The Genetics of Non-Syndromic Primary Ovarian
Insufficiency: A Systematic Review
Several causes for primary ovarian insufficiency (POI) have been described, including iatrogenic and environmental
factor, viral infections, chronic disease as well as genetic alterations. The aim of this review was to collect all the ge-
netic mutations associated with non-syndromic POI. All studies, including gene screening, genome-wide study and as-
sessing genetic mutations associated with POI, were included and analyzed in this systematic review. Syndromic POI
and chromosomal abnormalities were not evaluated. Single gene perturbations, including genes on the X chromosome
Primary ovarian failure (POF) or primary ovarian insufficiency (POI) is defined as primary or secondary amenorrhea in women younger than 40 years of age with follicle stimulating hormone (FSH) .40 IU/L and estradiol levels .50 pg/mL (1-3). The anti-mullerian hormone (AMH) is another indicator of POI risk (2). Recently Venturella et al. (4) described a new methodology to quantify ovarian reserve combining clinical, biochemical and 3D-ultrasonographic parameters called ovAGE.
Several causes for POI have been described, including iatrogenic and environmental factor, viral infections and chronic disease as well as genetic alterations (1, 5). Numerical defects of X chromosome, such as 45,X and 47,XXX, are often associated with ovarian dysgenesis and accelerated follicular atresia (1). Recently, single genes causing non-syndromic POI have been evaluated (6). The aim of this review was to collect all genetic mutations associated with non- syndromic POI.
Materials and Methods
Electronic databases were searched from inception of each database, until February 2018 (7). The research was conducted using MEDLINE, EMBASE, Web of Sciences, Scopus, ClinicalTrial.gov, OVID and Cochrane Library as electronic databases. Review of articles also included the abstracts of all references retrieved from the search. We used the following keywords and text words: “Ovarian”, “Failure”, “POF”, “POI”, “Genetic”, “Genomic”, “Syndrome”, “Chromosomal”, “Premature”, “Primary” and “Infertility.”
All studies assessing genetic mutations associated with non-syndromic POI, including mutations located in X and autosomal chromosomes, were analyzed. Syndromic POI and chromosomal abnormalities (e.g. numerical defects, X-structural abnormalities, X-autosome translocations and autosomal rearrangements) were not evaluated. Pleiotropic single gene disorders (e.g. Fragile X syndrome), mitochondrial gene diseases (e.g. Perrault syndrome), and multiple malformation syndromes (e.g. cerebellar ataxia) were also excluded.
Single genes causing non-syndromic primary ovarian insufficiency
Many genes whose product is known playing a role in human folliculogenesis (candidate genes) have been studied (6).
Genes on the X chromosome
Bone morphogenetic protein 15 (BMP15) (Xp 11.2)
BMP15 is a member of the transforming growth factor
(TGF) family involved in stimulating folliculogenesis. It
promotes follicle maturation by regulating granulosa cell
differentiation and proliferation (8). Evidences from animal
models primarily suggested the possible involvement
of BMP15 in pathogenesis of POI. Bmp15 knockout female
mice presented subfertility and defective ovulation processes
(9). Concerning human disease, the first evidence was
reported in the 2004 (10). They identified a heterozygous
p.Y235C missense mutation in two POI patients, caused by
decrease of granulosa cell proliferation through a dominant
negative effect. Many variants in
Progesterone receptor membrane component I (PGRMC1)
PGRMC1 is a putative progesterone-binding membrane
receptor, expressed in various tissues (18-22). Authors
(21) have identified a mother and daughter with POI carrying
an X-autosome translocation [t(X;11)(q24;q13)]
and a sporadic missense mutation (p.H165R), in the cytochrome
b5 binding domain of
Androgen receptor (AR) (Xq12)
Premature ovarian failure, IB (POFIB) (Xq21.2)
POFIB is considered as a region codified by OMIM, located within the critical POI1 region. In a patient with secondary amenorrhea (POI), this region was interrupted by a breakpoint in an X-autosome translocation. Lacombe et al. (31) proved linkage to Xq21 in a family having five patients with POI. A homozygous p.R329Q mutation was identified, leading to decreased ability to bind actin filaments.
