{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,22]],"date-time":"2026-03-22T23:02:18Z","timestamp":1774220538148,"version":"3.50.1"},"reference-count":30,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2024,9,11]],"date-time":"2024-09-11T00:00:00Z","timestamp":1726012800000},"content-version":"vor","delay-in-days":254,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Portuguese Foundation for Science and Technology","award":["PTDC\/SAU-GMG\/098419\/2008"],"award-info":[{"award-number":["PTDC\/SAU-GMG\/098419\/2008"]}]},{"name":"Portuguese Foundation for Science and Technology","award":["UIDB\/00709\/2020"],"award-info":[{"award-number":["UIDB\/00709\/2020"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,5,25]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>STUDY QUESTION<\/jats:title>\n                  <jats:p>What is the contribution of genetic defects in Portuguese patients with congenital hypogonadotropic hypogonadism (CHH)?<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>SUMMARY ANSWER<\/jats:title>\n                  <jats:p>Approximately one-third of patients with CHH were found to have a genetic cause for their disorder, with causal pathogenic and likely pathogenic germline variants distributed among 10 different genes; cases of oligogenic inheritance were also included.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>WHAT IS KNOWN ALREADY<\/jats:title>\n                  <jats:p>CHH is a rare and genetically heterogeneous disorder characterized by deficient production, secretion, or action of GnRH, LH, and FSH, resulting in delayed or absent puberty, and infertility.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>STUDY DESIGN, SIZE, DURATION<\/jats:title>\n                  <jats:p>Genetic screening was performed on a cohort of 81 Portuguese patients with CHH (36 with Kallmann syndrome and 45 with normosmic hypogonadotropic hypogonadism) and 263 unaffected controls.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>PARTICIPANTS\/MATERIALS, SETTING, METHODS<\/jats:title>\n                  <jats:p>The genetic analysis was performed by whole-exome sequencing followed by the analysis of a virtual panel of 169 CHH-associated genes. The main outcome measures were non-synonymous rare sequence variants (population allele frequency &amp;lt;0.01) classified as pathogenic, likely pathogenic, and variants of uncertain significance (VUS).<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>MAIN RESULTS AND THE ROLE OF CHANCE<\/jats:title>\n                  <jats:p>A genetic cause was identified in 29.6% of patients. Causal pathogenic and likely pathogenic variants were distributed among 10 of the analysed genes. The most frequently implicated genes were GNRHR, FGFR1, ANOS1, and CHD7. Oligogenicity for pathogenic and likely pathogenic variants was observed in 6.2% of patients. VUS and oligogenicity for VUS variants were observed in 85.2% and 54.3% of patients, respectively, but were not significantly different from that observed in controls.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>LARGE SCALE DATA<\/jats:title>\n                  <jats:p>N\/A.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>LIMITATIONS, REASONS FOR CAUTION<\/jats:title>\n                  <jats:p>The identification of a large number of VUS presents challenges in interpretation and these may require reclassification as more evidence becomes available. Non-coding and copy number variants were not studied. Functional studies of the variants were not undertaken.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>WIDER IMPLICATIONS OF THE FINDINGS<\/jats:title>\n                  <jats:p>This study highlights the genetic heterogeneity of CHH and identified several novel variants that expand the mutational spectrum of the disorder. A significant proportion of patients remained without a genetic diagnosis, suggesting the involvement of additional genetic, epigenetic, or environmental factors. The high frequency of VUS underscores the importance of cautious variant interpretation. These findings contribute to the understanding of the genetic architecture of CHH and emphasize the need for further studies to elucidate the underlying mechanisms and identify additional causes of CHH.