High Population Frequency of GNRHR p.Q106R in Malta: An Evaluation of Fertility and Hormone Profiles in Heterozygotes

Clayton John Axiak; Adrian Pleven; Ritienne Attard; Francesca Borg Carbott; Jean-Paul Ebejer; Ian Brincat; Karen Cassar; Mark Gruppetta; Josanne Vassallo; Stephanie Bezzina Wettinger; Rosienne Farrugia

doi:10.1210/jendso/bvad172

High Population Frequency of GNRHR p.Q106R in Malta: An Evaluation of Fertility and Hormone Profiles in Heterozygotes

J Endocr Soc. 2023 Dec 29;8(2):bvad172. doi: 10.1210/jendso/bvad172. eCollection 2024 Jan 5.

Authors

Clayton John Axiak¹, Adrian Pleven^{1

2}, Ritienne Attard¹, Francesca Borg Carbott¹, Jean-Paul Ebejer³, Ian Brincat², Karen Cassar⁴, Mark Gruppetta^{4

5}, Josanne Vassallo^{3

4

5}, Stephanie Bezzina Wettinger^{1

3}, Rosienne Farrugia^{1

3}

Affiliations

¹ Department of Applied Biomedical Science, Faculty of Health Sciences, University of Malta, Msida, MSD 2080, Malta.
² Clinical Chemistry Section, Department of Pathology, Mater Dei Hospital, Msida, MSD 2080, Malta.
³ Centre for Molecular Medicine and Biobanking, University of Malta, Msida, MSD 2080, Malta.
⁴ Department of Medicine, Faculty of Medicine and Surgery, University of Malta, Msida, MSD 2080, Malta.
⁵ Division of Endocrinology and Diabetes, Department of Medicine, Mater Dei Hospital, Msida, MSD 2080, Malta.

Abstract

Context: The gonadotropin-releasing hormone receptor variant GNRHR 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).

Objective: To determine whether GNRHR 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).

Design setting and participants: Analysis of questionnaire data relating to puberty and fertility, genotyping of the GNRHR p.Q106R variant, and hormone profiling of a highly phenotyped Maltese adult cohort from the Maltese Acute Myocardial Infarction Study.

Main outcome and results: Out of 978 adults, 43 GNRHR 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.

Conclusion: Hormone data and baseline fertility characteristics of GNRHR 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. GNRHR 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 GNRHR p.Q106R is likely a founder variant due to its overrepresentation and prevalence in the island population of Malta.

Keywords: GNRHR founder effect; GnRH deficiency; hormone profiles; idiopathic hypogonadotropic hypogonadism; infertility; puberty.