Genetics of Human Infertility

P. H. Vogt

• Publisher: S. Karger
• Year: 2017
• ISBN:
  9783318060980
• Topic: Medicine
• Subtopic: Medical Theory, Practice & Reference

Infertility affects more than one in ten couples worldwide and is related to highly heterogeneous pathologies sometimes only discernible in the germ line. Its complex etiology often, but not always, includes genetic factors besides anatomical defects, immunological interference, and environmental aspects. Nearly 30% of infertility cases are probably caused only by genetic defects. Thereby experimental animal knockout models convincingly show that infertility can be caused by single or multiple gene defects. Translating those basic research findings into clinical studies is challenging, leaving genetic causes for the vast majority of infertility patients unexplained. Nevertheless, a large number of candidate genes have been revealed by sophisticated molecular methods. This book provides a comprehensive overview on the subject of infertility written by the leading authorities in this field. It covers topics including basic biological, cytological, and molecular studies, as well as common and uncommon syndromes. It is a must-read for human geneticists, endocrinologists, epidemiologists, zoologists, and counsellors in human genetics, infertility, and assisted reproduction.

Vogt PH (ed): Genetics of Human Infertility. Monogr Hum Genet.
Basel, Karger, 2017, vol 21, pp 17–39 (DOI: 10.1159/000477276)

______________________

Genetics of Premature Ovarian Failure: New Developments in Etiology

Yinying Qin^a–d · Joe Leigh Simpson^{g, h} · Zi-Jiang Chen^a–f

^aCenter for Reproductive Medicine, Shandong Provincial Hospital, Shandong University, ^bNational Research Center for Assisted Reproductive Technology and Reproductive Genetics, ^cThe Key Laboratory for Reproductive Endocrinology of the Ministry of Education, and ^dShandong Provincial Key Laboratory of Reproductive Medicine, Jinan, and ^eCenter for Reproductive Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, and ^fShanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai, China; ^gThe March of Dimes Foundation, White Plains, NY, and ^hHerbert Wertheim College of Medicine, Florida International University, Miami, FL, USA

______________________

Abstract

Premature ovarian failure (POF), also termed primary ovarian insufficiency, is a common disorder in women of reproductive age. This discussion focuses predominately on single genes whose perturbations are associated with POF. Perturbations known to have deleterious effects were initially derived from hypothesis-driven candidate gene interrogations. Genes on the X chromosome considered causative for isolated POF include FMR1, PGRMCI, and BMP15. Genes identified on autosomes include FSHR, GDF9, NR5A1, NOBOX, FIGLA, STAG3, FOXL2, HFM1, SOHLH1, MCM8, MCM9, and MSH5. The most common single nuclear causative gene in syndromic POF is a premutation of FMR1, but other examples of proven syndromic POF include the blepharophimosis-ptosis-epicanthus inversus syndrome due to FOXL2, and proximal symphalangism (SYM1) and multiple synostosis syndrome (SYNS1) due to NOG perturbations. Mitochondrial DNA mutations or nuclear DNA mutations disrupting mitochondrial function can also be causative for syndromic POF, as illustrated by Perrault syndrome (several genes) and progressive external ophthalmoplegia due to DNA polymerase γ. Genome-wide association studies are also revealing regions potentially associated with POF, some of which are plausible, but often without obvious causative genes.

© 2017 S. Karger AG, Basel

In premature ovarian failure (POF), menstruation ceases before the expected age of menopause. Diagnosis is traditionally confirmed by elevated serum FSH levels (>40 IU/L) prior to the age of 40 years. More recently a threshold of >25IU/L has been proposed [1].

Approximately 1% of the women are affected with POF before the age of 40 years, and perhaps 0.1% before the age of 30 years. The spectrum of causes includes genetic, autoimmune, metabolic, infectious, and iatrogenic etiologies. However, the etiology remains to be elucidated in most cases. The importance of genetic causation is evident as 10–15% of cases have an affected first-degree relative [2].