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>STUDY FUNDING\/COMPETING INTEREST(S)<\/jats:title>\n                  <jats:p>This research was funded by the Portuguese Foundation for Science and Technology (grant numbers PTDC\/SAU-GMG\/098419\/2008, UIDB\/00709\/2020, CEECINST\/00016\/2021\/CP2828\/CT0002, and 2020.04924.BD) and by Sidra Medicine\u2014a member of the Qatar Foundation (grant number SDR400038). The authors declare no competing interests.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/hropen\/hoae053","type":"journal-article","created":{"date-parts":[[2024,9,11]],"date-time":"2024-09-11T22:29:58Z","timestamp":1726093798000},"source":"Crossref","is-referenced-by-count":6,"title":["Genetic architecture of congenital hypogonadotropic hypogonadism: insights from analysis of a Portuguese cohort"],"prefix":"10.1093","volume":"2024","author":[{"given":"Josianne Nunes","family":"Carri\u00e7o","sequence":"first","affiliation":[{"name":"CICS-UBI, Health Sciences Research Centre, University of Beira Interior , Covilh\u00e3, Portugal"}]},{"given":"Catarina In\u00eas","family":"Gon\u00e7alves","sequence":"additional","affiliation":[{"name":"CICS-UBI, Health Sciences Research Centre, University of Beira Interior , Covilh\u00e3, Portugal"}]},{"given":"Asma","family":"Al-Naama","sequence":"additional","affiliation":[{"name":"Sidra Medicine , Doha, Qatar"}]},{"given":"Najeeb","family":"Syed","sequence":"additional","affiliation":[{"name":"Sidra Medicine , Doha, Qatar"}]},{"given":"Jos\u00e9 Maria","family":"Arag\u00fc\u00e9s","sequence":"additional","affiliation":[{"name":"Servi\u00e7o de Endocrinologia, Diabetes e Metabolismo, Hospital de Santa Maria, Centro Hospitalar Universit\u00e1rio Lisboa Norte , Lisboa, Portugal"}]},{"given":"Margarida","family":"Bastos","sequence":"additional","affiliation":[{"name":"Servi\u00e7o de Endocrinologia, Diabetes e Metabolismo, Centro Hospitalar Universit\u00e1rio de Coimbra , Coimbra, Portugal"}]},{"given":"Fernando","family":"Fonseca","sequence":"additional","affiliation":[{"name":"Servi\u00e7o de Endocrinologia, Hospital de Curry Cabral, Centro Hospitalar Universit\u00e1rio Lisboa Central , Lisboa, Portugal"}]},{"given":"Teresa","family":"Borges","sequence":"additional","affiliation":[{"name":"Unidade de Endocrinologia Pedi\u00e1trica, Servi\u00e7o de Pediatria, Centro Materno Infantil do Norte, Centro Hospitalar Universit\u00e1rio de Santo Ant\u00f3nio , Porto, Portugal"}]},{"given":"Bernardo Dias","family":"Pereira","sequence":"additional","affiliation":[{"name":"Servi\u00e7o de Endocrinologia e Diabetes, Hospital Garcia de Orta , Almada, Portugal"}]},{"given":"Duarte","family":"Pignatelli","sequence":"additional","affiliation":[{"name":"Servi\u00e7o de Endocrinologia, Diabetes e Metabolismo, Centro Hospitalar Universit\u00e1rio de S\u00e3o Jo\u00e3o , Porto, Portugal"}]},{"given":"Davide","family":"Carvalho","sequence":"additional","affiliation":[{"name":"Servi\u00e7o de Endocrinologia, Diabetes e Metabolismo, Centro Hospitalar Universit\u00e1rio de S\u00e3o Jo\u00e3o , Porto, Portugal"}]},{"given":"Filipe","family":"Cunha","sequence":"additional","affiliation":[{"name":"Servi\u00e7o de Endocrinologia, Diabetes e Metabolismo, Centro Hospitalar Universit\u00e1rio de S\u00e3o Jo\u00e3o , Porto, Portugal"}]},{"given":"Ana","family":"Saavedra","sequence":"additional","affiliation":[{"name":"Servi\u00e7o de Endocrinologia, Diabetes e Metabolismo, Centro Hospitalar Universit\u00e1rio de S\u00e3o Jo\u00e3o , Porto, Portugal"}]},{"given":"Elisabete","family":"Rodrigues","sequence":"additional","affiliation":[{"name":"Servi\u00e7o de Endocrinologia, Diabetes e Metabolismo, Centro Hospitalar Universit\u00e1rio de S\u00e3o Jo\u00e3o , Porto, Portugal"}]},{"given":"Joana","family":"Saraiva","sequence":"additional","affiliation":[{"name":"Servi\u00e7o de Endocrinologia, Diabetes e Metabolismo, Centro Hospitalar Universit\u00e1rio de Coimbra , Coimbra, Portugal"}]},{"given":"Luisa","family":"Ruas","sequence":"additional","affiliation":[{"name":"Servi\u00e7o de Endocrinologia, Diabetes e Metabolismo, Centro Hospitalar Universit\u00e1rio de Coimbra , Coimbra, Portugal"}]},{"given":"Nuno","family":"Vicente","sequence":"additional","affiliation":[{"name":"Servi\u00e7o de Endocrinologia, Diabetes e Metabolismo, Centro Hospitalar Universit\u00e1rio de Coimbra , Coimbra, Portugal"}]},{"given":"Jo\u00e3o","family":"Martin Martins","sequence":"additional","affiliation":[{"name":"Servi\u00e7o de Endocrinologia, Diabetes e Metabolismo, Hospital de Santa Maria, Centro Hospitalar Universit\u00e1rio Lisboa Norte , Lisboa, Portugal"}]},{"given":"Adriana","family":"De Sousa Lages","sequence":"additional","affiliation":[{"name":"Servi\u00e7o de Endocrinologia, Diabetes e Metabolismo, Centro Hospitalar Universit\u00e1rio de Coimbra , Coimbra, Portugal"}]},{"given":"Maria Jo\u00e3o","family":"Oliveira","sequence":"additional","affiliation":[{"name":"Unidade de Endocrinologia Pedi\u00e1trica, Servi\u00e7o de Pediatria, Centro Materno Infantil do Norte, Centro Hospitalar Universit\u00e1rio de Santo Ant\u00f3nio , Porto, Portugal"}]},{"given":"C\u00edntia","family":"Castro-Correia","sequence":"additional","affiliation":[{"name":"Unidade de Endocrinologia e Diabetologia Pedi\u00e1trica, Departamento de Pediatria, Centro Hospitalar Universit\u00e1rio de S\u00e3o Jo\u00e3o , Porto, Portugal"}]},{"given":"Miguel","family":"Melo","sequence":"additional","affiliation":[{"name":"Servi\u00e7o de Endocrinologia, Diabetes e Metabolismo, Centro Hospitalar Universit\u00e1rio de Coimbra , Coimbra, Portugal"}]},{"given":"Raquel Gomes","family":"Martins","sequence":"additional","affiliation":[{"name":"Servi\u00e7o de Endocrinologia, Instituto Portugu\u00eas de Oncologia do Porto , Porto, Portugal"}]},{"given":"Joana","family":"Couto","sequence":"additional","affiliation":[{"name":"Servi\u00e7o de Endocrinologia, Instituto Portugu\u00eas de Oncologia do Porto , Porto, Portugal"}]},{"given":"Carolina","family":"Moreno","sequence":"additional","affiliation":[{"name":"Servi\u00e7o de Endocrinologia, Diabetes e Metabolismo, Centro Hospitalar Universit\u00e1rio de Coimbra , Coimbra, Portugal"}]},{"given":"Diana","family":"Martins","sequence":"additional","affiliation":[{"name":"Servi\u00e7o de Endocrinologia, Diabetes e Metabolismo, Centro Hospitalar Universit\u00e1rio de Coimbra , Coimbra, Portugal"}]},{"given":"Patr\u00edcia","family":"Oliveira","sequence":"additional","affiliation":[{"name":"Servi\u00e7o de Endocrinologia, Diabetes e Metabolismo, Centro Hospitalar Universit\u00e1rio de Coimbra , Coimbra, Portugal"}]},{"given":"Teresa","family":"Martins","sequence":"additional","affiliation":[{"name":"Servi\u00e7o de Endocrinologia, Instituto Portugu\u00eas de Oncologia de Coimbra , Coimbra, Portugal"}]},{"given":"Sofia Almeida","family":"Martins","sequence":"additional","affiliation":[{"name":"Unidade de Endocrinologia Pedi\u00e1trica, Servi\u00e7o de Pediatria, Hospital de Braga , Braga, Portugal"}]},{"given":"Olinda","family":"Marques","sequence":"additional","affiliation":[{"name":"Servi\u00e7o de Endocrinologia, Hospital de Braga , Braga, Portugal"}]},{"given":"Carla","family":"Meireles","sequence":"additional","affiliation":[{"name":"Servi\u00e7o de Pediatria, Hospital da Senhora da Oliveira Guimar\u00e3es , Guimar\u00e3es, Portugal"}]},{"given":"Ant\u00f3nio","family":"Garr\u00e3o","sequence":"additional","affiliation":[{"name":"Departamento de Endocrinologia, Hospital da Luz Lisboa , Lisboa, Portugal"}]},{"given":"Cl\u00e1udia","family":"Nogueira","sequence":"additional","affiliation":[{"name":"Servi\u00e7o de Endocrinologia, Diabetes e Metabolismo, Centro Hospitalar Universit\u00e1rio de S\u00e3o Jo\u00e3o , Porto, Portugal"}]},{"given":"Carla","family":"Baptista","sequence":"additional","affiliation":[{"name":"Servi\u00e7o de Endocrinologia, Diabetes e Metabolismo, Centro Hospitalar Universit\u00e1rio de Coimbra , Coimbra, Portugal"}]},{"given":"Susana","family":"Gama-de-Sousa","sequence":"additional","affiliation":[{"name":"Servi\u00e7o de Pediatria, Centro Hospitalar do M\u00e9dio