Genetic profiles and three-year follow-up study of Chinese males with congenital hypogonadotropic hypogonadism

Abstract

Genotypes-phenotypes correlation and treatment outcomes for 73 Chinese CHH male patients was performed in this study. Patients self-selected one of the four treatments: pulsatile Gonadorelin® pump, cyclical gonadotropins therapy, human menopausal gonadotropin monotherapy, or testosterone replacement treatment. Clinical assessments were performed every 3 months for 3 years. Baseline clinical features, spermatogenesis and secondary sexual development outcomes were analyzed. Whole exome sequencing identified 63 variants in 52 patients (70%), 18 of which were novel. Variants on FGFR1, PROKR2, CHD7, ANOS1 and NSMF gene were 10 (15.87%), 10 (15.87%), 7(11.11%), 5(7.93%) and 5(7.93%) respectively. Some null variants could lead to severe clinical manifestations than missense variants on FGFR1 and CHD7. The Lasso regression model for spermatogenic failure risk showed that cryptorchidism history, abnormal epididymis or prostate, lower basal LH and peak-LH post Triptore-lin® stimulation were significant predictors. Approximately, 30% normosmic patients defined by simple olfactory assessment showed olfactory nerve center maldevelopment with nasal sinus MRI. The severity of reproductive system was attributed to spermatogenesis that could be predicted by nomogram model. No direct correlation was observed between candidate genes and spermatogenic outcome, however, the clinical severity is partially related with specific variants, and clinical features might in turn affect the treatment efficacy.

Genetic spectrum of Kallmann syndrome: Single‐center experience and systematic review

“…ANOS1 variants, usually associated with severe CHH, 21 contributed to 50% of the genetically resolved cases in our cohort, which may explain the higher molecular diagnostic rate in KS patients with severe reproductive phenotype. Similarly, a study from China had a higher yield (45.6%), likely due to a higher percentage of patients with cryptorchidism (a marker of severe phenotype) 17 . Similarly, pediatric cohorts with a higher rate of cryptorchidism reported a higher rate of molecular diagnosis (58.8% and 72.2%) 9,16 .…”

“…Few studies were included after going through the references of the selected studies and review articles. After exclusions (Figure 1), 13 study cohorts 2,8–18 (including our center KS cohort) were included for the final analysis. Classification of the reported variants was done using the VarSome prediction tool (http://varsome.com) 7 as per ACMG variant classification guidelines 19 .…”

CHD7 in oocytes is essential for female fertility

“…However, the clinical and molecular genetic features of patients with CHD7 allelic variants remain unclear. Firstly, not all patients with CHD7 alterations and CHH symptoms respond well to cyclical gonadotropin therapy (16).…”