Clinical Characteristics and Genetic Analyses of Patients with Idiopathic Hypogonadotropic Hypogonadism

INTRODUCTION: Idiopathic hypogonadotropic hypogonadism (IHH) is classified into two groups - Kalman Syndrome (KS) and normosmic IHH (nIHH). Half of all cases can be explained by mutations in >50 genes. Targeted gene panel testing (NGS) is required for patients without typical phenotypic findings. This study was carried out to determine the genetic etiologies of patients with IHH using NGS, including 54 IHH-associated genes, and to present protein homology modeling and protein stability analyzes of the detected variations.
METHODS: Clinical and demographic data of 16 patients (8 women, 8 men), between age of 11.6-17.8 years old, from different families was assessed. All patients were followed up with a diagnosis of nIHH, had normal cranial imaging, were without anterior pituitary hormone deficiency other than gonadotropins, had no sex chromosome anomaly, had no additional disease, and underwent genetic analysis with NGS between the years 2008-2021. Rare variants were classified according to the variant interpretation framework of the American College of Medical Genetics and Genomics (ACMG)/Association for Molecular Pathology (AMP). Changes in protein structure caused by variations were modeled using RoseTTAFold and changes in protein stability resulting from variation were analyzed.
RESULTS: Half of the 16 had no detectable variation. Three (18.75%) had a homozygous (pathogenic) variant in the GNRHR gene, one (6.25%) had a compound heterozygous (likely pathogenic-VUS) variant in PROK2 and four (25%) had a heterozygous (VUS) variant in HESX1, FGF8, FLRT3 and DMXL2. Protein models showed that variants interpreted as VUS according to ACMG could account for the clinical IHH.
DISCUSSION AND CONCLUSION: The frequency of variation detection was similar to the literature. It was shown that the variant in five different genes, interpreted as VUS according to ACMG, could explain the clinical IHH.