Genetic basis of eugonadal and hypogonadal female reproductive disorders

Best Practice & Research Clinical Obstetrics and Gynaecology xxx (2017) 1e12

Contents lists available at ScienceDirect

Best Practice & Research Clinical Obstetrics and Gynaecology journal homepage: www.elsevier.com/locate/bpobgyn

1

Genetic basis of eugonadal and hypogonadal female reproductive disorders Tatiana Trofimova, MD a, 1, Daria Lizneva, MD, PhD a, b, 1, 2, Larisa Suturina, MD, PhD a, c, 1, 3, Walidah Walker, MPH b, 2, Yen-Hao Chen, PhD b, 2, Ricardo Azziz, MD, MPH b, d, 2, 4, Lawrence C. Layman, MD b, *, 2 a Department of Reproductive Health Protection, Scientific Center of Family Health and Human Reproduction, 16, Timiryazeva Street, 664003, Irkutsk, Russian Federation b Section of Reproductive Endocrinology, Infertility, & Genetics, Department of Obstetrics & Gynecology, Medical College of Georgia, Augusta University, 1120 15th Street, 30912 Augusta, GA, USA c Irkutsk State Medical Academy for Postgraduate Education, 100, Yubileyniy, 664049, Irkutsk, Russian Federation d State University of New York (SUNY), State University Plaza, 353 Broadway, Albany, NY, USA 12246

Key words: fibroids Mullerian aplasia POF OHSS hypogonadism Kallmann syndrome PCOS endometriosis

This review discusses the current state of our understanding regarding the genetic basis of the most important reproductive disorders in women. For clarity, these disorders have been divided into eugonadal and hypogonadal types. Hypogonadal disorders have been further subdivided according to serum gonadotropin levels. Our review focuses on historical and recent data regarding the genetics of the hypothalamicepituitaryegonadal axis dysfunction, as well as the development and etiology of eugonadal disorders including leiomyomata, endometriosis, spontaneous ovarian hyperstimulation syndrome, polycystic ovarian syndrome, mullerian aplasia, and steroid hormone resistance syndromes. We discuss the known genes most commonly involved in hypergonadotropic hypogonadism (Turner syndrome and premature

* Corresponding author. 1120 15th Street, Augusta, GA, USA, 30912 Tel.: þ1 7067213832; Fax: þ1 7067216211. E-mail address: [email protected] (L.C. Layman). 1 Tel.: þ7 3952 292207; Fax þ7 3952207636. 2 Tel.: þ1 7067213832; Fax þ1 7067216211. 3 Tel.: þ7 3952 465326; Fax þ7 3952 462801. 4 Tel.: þ1 5184454090. http://dx.doi.org/10.1016/j.bpobgyn.2017.05.003 1521-6934/© 2017 Published by Elsevier Ltd.

Please cite this article in press as: Trofimova T, et al., Genetic basis of eugonadal and hypogonadal female reproductive disorders, Best Practice & Research Clinical Obstetrics and Gynaecology (2017), http:// dx.doi.org/10.1016/j.bpobgyn.2017.05.003

2

T. Trofimova et al. / Best Practice & Research Clinical Obstetrics and Gynaecology xxx (2017) 1e12

ovarian failure) and hypogonadotrophic hypogonadism (Kallmann syndrome and normosmic types). In addition, we summarize the current clinical testing approaches and their utility in practical application. © 2017 Published by Elsevier Ltd.

