi-asserted-by":"publisher","unstructured":"Xu Y, Wang Y, Li N, Yao R, Li G, Li J, et al. New insights from unbiased panel and whole-exome sequencing in a large Chinese cohort with disorders of sex development. Eur J Endocrinol. 2019;181:3:311\u2009\u2212\u200923; https:\/\/doi.org\/10.1530\/EJE-19-0111.","DOI":"10.1530\/EJE-19-0111"},{"key":"648_CR70","doi-asserted-by":"publisher","unstructured":"Fan L, Song Y, Polak M, Li L, Ren X, Zhang B, et al. Clinical characteristics and genotype-phenotype correlations of 130 Chinese children in a high-homogeneity single-center cohort with 5alpha-reductase 2 deficiency. Mol Genet Genomic Med. 2020;8:10:e1431; https:\/\/doi.org\/10.1002\/mgg3.1431.","DOI":"10.1002\/mgg3.1431"},{"key":"648_CR71","doi-asserted-by":"publisher","unstructured":"Xie QG, Luo P, Xia K, Li ZQ, Xu Z, Su C, et al. 46,XY disorders of sex development: the use of NGS for prevalent variants. Hum Genet. 2022;141:12:1863-73; https:\/\/doi.org\/10.1007\/s00439-022-02465-6.","DOI":"10.1007\/s00439-022-02465-6"},{"key":"648_CR72","doi-asserted-by":"publisher","unstructured":"Tang Y, Chen Y, Wang J, Zhang Q, Wang Y, Xu Y, et al. Clinical characteristics and genetic expansion of 46,XY disorders of sex development children in a Chinese prospective study. Endocr Connect. 2023;12:10; https:\/\/doi.org\/10.1530\/EC-23-0029.","DOI":"10.1530\/EC-23-0029"},{"key":"648_CR73","doi-asserted-by":"publisher","unstructured":"White S, Ohnesorg T, Notini A, Roeszler K, Hewitt J, Daggag H, et al. Copy number variation in patients with disorders of sex development due to 46,XY gonadal dysgenesis. PLoS One. 2011;6:3:e17793; https:\/\/doi.org\/10.1371\/journal.pone.0017793.","DOI":"10.1371\/journal.pone.0017793"}],"container-title":["Biology of Sex Differences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13293-024-00648-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13293-024-00648-6\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13293-024-00648-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,9,18]],"date-time":"2024-09-18T12:33:14Z","timestamp":1726662794000},"score":1,"resource":{"primary":{"URL":"https:\/\/bsd.biomedcentral.com\/articles\/10.1186\/s13293-024-00648-6"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,9,16]]},"references-count":73,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["648"],"URL":"https:\/\/doi.org\/10.1186\/s13293-024-00648-6","relation":{},"ISSN":["2042-6410"],"issn-type":[{"value":"2042-6410","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,9,16]]},"assertion":[{"value":"13 March 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"5 September 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 September 2024","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"This study was approved by the local IRB (2018-IRB-076) and informed consent was obtained prior to recruitment.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"73"}}