İnönü University Faculty of Medicine, Department of Pediatric Endocrinology, Malatya, Turkey
Turgut Özal University Faculty of Biomedical Engineering, Malatya, Turkey
J Clin Res Pediatr Endocrinol. 2023 May 29;15(2):160-171. doi: 10.4274/jcrpe.galenos.2023.2022-10-14. Epub 2023 Jan 26.
Idiopathic hypogonadotropic hypogonadism (IHH) is classified into two groups-Kalman syndrome and normosmic IHH (nIHH). Half of all cases can be explained by mutations in >50 genes. Targeted gene panel testing with nexrt generation sequencing (NGS) is required for patients without typical phenotypic findings. The aim was 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.
Clinical and demographic data of 16 patients (eight female), aged between 11.6-17.8 years, from different families were assessed. All patients were followed up for 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. Changes in protein structure caused by variations were modeled using RoseTTAFold and changes in protein stability resulting from variation were analyzed.
Half of the 16 had no detectable variation. Three (18.75%) had a homozygous (pathogenic) variant in the gene, one (6.25%) had a compound heterozygous [likely pathogenic-variants of uncertain significance (VUS)] variant in and four (25%) each had a heterozygous (VUS) variant in and . Protein models showed that variants interpreted as VUS according to ACMG could account for the clinical IHH.
The frequency of variation detection was similar to the literature. Modelling showed that the variant in five different genes, interpreted as VUS according to ACMG, could explain the clinical IHH.
特发性低促性腺激素性性腺功能减退症（IHH）分为 Kalman 综合征和正常嗅性 IHH（nIHH）两组。超过 50 个基因的突变可以解释一半的病例。对于没有典型表型发现的患者，需要进行靶向基因panel 检测，采用下一代测序（NGS）。本研究旨在通过 NGS 检测 IHH 患者的遗传病因，包括 54 个与 IHH 相关的基因，并对检测到的变异进行蛋白质同源建模和蛋白质稳定性分析。
评估了来自不同家庭的 16 名患者（8 名女性）的临床和人口统计学数据，年龄在 11.6-17.8 岁之间。所有患者均被随访诊断为 nIHH，头颅影像学正常，除促性腺激素外无其他前垂体激素缺乏，无性染色体异常，无其他疾病，并于 2008-2021 年期间接受 NGS 基因分析。根据美国医学遗传学与基因组学学院（ACMG）/分子病理学协会的变异解释框架对罕见变异进行分类。使用 RoseTTAFold 对变异引起的蛋白质结构变化进行建模，并分析变异导致的蛋白质稳定性变化。
有一半的患者未检测到变异。有 3 名（18.75%）患者在 基因中存在纯合（致病性）变异，1 名（6.25%）患者在 基因中存在复合杂合[可能致病性-意义不明的变异（VUS）]变异，4 名（25%）患者各在 和 基因中存在杂合（VUS）变异。蛋白质模型表明，根据 ACMG 解释为 VUS 的变异可以解释临床 IHH。
变异检测的频率与文献相似。建模表明，根据 ACMG 解释为 VUS 的五个不同基因中的变异可以解释临床 IHH。