Introduction Sexual and reproductive development and function in humans are critically dependent on GnRHsynthesizing neurons, which originate outside the brain and migrate during embryological development to the hypothalamus [1]. GnRH produced in the hypothalamic arcuate nucleus is released into hypophyseal-portal capillaries, reaching the anterior pituitary where it binds to its cell surface receptor on pituitary gonadotrope cells, inducing synthesis and secretion of the gonadotropins follicle stimulating hormone (FSH) and luteinizing hormone (LH). In turn, gonadotropins stimulate steroidogenesis in the gonads through interaction with their G-protein coupled receptors. Because of inhibitory feedback on the hypothalamus and anterior pituitary, sex steroid hormones control the synthesis of gonadotropins [2]. Recently, a number of other factors have been identified as important in the regulation of reproductive function, including gonadotropin inhibitory hormone, which directly inhibits pituitary gonadotrophin synthesis and release, kisspeptin, inhibins, antimullerian hormone, and many other growth factors [2]. Disorders of the human reproductive system can be classified based on the functional activity of the gonads as either hypogonadal (low estrogen state) or eugonadal (normal estrogen state). In the recent past, our scientific understanding regarding the genetic etiology of female reproductive dysfunctions has significantly increased [3]. In general, eugonadal conditions are much more common than hypogonadal disorders, but the molecular basis is much better known for hypogonadal conditions. Hypogonadal conditions also represent more severe clinical phenotypes compared to eugonadal dysfunction. The critical role of specific gene mutations has been relatively well established for many hypogonadal disorders, but only for two eugonadal disorders [i.e., ovarian hyperstimulation syndrome (OHSS) and mullerian aplasia]. For the other eugonadal disorders, such as leiomyoma, endometriosis, and polycystic ovary syndrome (PCOS), no specific causative genes have been identified. Association studies have shown certain loci that are linked with these disorders, but these data do not signify causation. Causation requires the demonstration of gene mutations that impair normal function, segregate with the disease phenotype, and have in vitro evidence demonstrating biological plausibility. This review summarizes the current scientific data available on the genetics of selected eugonadal disorders and hypogonadal conditions and provides practical recommendations for clinicians. Eugonadal disorders Leiomyomata Uterine leiomyomas are monoclonal, diploid, somatic cell tumors that arise from uterine smoothmuscle tissue. Leiomyomata (fibroids) are one of the most common diseases in gynecological practice, occurring in at least half of women. Although many are asymptomatic, some women manifest heavy uterine bleeding and pelvic pain resulting in hysterectomy. The inheritance pattern of fibroids is largely unknown [4] except for some rare Mendelian types, which develop in unusual locations and are associated with other anomalies. Hereditary leiomyomatosis and renal tumors are caused by autosomal dominant mutations in the fumarate hydratase (FH) [5]. Diffuse leiomyomatosis and Alport syndrome, an X-linked dominant contiguous gene deletion syndrome affecting COL4A5 and COL4A6, consist of glomerulonephritis, hearing loss, and eye disease [6]. Classical cytogenetic analysis of uterine leiomyoma demonstrates low-frequency chromosomal aberrations, including 7q deletions, trisomy 12, and translocations at chromosome 12q14, which Please cite this article in press as: Trofimova T, et al., Genetic basis of eugonadal and hypogonadal female reproductive disorders, Best Practice & Research Clinical Obstetrics and Gynaecology (2017), http:// dx.doi.org/10.1016/j.bpobgyn.2017.05.003

T. Trofimova et al. / Best Practice & Research Clinical Obstetrics and Gynaecology xxx (2017) 1e12

3

includes the high-mobility group AT-hook 2 (HMGA2). The most significant genetic finding in uterine leiomyomata is the presence of heterozygous, clonal, somatic mutations in the mediator complex subunit 12 (MED12). In their initial report, investigators found that 75% of women and 70% of uterine fibroids had variants in the MED12 gene. Half of the variants were found in exon 2, and these were predicted to be deleterious [7]. MED12 consists of 26 subunit transcriptional regulators and is localized on chromosome Xq13.1. It is interesting that germline mutations in this gene result in X-linked intellectual disability in males without predisposition to fibroids [7]. Although somatic variants have been identified, it is not known if germline gene mutations contribute to the genesis and inheritance of fibroids. Several investigative methods have been employed but principally consist of genome wide association studies (GWAS), which are case-control studies to determine if certain markers (usually single nucleotide polymorphisms or SNPS) are more frequent in cases vs. controls. GWAS studies consist of two parts: [1] the initial GWAS and [2] a replication study. Because of the large number of loci studied, many of the findings in the initial GWAS could be found to be associated with the disorder in question by chance alone, so a replication study is required. For the replication, the markers deemed significant from the initial phase are studied in a new sample of cases and controls. Several chromosomal loci have been identified from the available GWAS in women with leiomyomata (Table 1) [8]. One study combined genome wide linkage analysis (study of family members) and GWAS. Interestingly, one SNP at 17q25.3 was in linkage disequilibrium with three genes, one of which (FASN), was increased threefold in leiomyoma vs. adjacent normal myometrial tissue. FASN transcripts and the FAS protein have been found to be upregulated in a variety of tumors [9]. However, FASN association was not confirmed on subsequent replication [10]. To date, GWAS studies provide preliminary information concerning potential genetic loci in fibroids but have not identified a gene as being causative. Endometriosis Endometriosis is a common hormone-dependent disorder in females resulting in pelvic pain, dysmenorrhea, and infertility. Histologically, lesions are characterized by ectopic endometrial glands and stroma located outside the uterusdcommonly to other organs in the pelvis and beyond. Endometriosis is a disease of inflammatory origin, probably polygenic or multifactorial [11]. Similar to leiomyomata, the study of endometriosis has been complicated, and currently, no clear germline mutation has been identified. Gogusev and colleagues reported copy number variants (CNVs)

Table 1 Genome Wide Association Studies (GWAS) of reproductive disorders. Disorder A.

