Premature Ovarian Insufficiency: New Perspectives on Genetic Cause and Phenotypic Spectrum

Abstract

Premature ovarian insufficiency (POI) is one form of female infertility, defined by loss of ovarian activity before the age of 40 and characterized by amenorrhea (primary or secondary) with raised gonadotropins and low estradiol. POI affects up to one in 100 females, including one in 1000 before the age of 30. Substantial evidence suggests a genetic basis for POI; however, the majority of cases remain unexplained, indicating that genes likely to be associated with this condition are yet to be discovered. This review discusses the current knowledge of the genetic basis of POI. We highlight genes typically known to cause syndromic POI that can be responsible for isolated POI. The role of mouse models in understanding POI pathogenesis is discussed, and a thorough list of candidate POI genes is provided. Identifying a genetic basis for POI has multiple advantages, such as enabling the identification of presymptomatic family members who can be offered counseling and cryopreservation of eggs before depletion, enabling personalized treatment based on the cause of an individual's condition, and providing better understanding of disease mechanisms that ultimately aid the development of improved treatments.

Molecular Aspects and Clinical Relevance of GDF9 and BMP15 in Ovarian Function

“…POI is a dysfunction of the ovary caused by heterogeneous factors (viral infections, autoimmune disorders, genetic disorders, iatrogenic causes), among which the genetic component plays a substantial role, as the synergistic action of different mutations may underlie the development of this phenotype (Rossetti, Ferrari, Bonomi, & Persani, 2017; Tucker, Grover, Bachelot, Touraine, & Sinclair, 2016). Relatively a few genes are considered involved in the development of syndromic and nonsyndromic POI (Cox & Liu, 2014; Fortuno & Labarta, 2014).…”

Iatrogenic and non‐iatrogenic causes of female fertility loss that may indicate fertility preservation

“…Aneuploidies comprise 13% of all POI cases, whereas X‐chromosome structural abnormalities, for example, Xq isochromosome, translocations or deletion, are seen less frequently. Another sex chromosomal abnormality leading to streak ovaries is 46,XY gonadal dysgenesis …”

A Novel Homozygous Missense <b><i>FSHR</i></b> Variant Associated with Hypergonadotropic Hypogonadism in Two Siblings from a Brazilian Family

“…Mutations in FMR1 , NR5A1 , NOBOX , FIGLA , FOXL2 , SOHLH1/2 , BMP15 , GDF9 , INHA , and ESR1 , in addition to FSHR and LHR, have been implicated in congenital defects of folliculogenesis and ovarian development and function [Tucker et al, 2016]. Previous work from our group has shown that mutations in NANOS3 , which were also identified by Sanger sequencing, are implicated in POF etiology through a mechanism involving increased apoptosis of the primordial germ cells during embryonic cell migration [Santos et al, 2014].…”

“…Although a number of chromosome abnormalities have been associated with HH, a monogenic cause is still unknown. Primary ovarian failure (POF), also known as premature ovarian insufficiency, is the loss of ovarian function before the age of 40 years and is characterized by amenorrhea, hypoestrogenism, and elevated gonadotropin levels (follicle-stimulating hormone [FSH] >40 U/L), resulting in loss of fertility [Shelling, 2010;Tucker et al, 2016]. Chemotherapy or radiotherapy, autoimmune disease, X chromosome abnormalities, and genetic conditions have been described as causes of POF; however, approximately 65% of POF casKeywords FSHR · Homozygous missense · Hypergonadotropic hypogonadism · Infertility · Whole-exome sequencing Abstract Hypergonadotropic hypogonadism (HH) is defined by increased gonadotropin levels in men and women.…”