Dachshund family transcription factor 2 (DACH2) (Xq21.3)
Fragile X mental retardation I (FMRI) (Xq27.3)
Genes on autosomal chromosomes
Growth differentiation factor 9 (GDF9) (5q31.1)
Folliculogenesis specific bHLH transcription factor (FIGLA)
New ovary homeobox gene (NOBOX) (7q35)
Nuclear receptor subfamily 5, group A, member I (NR5AI):
Steroidogenic factor1 (SF1) (9q33)
Estrogen receptor 1 (ESR1) (6q25.1)
FSH receptor (FSHR) (2p21-p16)
FSH/FSHR signaling has an important role in regular gonadal function. A study, composed of 75 patients with hypergonadotrophic ovarian dysgenesis and primary or secondary amenorrhea cases, discovered homozygous mutations (59-61). These mutations are common (0.96%) in Finnish women, but rare in the other populations (13, 62-70).
TGF, beta receptor III (TGFBR3) (1p33-p32)
G protein-coupled receptor 3 (GPR3) (1p36.1-p35)
Wingless-type MMTV integration site family, member 4
Inhibins (INH): Inhibin, alpha (INHA) (2q35), Inhibin,
beta A (INHBA) (7p15-p13), Inhibin, beta B (INHBB)
INH is a member of TGF-b family. In New Zealand
(7%), Indian (11.2%) and Italian (4.5%) women with POI
a common missense variation c.769G.A (p.A257T) was
found in the
POU class 5 homeobox 1 (POU5FI) (6p21.31)
Class 5 homeobox MutS homolog 4 (MSH4) (1p31) and
Cbp/p300-interacting transactivator, with Glu/Asp-rich carboxy-
terminal domain, 2 (CITED2) (6q23.3)
Spermatogenesis and oogenesis specific basic helix-loop-helix
transcription factor I (SOHLHI) (9q31.3) and SOHLH2
Phosphatase and tensin homolog (PTEN) (10q23.3)
Nanos homolog 1, 2, 3 (Drosophilia):
NANOS2 (19q13.32), NANOS3 (19q13.13)
Cyclin-dependent kinas inhibitor IB (CDKNIB) (12p13.1-p12)
CDKN1B, also known as P27 or KIP1, translates an
inhibitor involved in growth and differentiation of several
tissue. It is responsible for follicle atresia. Authors,
showed early follicle depletion in
Anti-mullerian hormone receptor, type II (AMHR2) (12q13)
Forkhead box protein L2 (FOXL2) (3q23)
Forkhead box 03 (FOX03) (6q21)
Forkhead box 01 (FOX01) (13q14.1)
The Wilms tumor 1 (WT1) gene (11p13)
The Splicing Factor 1 (SF1) gene (11q13.1)
SF1 has a significant role in ovarian development and it appears to cause POI in Tunisian women by reducing estradiol levels.
Spalt-like transcription factor 4 (SALL4) (20q13.2)
Meiotic protein covalently bound to DSB (SP011) (20q13.31)
DNA meiotic recombinase I (DMCI) (22q13.1)
Genome-wide studies in primary ovarian insufficiency
The candidate gene approach and cytogenetic studies have provided some important results so far. Recently, new strategies have been performed for identifying new genes and unknown pathways associated with POI development. These strategies include linkage analysis in families with multiple affected patients, array-CGH for analysis of copy number variants (CNVs), genome-wide association (GWA) studies (GWAS), genome-wide sequencing of exomes (WES) and the whole genome sequencing (WGS) as well as the next generation sequencing (NGS) (6).
Genome-wide association studies
In genetics, a GWAS consists of the analysis of a genome- wide set of genetic variants to discover their association with a trait. Especially, GWASs focus on SNPs. GWA studies use high-throughput genotyping technologies to investigate the entire genome and common SNPs assay, without any prior hypotheses regarding the mechanism or biological pathways. Then, this analysis consists of studying SNPs in affected and control women.