Leiomyomata

B.

Endometriosis

C.

PCOS

Loci Associated by Replication

Gene

Reference

10q24.33 22q13.1 11p15.5 10q26 7p15.2 1p36 2p16.3 2p21 9q33.3 9q22.32 11p14.1 11q22.1 12q14.3 12q13.2 16q12.1 19p13.3 20q13.2

SLK and OBFC1 TNCRB6 ODF3-BET1L-RIC8A-SIRT3 EMX2 NFE2L3 and HOXA10 WNT4 LHCGR, FSHR THADA DENND1A C9orf3 FSHR YAP1 HMGA2 RAB5/SUOX TOX3 INSR SUMO1P1

[8] [8] [8] [13] [14,15] [14,15] [44e53] [44,45,48,49,52] [47,49] [48,49,54] [45,48,49,55] [48,55] [45,48] [44,45,48,49] [45,48] [45,52] [52]

Only loci confirmed by replication analysis are depicted. Loci confirmed in GWAS of PCOS without replication analysis include 2q34 and 5q31 (ERBB4 and RAD 50, respectively) [48], and 8p32 and 12q21.2 (GATA4 and KRR1, respectively) [49].

Please cite this article in press as: Trofimova T, et al., Genetic basis of eugonadal and hypogonadal female reproductive disorders, Best Practice & Research Clinical Obstetrics and Gynaecology (2017), http:// dx.doi.org/10.1016/j.bpobgyn.2017.05.003

4

T. Trofimova et al. / Best Practice & Research Clinical Obstetrics and Gynaecology xxx (2017) 1e12

in three chromosomal regions (1p36, 7p22.1, and 22q12) in patients with endometriosis [12]. In addition, linkage analysis conducted in Australia and the UK identified significant linkage at chromosome 10q26, but no causal gene was found [13] A GWAS study in Australia [14] implicated loci 7p15.2 (near the HOXA10 and NFE2L3 genes) and 1p36 (containing the WNT4 gene). A Japanese GWAS [14,15] also identified the locus 1p36 (Table 1). More recently, retinoid deficiency has been suggested to have a causative role in the etiology of endometriosis. Abnormal methylation of the promoters of genes such as GATA6, ESR2, and NR5A1 in endometrial implants leads to an increase in local estrogen and prostaglandin levels, causing the inhibition of progesterone receptors. This in turn results in the reduced synthesis and absorption of retinoids. These molecular abnormalities have detrimental effects upon cell differentiation, increased survival, and enhanced inflammation, and consequentially could result in the development of endometriosis [16]. PCOS Polycystic ovary syndrome (PCOS) is one of the most prevalent endocrine disorders in females [17]. PCOS patients demonstrate a spectrum of clinical symptoms, including hyperandrogenism, menstrual dysfunction/oligo-anovulation, and polycystic ovarian morphology [18]. Women with PCOS are at a higher risk for infertility, dysfunctional uterine bleeding, metabolic disorders (dyslipidemia, obesity, and type 2 diabetes mellitus), and cardiovascular disease [18]. PCOS is a complex polygenic, multifactorial disease. Since insulin resistance and secondary hyperinsulinemia are a common finding in up to 85% of women with PCOS, insulin (INS) and its receptor (INSR) became prime candidate genes. It has been well known that mutations in INSR lead to insulin resistance, acanthosis nigricans, and type 2 diabetes mellitus. INSR mutations may also cause the more severe phenotype of the Donohue syndrome (leprechaunism), a serious autosomal recessive disease, characterized by the development of somatic abnormalities, hyperinsulinemia, hypoglycemia, hypertrichosis, and acanthosis nigricans [19]. The molecular basis is also known for a number of congenital generalized lipodystrophies, which may overlap in phenotype with that of PCOS [20]. Women with forms of congenital generalized lipodystrophies have a selective regional loss of body fat and extreme insulin resistance, and their phenotype may be either congenital generalized lipodystrophy (autosomal recessive) or familial partial lipodystrophy (autosomal dominant) [20]. Numerous candidate genes have been studied to try to understand the molecular basis of PCOS. Approaches have largely consisted of association studies, either using a candidate gene approach, transmission disequilibrium test (family based association), or GWAS (Table 1). Throughout the past decade, select candidate genes have come in and out of favor as additional studies have been performed. Genes studied have included INSR FBN3, but more recently DENND1A, FSHR, LHR, RAB5B, and THADA have been in favor. More recently, ERBB4, C9orf3, FSHB, YAP1, and HMGA2 have been confirmed in replication cohorts of GWAS [21]. Nevertheless, none of the variants identified so far is known to directly affect function. However, some of the loci identified do appear to be linked to the underlying biology of PCOS. For example, a number of the loci identified are proximate to genes that modulate or determine gonadotropic function [22]. Further, in 2014, McAllister and colleagues also published results on the function of the product of a locus identified in PCOS GWASs [23]. DENND1A encodes a protein associated with clathrin-coated pits, where cell-surface receptors reside. DENND1A was found in the cytoplasm and nuclei of ovarian theca cells, suggesting a role in gene regulation; immunostaining was more intense in cells from individuals with PCOS than from unaffected controls. Overexpression of DENND1A variant 2 in normal theca cells resulted in a PCOS-like phenotype, and knock-down of DENND1A.V2 in PCOS theca cells reversed this phenotype. We should note that while the heritability of PCOS estimated in a monozygotic twin study is approximately 70% [24], the proportion of heritability accounted for by the PCOS loci identified so far by GWAS is <10%, although similar to that observed with other complex genetic traits. However, additional GWAS may still identify additional loci, and fine mapping of known loci might detect specific genes and functional variants of interest. In addition, other factors accounting for the high heritability of PCOS must also be investigated, including genomic structural variations and epigenetic factors. In Please cite this article in press as: Trofimova T, et al., Genetic basis of eugonadal and hypogonadal female reproductive disorders, Best Practice & Research Clinical Obstetrics and Gynaecology (2017), http:// dx.doi.org/10.1016/j.bpobgyn.2017.05.003

