ESPE Abstracts (2018) 89 RFC9.2

Novel Variant in GNRHR Gene Regulatory Region in a Pedigree with Maternally Inherited Precocious Puberty

Magdalena Avbelj Stefanijaa, Jernej Kovača, Galia Yablonskib,c,d, Moshe Phillipc,d, Tadej Battelinoa,e & Liat de Vriesc,d


aUniversity Children’s Hospital Ljubljana, Ljubljana, Slovenia; bFelsentein Medical Research Center, Petah Tikva, Israel; cThe Jesse Z and Sara Lea Shafer Institute for Endocrinology and Diabetes, Schneider Children’s Medical Center of Israel, Petah Tikva, Israel; dSackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; eFaculta of Medicine, University of Ljubljana, Ljubljana, Slovenia


Background: Gonadotropin-releasing hormone (GNRH) and its receptor (GNRHR) are central regulators of puberty. Loss-of-function mutations of the GNRH-GNRHR signaling pathway are associated with congenital hypogonadotropic hypogonadism, but no mutations were reported so far in patients with central precocious puberty (CPP). Animal data demonstrate the importance of microRNAs in pubertal timing regulation. Among others, miR200b regulates Gnrh1 gene expression in GnRH neurons and Lhb gene expression in gonadotrophs through transcriptional regulation of the transcription factor Zeb1.

Objectives: To identify genetic causes of maternally inherited CPP.

Population and Methods: Whole genome sequencing of eight family trios affected with CPP, demonstrating maternal inheritance pattern, was performed. A family trio analysis approach was utilized as a first tier analysis to generate a set of potential causative genetic variants inherited in the autosomal dominant pattern. The minor allele frequency threshold for known variants was set at 0.2%, all variants exceeding this value were excluded from further analysis. Genetic variants with coverage >10x were retained and analyzed with Variant Studio 3.0 software. Identified candidate variant and its family segregation were verified by Sanger sequencing. By targeted approach, coding and regulatory regions and copy number variants (CNV) of 398 genes reported to be associated with age at menarche by genome-wide association studies were analyzed for rare variants. In silico tool miRIAD was used to predict miRNA seed regions.

Results: The average coverage of each genome was 38x and around 3.8M SNVs and InDels, 5k SVs and 600 CNVs were detected on average per single sample. In a single pedigree, a variant in 3’untranslated region of GNRHR gene segregating with CPP, NM_000406.2:c.*1509G>A, was identified. The variant was not reported in the gnomAD database; furthermore, it is in the predicted seed region of miR200b. The proband carrier was diagnosed with CPP at the age of 6,5 years with breast stage 2-3, advanced bone age, normal weight, height at 97th percentile, increased basal and peak luteinizing hormone (LH). Her mother had menarche at 9 years.

Conclusions: With this preliminary result, we hypothesize deranged regulation of GNRHR mRNA translation by miR200b influences pubertal timing in the affected pedigree. Further investigation is planned to test the presented hypothesis. If confirmed, our result would be not only the first evidence of implication of GNRHR in familial CPP but also an evidence of a novel biologic mechanism of regulation of pubertal timing at the level of gonadotrophs.

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