<b><i>GNRH1</i></b> Variants in Congenital Hypogonadotropic Hypogonadism: Single-Center Experience and Systematic Literature Review

<b><i>Objective:</i></b> As <i>GNRH1</i> genotype-phenotype correlation in CHH is not well studied, we aim to describe the <i>GNRH1</i> variants in our CHH cohort and present a systematic review as well as genotype-phenotype analysis of all mutation-positive cases reported in the world literature. <b><i>Design:</i></b> This is a retrospective study of <i>GNRH1</i> mutation-positive patients from a western Indian center. PRISMA guidelines-based PubMed search of the published literature of all <i>GNRH1</i> mutation-positive patients was conducted. <b><i>Setting:</i></b> This study was conducted in an academic medical center. <b><i>Patient(s):</i></b> This study included 2 probands from our cohort and 19 probands from the world literature. <b><i>Main Outcome Measure(s):</i></b> Demographic details, clinical presentation, biochemistry, imaging, treatment details, and genotypic data were recorded. <b><i>Result(s):</i></b> Two probands in our cohort carried two novel pathogenic biallelic GNRH1 variants (p.Glu24Leu, c.238-2A&#x3e;G). Both had a severe reproductive phenotype. We report successful gonadotropin therapy and fertility in 1 proband. We included 19 probands from 12 studies after the literature review. Ten CHH probands (inclusive 2 from this study) with biallelic GNRH1 variants had severe reproductive phenotype, low gonadotropin levels, low/normal prolactin, normal pituitary imaging, and no extra-reproductive phenotype. Of seven biallelic variants reported, three were frameshift, two were splice-site, and two were missense mutations. All of them were pathogenic/likely pathogenic without oligogenicity. Of seven monoallelic GNRH1 variants reported in 11 probands, 4 had nonreproductive phenotype, 3 were benign/likely benign, and 4 were oligogenic. <b><i>Conclusion(s):</i></b> <i>GNRH1</i> biallelic variants lead to severe reproductive phenotype, with low gonadotropin levels without nonreproductive features or oligogenicity. However, the role of <i>GNRH1</i> monoallelic variants in CHH pathophysiology for reported variants remains questionable.