T. Trofimova et al. / Best Practice & Research Clinical Obstetrics and Gynaecology xxx (2017) 1e12

5

addition, the impact of the different PCOS phenotypes (Phenotypes A and B or “classic PCOS,” Phenotype C or “ovulatory PCOS,” and Phenotype D or “non-hyperandrogenic PCOS”) on these findings remains to be determined. Spontaneous ovarian hyperstimulation syndrome Typically, OHSS occurs because of exogenous gonadotropins with infertility treatment. Clinical manifestations of OHSS range from mild (elevated serum estradiol levels and increased ovarian volume with abdominal pain only) to severe (the aforementioned in combination with ascites, hydrothorax, and renal and hepatic insufficiency). Interestingly, a handful of patients developed spontaneous OHSS (sOHSS) during pregnancy following natural conception. At least two familial and three sporadic cases have been described, all of whom have activating mutations of the follicle stimulating hormone receptor (FSHR) gene [25]. This trait appears to be inherited in an autosomal dominant fashion, and the phenotype in affected patients consists of OHSS symptoms in the first trimester (nausea, pain, enlarged ovaries, and ascites) which resolve when the pregnancy is completed. The outcome may be live birth or miscarriage, and not every pregnancy is affected. In all cases, the mutant FSHR was able to be stimulated by human chorionic gonadotropin, which is most elevated in the first trimester, thereby explaining the onset of symptoms. In some cases, the FSHR is constitutively active (requiring no activation by FSH ligand), and in others, the mutant receptor is activated by thyroid stimulating hormone [25]. MayereRokitanskyeKustereHauser syndrome MayereRokitanskyeKustereHauser (MRKH) syndrome, also referred to as mullerian aplasia (patients prefer the name MRKH), is a severe anomaly of the female reproductive tract. The phenotype is manifested by the absence of the vagina, cervix, and most of the uterus in women with a 46,XX karyotype. This syndrome occurs in approximately 1:5000 women and affects 10% of patients with primary amenorrhea [26]. Typically, MRKH syndrome has two subtypes [27]: [1] subtype 1, which is characterized by isolated mullerian aplasia and [2] subtype 2, which includes additional anomalies (renal agenesis, skeletal abnormalities, congenital heart defects, and deafness) [28]. Generally, MRKH is sporadic, but familial cases suggest an autosomal dominant pattern of inheritance with incomplete penetrance and variable expressivity or polygenic inheritance in some cases [27]. Numerous candidate genes (AMH, AMHR, WT1, CFTR, WNT7A, GALT, HOXA7, PBX1, HOXA13, PAX2, HOXA10, RARG, RXRA, CTNNB1, LAMC1, DLGH1, and SHOX) were studied in small numbers of patients, but no mutations were found. For other genes (RBM8A, WNT9B, LHX1, and TBX6), variants have been found; but their significance is unknown. Only WNT4 and HNF1B have been identified as causative genes [29]. One family with renal cysts, maturity onset diabetes of the young (MODY) type 5, and mullerian aplasia had a heterozygous intragenic deletion of HNF1B, impairing function in vitro. The prevalence of mutations in WNT4 and HNF1B in patients with MRKH syndrome appears to be very low. Chromosomal microarrays have been used to determine if CNVs not detectable by karyotype could be present, with many chromosomal regions implicated. Some CNVs that have been repetitively identified