Hypogonadotropic hypogonadism is a rare but clinically, genetically, and phenotypically highly heterogeneous disorder. The congenital form arises due to genetic changes in numerous genes encoding proteins responsible for the development and migration of gonadotropin-releasing hormone neurons, the regulation of its secretion, and its action on the pituitary gland. Deficiency in gonadotropin-releasing hormone, gonadotropins (follicle-stimulating hormone and luteinizing hormone), and consequently sex hormones is the cause of absent or delayed puberty and often infertility. Clinical signs encompass a wide range of associated symptoms. There are several forms of congenital hypogonadotropic hypogonadism, classified based on the presence (normosmic hypogonadotropic hypogonadism) or absence of the ability to smell (Kallmann syndrome). For diagnosis, an extensive discussion with the patient about their symptoms and family history is crucial, followed by a thorough physical examination. Subsequently, laboratory, imaging, and molecular genetic tests are conducted, essential for defining the genetic cause of the disease. To date, pathogenic variants in more than 30 genes associated with congenital hypogonadotropic hypogonadism have been described. Despite recent advances in understanding genetic etiology, over 50% of cases remain without a known genetic cause.
The purpose of the master's thesis was to identify pathogenic variants in ANOS1, FGFR1, GNRHR, KISS1R, GNRH1, NELF, PROK2, and PROKR2 in a population of patients clinically diagnosed with hypogonadotropic hypogonadism using the multiplex ligation-dependent Probe lmplification method (MLPA). The selection of the genes was based on commercially manufactured kits by MRC Holland. Some patients had previously been analyzed using FISH, Sanger or next generation sequencing. The study included 36 patients managed at the Department of Pediatric Endocrinology, Diabetes, and Metabolic Diseases and the Medical Genetics Outpatient clinic at the University Children’s Hospital Ljubljana. A pathogenic genetic variant was confirmed in one patient, representing 2,8% of the research group, which is comparable to the previously published data. The identified variant was a deletion of exons 4 to 6 in the ANOS1 gene, not previously documented in currently available literature and public databases but nevertheless confirming the clinical diagnosis of Kallmann syndrome. Previously no additional genetic variants had been detected in this patient using other methods.
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