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

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.

Figure 1.

Frequency and percentage distribution of offspring by sex for individuals that are heterozygous for GNRHR p.Q106R. Of the 8 without offspring, 6 are single and have never been in a steady relationship.

Figure 2.

Scattergrams (median and interquartile ranges) by zygosity in men with age <50 and ≥50 years in the Maltese Acute Myocardial Infarction cohort for cortisol, prolactin, GH, TSH, and free T4. Median levels between the genotypes were compared using the Kruskal–Wallis test. Solid circles are used to show wild-type samples and open circles show heterozygous samples. Data points that fall within the grey area along the y-axis are within the reference range of each respective hormone. There is no statistically significant difference between the median hormone levels of heterozygous and wild-type individuals unless marked. * P < .01.

Figure 3.

Scattergrams (median and interquartile ranges) by zygosity in men with age <50 and ≥50 years in the Maltese Acute Myocardial Infarction cohort for dehydroepiandrosterone sulfate (DHEA-SO₄), sex hormone-binding globulin (SHBG), LH, FSH, and calculated free testosterone. Median levels between the genotypes were compared using the Kruskal–Wallis test. Solid circles are used to show wild-type samples and open circles show heterozygous samples. Data points that fall within the grey area along the y-axis are within the reference range of each respective hormone. There is no statistically significant difference between the median hormone levels of heterozygous and wild-type individuals.

Figure 4.

Scattergrams (median and interquartile ranges) by zygosity in women with age <50 and ≥50 years in the Maltese Acute Myocardial Infarction cohort for cortisol, prolactin, GH, TSH, and free T4. Median levels between the genotypes were compared using the Kruskal–Wallis test. Solid circles are used to show wild-type samples and open circles show heterozygous samples. Data points that fall within the grey area along the y-axis are within the reference range of each respective hormone. There is no statistically significant difference between the median hormone levels of heterozygous and wild-type individuals.

Figure 5.

Scattergrams (median and interquartile ranges) by zygosity in women categorized by pre/perimenopausal and postmenopausal status in the Maltese Acute Myocardial Infarction cohort for dehydroepiandrosterone sulfate (DHEA-SO₄), sex hormone-binding globulin (SHBG), LH, FSH, and estradiol. Median levels between the genotypes were compared using the Kruskal–Wallis test. Solid circles are used to show wild-type samples and open circles show heterozygous samples. Data points that fall within the grey area along the y-axis are within the reference range of each respective hormone. There is no statistically significant difference between the median hormone levels of heterozygous and wild-type individuals.