include ~1 Mb deletions of 17q12 and 0.5 Mb deletions of 16p11 [30]. Interestingly, the 17q12 CNV contains the loci for LHX1 and HNF1B, while the 16p11 CNV contains TBX6. Despite these studies, there is no conclusive evidence that these CNVs are causative, and little else is known concerning the genetics of MRKH. Steroid hormone resistance syndromes Complete androgen insensitivity (CAIS) is an X-linked recessive condition that results in the absence of androgen effect in 46,XY males, which is caused by inactivating mutations in androgen receptor (AR) gene [31]. Patients with CAIS are phenotypic women, but they lack a uterus and vagina, and have little or no axillary and/or pubic hair. Serum testosterone levels in these patients are in the normal male Please cite this article in press as: Trofimova T, et al., Genetic basis of eugonadal and hypogonadal female reproductive disorders, Best Practice & Research Clinical Obstetrics and Gynaecology (2017), http:// dx.doi.org/10.1016/j.bpobgyn.2017.05.003

6

T. Trofimova et al. / Best Practice & Research Clinical Obstetrics and Gynaecology xxx (2017) 1e12

range. Gonadectomy should be strongly considered once pubertal development is complete since tumors more commonly occur after that time. Although CAIS is relatively common, alternatively patients with estrogen insensitivity syndrome have only rarely been identified. The first estrogen receptor-alpha (ESR1) gene mutation was identified in a 46,XY male in 1994 [32]. The first female with an ESR1 mutation was only recently described. Notably, the patient presented with absent breast development, enlarged cystic ovaries, mild acne, and reduced bone age with significantly elevated serum estradiol levels and mildly elevated gonadotropin levels [33]. Her ESR1 mutation significantly impaired estrogen function. Estrogen resistance is inherited as an autosomal recessive trait. Recently, another family with two affected females and an affected male were found to have ESR1 mutations with similar phenotypes [34]. Hypergonadal disorders Hypergonadotrophic hypogonadism (Table 2) Hypogonadism may present with absent breast development and primary amenorrhea, but may also develop during or after puberty. When a hypogonadal patient has elevated levels of gonadotropins, she is considered to suffer from hypergonadotropic hypogonadism reflecting ovarian failure or insufficiency [35]. Hypergonadotropic hypogonadism may be either chromosomally normal or abnormal. The most common form of karyotypically abnormal ovarian failure is Turner syndrome (TS), which may occur in ~15% of women with primary amenorrhea and 0.5e1% in patients with secondary amenorrhea [36]. TS is characterized by a complete absence of, or a defect in, one of the X chromosomes. The karyotype of these women is 45, X, with or without mosaicism, which may include 45, X/ 46, XX, 45, X/46, XY, 45, X/47, XXX, or 46, X,I (Xq) [37]. The most constant feature of TS is short stature, Table 2 Genes involved in 46,XX hypergonadotropic hypogonadism. Gene

Associated nonreproductive anomalies

Inheritance

References

FMR1

Fragile X syndrome in males (full expansion)Tremor/ataxia older male and female (permutation) None None APECED Adrenal insufficiency Sexual ambiguity and ovarian cysts Sexual ambiguity and adrenal failure Galactosemia Adrenoleukodystrophy Adrenoleukodystrophy Adrenoleukodystrophy Blepharophimosis-ptosis-epicanthus syndrome None None

