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.