Ave, Unidade de V. N. Famalic\u00e3o , Vila Nova de Famalic\u00e3o, Portugal"}]},{"given":"Cl\u00e1udia","family":"Amaral","sequence":"additional","affiliation":[{"name":"Servi\u00e7o de Endocrinologia, Centro Hospitalar Universit\u00e1rio de Santo Ant\u00f3nio , Porto, Portugal"}]},{"given":"Mariana","family":"Martinho","sequence":"additional","affiliation":[{"name":"Servi\u00e7o de Endocrinologia, Centro Hospitalar do T\u00e2mega e Sousa , Guilhufe, Portugal"}]},{"given":"Catarina","family":"Limbert","sequence":"additional","affiliation":[{"name":"Unidade de Endocrinologia Pedi\u00e1trica, Hospital Dona Estef\u00e2nia, Centro Hospitalar Universit\u00e1rio de Lisboa Central , Lisboa, Portugal"}]},{"given":"Luisa","family":"Barros","sequence":"additional","affiliation":[{"name":"Servi\u00e7o de Endocrinologia, Diabetes e Metabolismo, Centro Hospitalar Universit\u00e1rio de Coimbra , Coimbra, Portugal"}]},{"given":"In\u00eas Henriques","family":"Vieira","sequence":"additional","affiliation":[{"name":"Servi\u00e7o de Endocrinologia, Diabetes e Metabolismo, Centro Hospitalar Universit\u00e1rio de Coimbra , Coimbra, Portugal"}]},{"given":"Teresa","family":"Sabino","sequence":"additional","affiliation":[{"name":"Servi\u00e7o de Endocrinologia, Hospital de Curry Cabral, Centro Hospitalar Universit\u00e1rio Lisboa Central , Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4079-0396","authenticated-orcid":false,"given":"Lu\u00eds R","family":"Saraiva","sequence":"additional","affiliation":[{"name":"Sidra Medicine , Doha, Qatar"},{"name":"College of Health and Life Sciences, Hamad Bin Khalifa University , Doha, Qatar"},{"name":"Department of Comparative Medicine, Yale University School of Medicine , New Haven, CT, USA"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9326-8900","authenticated-orcid":false,"given":"Manuel Carlos","family":"Lemos","sequence":"additional","affiliation":[{"name":"CICS-UBI, Health Sciences Research Centre, University of Beira Interior , Covilh\u00e3, Portugal"}]}],"member":"286","published-online":{"date-parts":[[2024,9,11]]},"reference":[{"key":"2024092111210789400_hoae053-B1","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1038\/nrendo.2015.112","article-title":"Expert consensus document: European Consensus Statement on congenital hypogonadotropic hypogonadism\u2014pathogenesis, diagnosis and treatment","volume":"11","author":"Boehm","year":"2015","journal-title":"Nat Rev Endocrinol"},{"key":"2024092111210789400_hoae053-B2","doi-asserted-by":"crossref","first-page":"994","DOI":"10.7326\/M21-4109","article-title":"The challenge of genetic variants of uncertain clinical significance: a narrative review","volume":"175","author":"Burke","year":"2022","journal-title":"Ann Intern Med"},{"key":"2024092111210789400_hoae053-B3","doi-asserted-by":"crossref","first-page":"113","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":"2024092111210789400_hoae053-B4","doi-asserted-by":"crossref","first-page":"11703","DOI":"10.1073\/pnas.0903449106","article-title":"GNRH1 mutations in patients with idiopathic hypogonadotropic hypogonadism","volume":"106","author":"Chan","year":"2009","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2024092111210789400_hoae053-B5","doi-asserted-by":"crossref","first-page":"1166132","DOI":"10.3389\/fendo.2023.1166132","article-title":"The initiation and maintenance of gonadotropin-releasing hormone neuron identity in congenital hypogonadotropic hypogonadism","volume":"14","author":"Chung","year":"2023","journal-title":"Front Endocrinol (Lausanne)"},{"key":"2024092111210789400_hoae053-B6","doi-asserted-by":"crossref","first-page":"1597","DOI":"10.1056\/NEJM199711273372205","article-title":"A family with hypogonadotropic hypogonadism and mutations in the gonadotropin-releasing hormone receptor","volume":"337","author":"de Roux","year":"1997","journal-title":"N Engl J Med"},{"key":"2024092111210789400_hoae053-B7","doi-asserted-by":"crossref","first-page":"4423","DOI":"10.3390\/ijms23084423","article-title":"A Novel FGFR1 Missense Mutation in a Portuguese Family with Congenital Hypogonadotropic