XLD

[39]

XLD AR AR, AD AR AR AR AR AR AR AR AD AD, sporadic AD, sporadic

[56] [57] [58] [59] [60] [61] [62] [63,64] [63,64] [63,64] [65,66] [67] [68,69]

BMP15 FSHR AIRE CYP17A1 CYP19A1 NR5A1 GALT EIFB2 EIFB4 EIFB5 FOXL2 FIGLA NOBOX New gene

Loci

Function

Inheritance

References

SYCE1 STAG HFM1 MCM8 MCM9 RCBTB1 SGO2 PSMC3IP NUP107

10q26.3 7q22.1 1p22.2 20p12.3 6q22.31 13q14.2 2q33.1 17q21.2 12q15

Apoptosis Cell division Apoptosis DNA damage repair DNA damage repair Gene expression Cell division Role in meiotic recombination Nucleoporin protein involved

AR AR AR AR AR AR AR AR AR

[70] [71,72] [73,74] [75,76] [76,77] [78] [79] [80] [81,82]

Only two of the above genes account for >3e4% of POF subjects, FMR1 and NR5A1. Other genes indicated account for <1e2% of POF subjects. AD ¼ autosomal dominant; AR ¼ autosomal recessive; XLD ¼ X-linked dominant.

Please cite this article in press as: Trofimova T, et al., Genetic basis of eugonadal and hypogonadal female reproductive disorders, Best Practice & Research Clinical Obstetrics and Gynaecology (2017), http:// dx.doi.org/10.1016/j.bpobgyn.2017.05.003

T. Trofimova et al. / Best Practice & Research Clinical Obstetrics and Gynaecology xxx (2017) 1e12

7

while other somatic anomalies (wide spaced nipples, webbed neck, and cubitus valgus) are less constant. However, two significant associated anomalies may occurdheart defects (coarctation of the aorta, dilated aortic root, and bicuspid aortic valve) in ~50% of patients, and renal abnormalities (horseshoe kidney, renal agenesis) in one-third [37]. These cardiac anomalies are considered severe, and affected women may have a several percent risk of aortic rupture during pregnancy. Patients with a Y cell line should have their gonads removed because of potential for germ cell tumor formation. Another karyotypically abnormal cause of hypergonadotropic hypogonadism in phenotypic females is the 46,XY disorder of sex differentiation (DSD), also known as Swyer syndrome. These patients have primary amenorrhea without breast development, but they do possess a uterus and vagina. SRY gene mutations occur in approximately 15% of these phenotypic females [38]. They have perhaps the highest risk of germ cell tumor formation of any patients with a Y cell line. For women with 46,XX hypergonadotropic hypogonadism, at least 23 genes are known to have mutations, which result in ovarian insufficiency (Table 2). By far, the most clinically significant known gene is FMR1, mutation of which causes Fragile X syndrome. Heterozygous females have an increased copy number of CGG repeats (premutation), so these carrier females have an increased probability of having a male with intellectual disability when the repeat number expands (full mutation) in meiosis. Females with the premutation also have an increased risk of premature ovarian failure (POF)/premature ovarian insufficiency (POI), and carrier males and females may have increased risks of tremor/ ataxia in later life. International studies of fragile X families report that 16% of the carriers of the premutation experience POF/POI before age 40. When women with POF are studied, the risk of premutation is 3e4% without a family history of POF. If there is a family history of POF, the risk increases to 12e15% [39]. All the other genes contributing to premature ovarian insufficiency generally have frequencies less than 1% except perhaps NRA5A encoding SF1, which is slightly higher, but may have familial adrenal insufficiency (Table 2). Hypogonadotropic hypogonadism Hypogonadotropic hypogonadism occurs due to impaired GnRH neuron migration or GnRH action at the pituitary so that gonadotropins are reduced. Therefore, there is reduced stimulation and secretion of sex steroid release in the gonads, and hypogonadism results. Patients manifest estrogen deficiency as the lack of development of secondary sexual characteristics and subsequent amenorrhea. Pituitary insufficiency and central nervous system and pituitary tumors must be excluded. When pituitary function is normal and there is no tumor detected by magnetic resonance imaging, it is commonly classified as idiopathic hypogonadotropic hypogonadism (IHH) or congenital hypogonadotropic hypogonadism [40]. IHH has two principal phenotypic variants: [1] those patients with a normal sense of smell, termed normosmic hypogonadotropic hypogonadism (nHH) and [2] those with an associated impaired sense of smell (anosmia or hyposmia), termed Kallmann syndrome (KS). The association of sense of smell and reproduction is attributed to the close association of the olfactory and GnRH neurons, which migrate together from outside the brain (in the nasal region) to the hypothalamus during development. nHH/ KS is a rare disorder, and it is difficult to determine its prevalence; nevertheless, most reports indicate that it is more common in males than in females. This is interesting because most of the genes identified are autosomal (Table 3). Traditionally, nHH/KS has been considered to be an irreversible cause of infertility, but some patients may have spontaneous reversal of their symptoms [41]. A wide variety of associated nonreproductive anomalies in patients with nHH/KS have been described including heart defects, renal agenesis, median facial deformities, deafness, and neurological disorders [42]. The molecular basis of nHH/KS has been characterized in 35e40% of patients. The first gene identified more than 25 years ago, KAL1, was found to cause X-linked recessive KS [43]. Initially, it was believed that since KS was more common in males, most patients would have KAL1 mutations. In families with several affected males, KAL1 mutations are common, but without this family history, mutations in any of a number of other genes are possible (Table 3). The first nHH gene found was GNRHR, mutations of which are inherited in an autosomal recessive fashion. It was not until many years later that mutations in the gene encoding the GnRH ligand (GNHR1), the most likely physiologic Please cite this article in press as: Trofimova T, et al., Genetic basis of eugonadal and hypogonadal female reproductive disorders, Best Practice & Research Clinical Obstetrics and Gynaecology (2017), http:// dx.doi.org/10.1016/j.bpobgyn.2017.05.003