Table 1. Autosomal genes causing POF that are codified in OMIM

OMIM nomenclature	Gene name	Chromosomal location
Location
POF1	FMR1	Xq27.3
POF2	DIAPH2 (POF2A)	Xq13.3-q21.1
	POF1B (POF2B)
POF3	FOXL2	3q23
POF4	BMP15	Xp11.2
POF5	NOBOX	7q35
POF6	FIGLA	2p13.3
POF7	NR5A1	9q33
POF8	STAG3	7q22.1
POF9	HFM1	1p22.2
POF10	MCM8	20p12.3
POF11	ERCC6 (PGBD3)	10q11.23

Nomenclature

In addition to POF, the designations primary ovarian insufficiency (POI) and premature menopause are also used and nearly synonymous. The latter is preferred by ESHRE [1]. However, in our view, POI better designates the broader spectrum of disorders with diminished ovarian reserve, regardless of any etiology, thus covering a larger cohort, including occult, biochemical, and overt stages. POF can therefore be considered the final stage of POI. The authoritative Online Mendelian Inheritance in Man (OMIM) has long applied the appellation POF to proven causative genes (Table 1). POF is then the appropriate term for of this genetic report.

Chromosomal Anomalies in Premature Ovarian Failure

Chromosomal abnormalities were initially the only way to verify a genetic etiology of POF. Long-known karyotypic abnormalities include numerical defects (monosomy X), X-chromosome deletions, X-autosome translocations, and isochromosomes. Prevalences range widely, with selection and ascertainment biases presumably accounting for differences in diverse cohorts [3].

Monosomy and Trisomy

The X chromosome plays an essential role in the maintenance of ovarian development and function. Females lacking an X chromosome are well known to display ovarian failure.

X monosomy (Turner syndrome) is characterized by ovarian dysgenesis due to accelerated follicular atresia, typically resulting in primary amenorrhea. However, in 1975, Simpson [4] reported that 3% (5/178) of 45,X patients menstruated. That is, 45,X women may present with POF and secondary amenorrhea as well as the more typical primary amenorrhea. Mosaicism may also result in POF with secondary amenorrhea.

X trisomy is also associated with ovarian dysfunction, 47,XXX women may sometimes experience oligomenorrhea, secondary amenorrhea, and early menopause. Goswami et al. [5] found 2 of 52 47,XXX cases to have POF (3.8%), and in a Chinese population, Jiao et al. [6] reported a prevalence of 1.5% (8/531). The association of 47,XXX with autoimmune diseases is a potential confounding explanation [5, 7]. Overexpression of genes that escape X inactivation could also explain POF in 47,XXX. However, the responsible genes remain to be defined [8]. Finally, the association of 3 X chromosomes could also result in a meiotic disturbance that might secondarily induce ovarian failure.

Structural Chromosomal Abnormalities

Many X chromosome deletions and X-autosome balanced translocations have frequently been reported in patients with POF. These cases have been studied to identify and localize causative genes. Thus, phenotypic-karyotypic correlations have revealed that almost all terminal deletions originating at the proximal X short arm (Xp13) are associated with primary amenorrhea, lack of breast development, and complete ovarian failure. The most proximal region of the X-short arm can be presumed to contain pivotal loci for ovarian maintenance [9, 10].

The X long arm likewise contains pivotal genes, independent of those on Xp. Of particular note are 2 loci on the X chromosome that appear critical for the POF phenotype and have been defined as critical regions (CR): CRI Xq13-Xq21 or POF2, and CRII Xq23-q27 or POF1. Given that XIST is in CRII, it has been reasonably proposed that epigenetic mechanisms downregulate the oocyte-expressed autosomal genes translocated to CRI [11–13]. By contrast, with CRII in terminal deletions arising at Xq25 or Xq26, the more common phenotype is not primary amenorrhea but POF. Similarly, the most distal deletions arising at Xq27 or Xq28 exert a less severe effect on stature than proximal deletions.

Autosomal rearrangements not involving the X chromosomes are also associated with premature or complete ovarian failure. Robertsonian or reciprocal autosomal translocations have been surveyed in Belgian, American, Japanese, and Chinese women [6, 14–16]. No autosome appears to be preferentially involved. Perturbations presumably confer cryptic haploinsufficiency or interrupt pivotal genes in these regions. Nonspecific defective meiotic pairing or a position effect on contiguous genes are also possible explanations [9, 17].

X-autosomal translocations are another way to detect genes causing the POF phenotype. X-autosome translocations frequently involve Xq21, but protein-coding genes have still not been identified with certainty. Other putative POF genes on the X chromosome identified in this fashion include DIAPH2 on Xq22, XPNPEP2 on Xq25, DACH2 on Xq21.3, POF1B on Xq21.1, CHM on Xq21.1, PGRMC1 on Xq24, COL4A6 on Xq22.3, and...