Axiak Clayton John, Pleven Adrian, Attard Ritienne, Borg Carbott Francesca, Ebejer Jean-Paul, Brincat Ian, Cassar Karen, Gruppetta Mark, Vassallo Josanne, Bezzina Wettinger Stephanie, Farrugia Rosienne
Department of Applied Biomedical Science, Faculty of Health Sciences, University of Malta, Msida, MSD 2080, Malta.
Clinical Chemistry Section, Department of Pathology, Mater Dei Hospital, Msida, MSD 2080, Malta.
J Endocr Soc. 2023 Dec 29;8(2):bvad172. doi: 10.1210/jendso/bvad172. eCollection 2024 Jan 5.
The gonadotropin-releasing hormone receptor variant p.Q106R (rs104893836) in homozygosity, compound heterozygosity, or single heterozygosity is often reported as the causative variant in idiopathic hypogonadotropic hypogonadism (IHH) patients with GnRH deficiency. Genotyping of a Maltese newborn cord-blood collection yielded a minor allele frequency (MAF) 10 times higher (MAF = 0.029; n = 493) than that of the global population (MAF = 0.003).
To determine whether p.Q106R in heterozygosity influences profiles of endogenous hormones belonging to the hypothalamic-pituitary axis and the onset of puberty and fertility in adult men (n = 739) and women (n = 239).
Analysis of questionnaire data relating to puberty and fertility, genotyping of the p.Q106R variant, and hormone profiling of a highly phenotyped Maltese adult cohort from the Maltese Acute Myocardial Infarction Study.
Out of 978 adults, 43 p.Q106R heterozygotes (26 men and 17 women) were identified. Hormone levels and fertility for all heterozygotes are within normal parameters except for TSH, which was lower in men 50 years or older.
Hormone data and baseline fertility characteristics of p.Q106R heterozygotes are comparable to those of homozygous wild-type individuals who have no reproductive problems. The heterozygous genotype alone does not impair the levels of investigated gonadotropins and sex steroid hormones or affect fertility. p.Q106R heterozygotes who exhibit IHH characteristics must have at least another variant, probably in a different IHH gene, that drives pathogenicity. We also conclude that p.Q106R is likely a founder variant due to its overrepresentation and prevalence in the island population of Malta.
纯合、复合杂合或单杂合的促性腺激素释放激素受体变体p.Q106R（rs104893836）常被报道为促性腺激素释放激素（GnRH）缺乏的特发性低促性腺激素性性腺功能减退（IHH）患者的致病变体。对马耳他新生儿脐带血样本进行基因分型，结果显示次要等位基因频率（MAF）比全球人群高10倍（MAF = 0.029；n = 493）（全球人群MAF = 0.003）。
确定杂合状态的p.Q106R是否会影响成年男性（n = 739）和女性（n = 239）下丘脑 - 垂体轴内源性激素水平、青春期启动及生育能力。
设计、地点和参与者：分析与青春期和生育相关的问卷数据、p.Q106R变体的基因分型以及来自马耳他急性心肌梗死研究的高度表型化马耳他成年队列的激素谱。
在978名成年人中，鉴定出43名p.Q106R杂合子（26名男性和17名女性）。除5０岁及以上男性的促甲状腺激素（TSH）较低外，所有杂合子的激素水平和生育能力均在正常范围内。
p.Q106R杂合子的激素数据和基线生育特征与无生殖问题 的纯合野生型个体相当。仅杂合基因型不会损害所研究的促性腺激素和性类固醇激素水平，也不会影响生育能力。表现出IHH特征的p.Q106R杂合子肯定至少还有另一种变体，可能存在于不同的IHH基因中，从而导致发病。我们还得出结论，由于p.Q106R在马耳他岛人群中过度出现和流行，它可能是一个奠基者变体。
