Volume 28, Issue 150, August 2024

The relationship between hypergonadotropic hypogonadism and gene variations? New mutations discovered by familial mutation screening and a review of the literature

Gülbahar Güzel Erdal, Mahmut Balkan

Dicle University, Institute of Medical Sciences, Department of Medical Biology and Genetic, Diyarbakır, Turkey

ABSTRACT

Hypergonadotropic ovarian failure with normal karyotype is a heterogeneously inherited disorder with Mendelian recessive inheritance in some cases. This condition is characterized by a wide range of clinical manifestations, ranging from primary amenorrhea associated with ovarian dysgenesis to post-pubertal secondary amenorrhea characterised by elevated gonadotropin levels and low estrogen levels. The objective of this study was to identify potential genetic mutations associated with ovarian dysfunction through genetic analysis in a 16- year-old female exhibiting a typical karyotype, who had previously been diagnosed with hypergonadotropic hypergonadism and sporadic ovarian failure, in addition to her first-degree relatives. Each of the seven family members underwent karyotype analysis for familial genetic screening. Using the Next Generation Sequencing (NGS) Sex Panel, a total of 41 genes were analysed. Five new gene variants (AMH [c.814C>G, rs546849156], SLC34A3 [c.1453C>T, rs145029982], FBN2 [c.8282C>T, rs201962592], NOTCH2 [c.6956C>T, rs373527990] and COL9A1 [c.1621G>A]) were identified in the proband. In the family screening of the proband, the karyotype analysis of the 14-year-old sister was found to be 46,XX,16qh+. The NGS scan of this sister revealed the same genetic mutations in the AMH, COL9A1, SLC34A3, FBN2, NOTCH2 and GP1BA genes as in the proband. These genetic variations play an important role in the regulation of many fundamental biological processes, including meiosis, follicular development, ovulation, cellular metabolism and regulation of the extracellular matrix. We suggest that these genetic variations may be directly or indirectly related to the mechanisms of folliculogenesis and may represent novel candidate gene mutations in ovarian failure, an oligogenic disease.

Keywords: Hypergonadotropic hypogonadism, ovarian failure, novel mutation, AMH, NOTCH2.

Medical Science, 2024, 28, e102ms3401

PDF

DOI: https://doi.org/10.54905/disssi.v28i150.e102ms3401

Published: 16 August 2024