Hypogonadism","volume":"23","author":"Fadiga","year":"2022","journal-title":"Int J Mol Sci"},{"key":"2024092111210789400_hoae053-B8","doi-asserted-by":"crossref","first-page":"1261","DOI":"10.1016\/j.fertnstert.2015.07.1142","article-title":"Novel FGFR1 mutations in Kallmann syndrome and normosmic idiopathic hypogonadotropic hypogonadism: evidence for the involvement of an alternatively spliced isoform","volume":"104","author":"Goncalves","year":"2015","journal-title":"Fertil Steril"},{"key":"2024092111210789400_hoae053-B9","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1530\/EC-17-0104","article-title":"GNRHR biallelic and digenic mutations in patients with normosmic congenital hypogonadotropic hypogonadism","volume":"6","author":"Goncalves","year":"2017","journal-title":"Endocr Connect"},{"key":"2024092111210789400_hoae053-B10","first-page":"704","article-title":"Expanding the genetic spectrum of ANOS1 mutations in patients with congenital hypogonadotropic hypogonadism","volume":"32","author":"Goncalves","year":"2017","journal-title":"Hum Reprod"},{"key":"2024092111210789400_hoae053-B11","doi-asserted-by":"crossref","first-page":"1597","DOI":"10.1038\/s41598-018-38178-y","article-title":"High frequency of CHD7 mutations in congenital hypogonadotropic hypogonadism","volume":"9","author":"Goncalves","year":"2019","journal-title":"Sci Rep"},{"key":"2024092111210789400_hoae053-B12","doi-asserted-by":"crossref","first-page":"101599","DOI":"10.1016\/j.beem.2021.101599","article-title":"Genetics of congenital central hypogonadism","volume":"36","author":"Grinspon","year":"2021","journal-title":"Best Pract Res Clin Endocrinol Metab"},{"key":"2024092111210789400_hoae053-B13","doi-asserted-by":"crossref","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":"2024092111210789400_hoae053-B14","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1038\/s41586-020-2308-7","article-title":"The mutational constraint spectrum quantified from variation in 141,456 humans","volume":"581","author":"Karczewski","year":"2020","journal-title":"Nature"},{"key":"2024092111210789400_hoae053-B15","doi-asserted-by":"crossref","first-page":"2501","DOI":"10.1016\/j.gim.2022.08.025","article-title":"The p190 RhoGAPs, ARHGAP35, and ARHGAP5 are implicated in GnRH neuronal development: evidence from patients with idiopathic hypogonadotropic hypogonadism, zebrafish, and in vitro GAP activity assay","volume":"24","author":"Lippincott","year":"2022","journal-title":"Genet Med"},{"key":"2024092111210789400_hoae053-B16","doi-asserted-by":"crossref","first-page":"111334","DOI":"10.1016\/j.mce.2021.111334","article-title":"Genetics of hypogonadotropic hypogonadism-human and mouse genes, inheritance, oligogenicity, and genetic counseling","volume":"534","author":"Louden","year":"2021","journal-title":"Mol Cell Endocrinol"},{"key":"2024092111210789400_hoae053-B17","doi-asserted-by":"crossref","first-page":"E2138","DOI":"10.1210\/jc.2014-2110","article-title":"The prevalence of CHD7 missense versus truncating mutations is higher in patients with Kallmann syndrome than in typical CHARGE patients","volume":"99","author":"Marcos","year":"2014","journal-title":"J Clin Endocrinol Metab"},{"key":"2024092111210789400_hoae053-B18","doi-asserted-by":"crossref","first-page":"1215","DOI":"10.1093\/nar\/16.3.1215","article-title":"A simple salting out procedure for extracting DNA from human nucleated cells","volume":"16","author":"Miller","year":"1988","journal-title":"Nucleic Acids Res"},{"key":"2024092111210789400_hoae053-B19","doi-asserted-by":"crossref","first-page":"9425","DOI":"10.3390\/ijms22179425","article-title":"The Differential Roles for Neurodevelopmental and Neuroendocrine Genes in Shaping GnRH Neuron Physiology and Deficiency","volume":"22","author":"Oleari","year":"2021","journal-title":"Int J Mol Sci"},{"key":"2024092111210789400_hoae053-B20","doi-asserted-by":"crossref","first-page":"444","DOI":"10.1007\/s11102-022-01209-z","article-title":"Regional genotypic variations in normosmic congenital hypogonadotropic hypogonadism: our experience and systematic