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CHH-associated rare sequence variants (RSVs) were identified by using a tailored next-generation sequencing panel and were interpreted in accordance with the American College of Medical Genetics and Genomics criteria. Clinical characteristics were recorded, and Kyoto Encyclopedia of Genes and Genomes analysis was conducted to assess pathways enriched in protein networks implicated in poor responses.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Outcomes<\/jats:title>\n                    <jats:p>The outcomes include testicular volume, serum hormonal profiles, parameters of semen analysis, pathogenicity classification, and pathway enrichment.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Among the 110 patients, 94.55% achieved normal serum testosterone and 54.55% achieved seminal spermatozoa appearance (SSA). PLXNB1, ROBO3, LHB, NRP2, CHD7, and PLXNA1 RSVs were identified in patients who had an abnormal serum testosterone level during treatment. In spermatogenesis, the number of CHH-associated RSVs was not significantly strongly associated with delayed SSA. After pathogenicity classification, pathogenic\/likely pathogenic (P\/LP) RSVs were identified in 30% (33\/110) of patients. Patients with P\/LP RSVs showed delayed SSA compared with noncarriers, and P\/LP PROKR2 RSVs showed the strongest association (48, 95% CI: 34.1\u201361.9 months, P = .043). Enriched pathways implicated in delayed SSA included neuroactive ligand-receptor interaction; Rap1, MAPK, PI3K-Akt signaling; and regulation of actin cytoskeleton.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Clinical Implications<\/jats:title>\n                    <jats:p>Male patients with CHH harboring P\/LP PROKR2 RSVs should be aware of a high probability of poor responses to hCG; If these patients desire fertility, it might be better to recommend hCG\/human menopausal gonadotropin, hCG\/recombinant follicle-stimulating hormone, or pulsatile GnRH administration before treatments start or as early as possible.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Strengths &amp; Limitations<\/jats:title>\n                    <jats:p>Strengths are the standardized regimen and extensive follow-up (median time of 40 months). However, included patients in the study voluntarily chose hCG treatment because of the burden of drug cost and\/or little fertility desire. Therefore, human menopausal gonadotropin or follicle-stimulating hormone was not added to this cohort. Our observed correlations should be further verified in patients with CHH undergoing other treatments.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Among all P\/LP RSVs, P\/LP PROKR2 RSVs might correlate with poor responses in CHH under hCG treatment; our study supports the pathogenicity assessment of American College of Medical Genetics and Genomics criteria in genetic counseling, to improve management of patients with CHH.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1016\/j.jsxm.2020.01.011","type":"journal-article","created":{"date-parts":[[2020,3,12]],"date-time":"2020-03-12T03:12:34Z","timestamp":1583982754000},"page":"645-657","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":15,"title":["Correlations Among Genotype and Outcome in Chinese Male Patients with Congenital Hypogonadotropic Hypogonadism Under HCG Treatment"],"prefix":"10.1093","volume":"17","author":[{"given":"Yinwei","family":"Chen","sequence":"first","affiliation":[{"name":"Institute of Urology , Wuhan, Hubei , China"},{"name":"Tongji Medical College , Wuhan, Hubei , China"},{"name":"Huazhong University of Science and Technology , Wuhan, Hubei , China"},{"name":"Department of Urology , Wuhan, Hubei , China"},{"name":"Tongji Medical College , Wuhan, Hubei , China"},{"name":"Huazhong University of Science and Technology , Wuhan, Hubei , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taotao","family":"Sun","sequence":"additional","affiliation":[{"name":"Institute of Urology , Wuhan, Hubei , China"},{"name":"Tongji Medical College , Wuhan, Hubei , China"},{"name":"Huazhong University of Science and Technology , Wuhan, Hubei , China"},{"name":"Department of Urology , Wuhan, Hubei , China"},{"name":"Tongji Medical College , Wuhan, Hubei , China"},{"name":"Huazhong University of Science and Technology , Wuhan, Hubei , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yonghua","family":"Niu","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery , Wuhan, Hubei , China"},{"name":"Tongji Hospital , Wuhan, Hubei , China"},{"name":"Tongji Medical College , Wuhan, Hubei , China"},{"name":"Huazhong University of Science and Technology , Wuhan, Hubei , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daoqi","family":"Wang","sequence":"additional","affiliation":[{"name":"Institute of Urology , Wuhan, Hubei , China"},{"name":"Tongji Medical College , Wuhan, Hubei , China"},{"name":"Huazhong University of Science and Technology , Wuhan, Hubei , China"},{"name":"Department of Urology , Wuhan, Hubei , China"},{"name":"Tongji Medical College , Wuhan, Hubei , China"},{"name":"Huazhong University of Science and Technology , Wuhan, Hubei , 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of Science and Technology , Wuhan, Hubei , China"},{"name":"Department of Urology , Wuhan, Hubei , China"},{"name":"Tongji Medical College , Wuhan, Hubei , China"},{"name":"Huazhong University of Science and Technology , Wuhan, Hubei , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Youlan","family":"Qiu","sequence":"additional","affiliation":[{"name":"Department of Pathology and Pathophysiology , Wuhan, Hubei , China"},{"name":"School of Basic Medicine , Wuhan, Hubei , China"},{"name":"Tongji Medical College , Wuhan, Hubei , China"},{"name":"Huazhong University of Science and technology , Wuhan, Hubei , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Sun","sequence":"additional","affiliation":[{"name":"Institute of Urology , Wuhan, Hubei , China"},{"name":"Tongji Medical College , Wuhan, Hubei , China"},{"name":"Huazhong University of Science and Technology , Wuhan, Hubei , China"},{"name":"Department of Urology , Wuhan, Hubei , China"},{"name":"Tongji Medical College , Wuhan, Hubei , China"},{"name":"Huazhong University of Science and Technology , Wuhan, Hubei , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianan","family":"Gong","sequence":"additional","affiliation":[{"name":"Institute of Urology , Wuhan, Hubei , China"},{"name":"Tongji Medical College , Wuhan, Hubei , China"},{"name":"Huazhong University of Science and Technology , Wuhan, Hubei , China"},{"name":"Department of Urology , Wuhan, Hubei , China"},{"name":"Tongji Medical College , Wuhan, Hubei , China"},{"name":"Huazhong University of Science and Technology , Wuhan, Hubei , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Wang","sequence":"additional","affiliation":[{"name":"Institute of Urology , Wuhan, Hubei , China"},{"name":"Tongji Medical College , Wuhan, Hubei , China"},{"name":"Huazhong University of Science and Technology , Wuhan, Hubei , China"},{"name":"Department 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