Thanking GWAS, several potentially POI related loci were identified in Chinese, Korean, and Dutch women, but no interesting finding was confirmed by replicating these studies. The major limitation of GWAS is lack of statistical power, due to population proportions and sample size. POI is actually a rare disease, so it could be difficult to increase the sample size.
Genome-wide association studies based family linkage analysis
Some GWAS studies also showed a dominant pattern of inheritance. A large consanguineous Middle-Eastern family with POI, presenting an autosomal recessive pattern of inheritance, was subject of GWA. They identified two regions including 7p21.1-p15.3 and 7q21.3-q22.2.
Genome-wide association studies based on age of menopause
A new strategy to identify genetic mechanism involved
in POI might consist of using evidences from shared genetic
susceptibility natural menopause or early menopause
women. Studies have identified a significant association
between POI and three SNPs including rs2278493
in hexokinase 3 (
Copy number variants
CNVs are a structural variants involving DNA regions
>1 kb. They consist of alterations in the copy number of
specific regions such as deletions and duplications. They
can be either inherited or spontaneously arisen de novo,
leading to phenotypic variations and disease. Recently,
array-CGH has been used to search CNVs potentially
involved in POI. Studies have identified eight statistically
significant different CNVs in chromosomal regions
(1p21.1, 5p14.3, 5q13.2, 6p25.3, 14q32.33, 16p11.2,
17q12 and Xq28) of five genes playing role in reproduction,
includingDynein axonemal heavy chain 5 (
Ledig et al. (13) performed array-CGH analysis in 74
German patients with POI and identified 44 rearrangements
(deletions and insertions) through several genes involved
in meiosis, DNA repair and folliculogenesis. Seventeen
novel microduplications and seven novel microdeletions,
six of which were located in the coding regions of 8q24.13,
10p15-p14, 10q23.31, 10q26.3, 15q25.2 and 18q21.32 have
been identified. Two novel microdeletions were discovered
to cause haploinsufficiency for
Whole exome sequencing
WES allows simultaneous analysis of base pairs across the entire exome. This was traditionally defined as the sequence encompassing all exons of protein coding genes in the genome. Six WES was performed in non-syndromic inherited POI. It has been indicated that majority of the candidate genes play role in meiosis and DNA repair, in this study (Table 1).
WES; Whole exome sequencing and POI; Primary Ovarian Insufficiency.
Whole genome sequencing and next generation sequencing
NGS has revolutionized genomic research. Thanks
to NGS an entire human genome can be sequenced in
a single day and new molecular players in POI can be
identified. Fonseca et al. (30) performed a retrospective
case-control cohort study including 12 patients with
non-syndromic POI and 176 controls. NGS was used to
sequence complete coding regions of 70 candidate genes
in POI patients and mutations in
This review includes almost all genetic abnormalities and genes linked with non-syndromic POI. This exhibits the importance and variability of genetic elements involved in POI genesis and identified by different techniques. Different conclusion can be made based on our review. First, several genes come out as POI candidates, but only a little part of them have been established unequivocally causative factor, by functional tests. Second, remarkable differences in frequency exist among different ethnic groups. New studies with a large sample sizes should more imply disparate ethnic groups. Moreover, interactions between gene-gene and protein-protein are not yet entirely clear. Recent and future advances in sequencing techniques will help find other novel genes involved in POI. Finally, discovering the pathogenesis and molecular bases of POI is useful not only to understand the ovarian physiology, but also to improve genetic and fertility counseling. Once new variants are found, they can help prognosticate the age of menopause. In future, findings from this review may help large genetic screening studies on infertility and may help women plan their fertility.
This review showed variability of the genetic factors associated with POI. These findings may help future genetic screening studies on large cohort of women.
There is no financial support and conflicts of interest in this study.
R.V., V.D.V., A.C., P.D.A., G.S., B.A., F.P.I., D.L., F.Z.; Participated in study design, data collection and evaluation, drafting and statistical analysis. E.R., C.D.M., G.V.; Contributed to conception and design. All authors participated in the protocol development, collection and analysis of the included data, writing of the manuscript and final approval.