review","volume":"25","author":"Patil","year":"2022","journal-title":"Pituitary"},{"key":"2024092111210789400_hoae053-B21","doi-asserted-by":"crossref","first-page":"804","DOI":"10.1111\/cen.14822","article-title":"Genetic spectrum of Kallmann syndrome: single-center experience and systematic review","volume":"97","author":"Patil","year":"2022","journal-title":"Clin Endocrinol (Oxf)"},{"key":"2024092111210789400_hoae053-B22","doi-asserted-by":"crossref","first-page":"2163","DOI":"10.1016\/j.ajhg.2022.10.013","article-title":"Calibration of computational tools for missense variant pathogenicity classification and ClinGen recommendations for PP3\/BP4 criteria","volume":"109","author":"Pejaver","year":"2022","journal-title":"Am J Hum Genet"},{"key":"2024092111210789400_hoae053-B23","doi-asserted-by":"crossref","DOI":"10.1530\/EC-22-0367","article-title":"The genetic diagnosis of rare endocrine disorders of sex development and maturation: a survey among Endo-ERN centres","volume":"11","author":"Persani","year":"2022","journal-title":"Endocr Connect"},{"key":"2024092111210789400_hoae053-B24","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"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","volume":"17","author":"Richards","year":"2015","journal-title":"Genet Med"},{"key":"2024092111210789400_hoae053-B25","doi-asserted-by":"crossref","first-page":"2228","DOI":"10.1210\/clinem\/dgac300","article-title":"Prevalence and phenotypic effects of copy number variants in isolated hypogonadotropic hypogonadism","volume":"107","author":"Stamou","year":"2022","journal-title":"J Clin Endocrinol Metab"},{"key":"2024092111210789400_hoae053-B26","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1007\/s00439-017-1779-6","article-title":"The Human Gene Mutation Database: towards a comprehensive repository of inherited mutation data for medical research, genetic diagnosis and next-generation sequencing studies","volume":"136","author":"Stenson","year":"2017","journal-title":"Hum Genet"},{"key":"2024092111210789400_hoae053-B27","doi-asserted-by":"crossref","first-page":"15140","DOI":"10.1073\/pnas.1009622107","article-title":"Oligogenic basis of isolated gonadotropin-releasing hormone deficiency","volume":"107","author":"Sykiotis","year":"2010","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2024092111210789400_hoae053-B28","doi-asserted-by":"crossref","first-page":"1069741","DOI":"10.3389\/fendo.2022.1069741","article-title":"Genetic architecture of self-limited delayed puberty and congenital hypogonadotropic hypogonadism","volume":"13","author":"Vezzoli","year":"2023","journal-title":"Front Endocrinol"},{"key":"2024092111210789400_hoae053-B29","doi-asserted-by":"crossref","first-page":"e1616","DOI":"10.1002\/wrna.1616","article-title":"Two sides of the same medal: noncoding mutations reveal new pathological mechanisms and insights into the regulation of gene expression","volume":"12","author":"Wachs","year":"2021","journal-title":"Wiley Interdiscip Rev RNA"},{"key":"2024092111210789400_hoae053-B30","doi-asserted-by":"crossref","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"}],"container-title":["Human Reproduction Open"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/hropen\/advance-article-pdf\/doi\/10.1093\/hropen\/hoae053\/59086436\/hoae053.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/hropen\/advance-article-pdf\/doi\/10.1093\/hropen\/hoae053\/59216446\/hoae053.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/hropen\/advance-article-pdf\/doi\/10.1093\/hropen\/hoae053\/59216446\/hoae053.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,9,21]],"date-time":"2024-09-21T11:21:28Z","timestamp":1726917688000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/hropen\/article\/doi\/10.1093\/hropen\/hoae053\/7755047"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024]]},"references-count":30,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2024,5,25]]}},"URL":"https:\/\/doi.org\/10.1093\/hropen\/hoae053","relation":{},"ISSN":["2399-3529"],"issn-type":[{"value":"2399-3529","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2024]]},"published":{"date-parts":[[2024]]},"article-number":"hoae053"}}