8

T. Trofimova et al. / Best Practice & Research Clinical Obstetrics and Gynaecology xxx (2017) 1e12

Table 3 Hypogonadotropic hypogonadism inheritance and phenotype. A. nHH/KS genes that are common and/or have associated anomalies Gene

Associated anomalies

Inheritance

Prevalence in nHH/KS

References

KAL1

Anosmia/hyposmia (KS), renal agenesis, synkinesia,

XLR

[43]

NR0B1

Adrenal hypoplasia

XLR

SOX3 SOX10 FGFR1 CHD7 HESX1 SOX2

CPHD; IGHD, intellectual disability Deafness Midline facial defects, synkinesia CHARGE Septoeoptic dysplasia or KS CPHD; eye defects, hearing loss, septoeoptic dysplasia, intellectual disability CPHD, IGHD, small or ectopic pituitary Hyperphagia, morbid obesity Spontaneous reversal of hypogonadism IHH and ataxia (Gordon-Holmes s.) IHH and ataxia (Gordon-Holmes s.) IHH and ataxia (Gordon-Holmes s.) nHH

XLR AD AD AD AD AD

5e10% males; 30e70% males in XLR families Rare unless congenital adrenal hypoplasia ? ? 10% nHH and KS 6% nHH and KS 1% ?

AD AR AR AR AR AR AR

? Rare 5e6% nHH ? ? ? 3e5% nHH

[86,93] [94] [95,96] [97] [97] [97] [98e100]

LHX4 LEP/LEPR TACR3 OTUD4 RNF216 STUB1 GNRHR

[83,84] [85,86] [87] [88,89] [90] [86,91] [86,92]

B. Other nHH/KS genes that are less common (<3% prevalence) or of unknown prevalence Inheritance Heterozygous WDR11 NELF HS6ST1 SEMA3A FGF17 IL17R SPRY4 FLRT3 PROKR2 IGSF10 Homozygous or Compound Heterozygous GNRH1 KISS1 KISS1R PROKR2 PCSK1 FEZF1 LHB FSHB PROP1 LHX3

Comments FGF8 DUSP6 PROK2

PROK2 TAC3 Cause isolated LH or FSH deficiency Combined pituitary deficiency

Some gene mutations in may just cause KS (KAL1) or just nHH (GNHR1, GNRHR, LEP, LEPR, KISS1, KISS1R, TAC3, or TACR3), while some may cause either nHH or KS (FGF8, FGFR1, PROK2, PROKR2, CHD7, WDR11, HS6ST1, SEMA3A). AD ¼ autosomal dominant; AR ¼ autosomal recessive; CPHD ¼ combined pituitary hormone deficiency; IGHD ¼ isolated growth hormone deficiency; XLR ¼ X-linked recessive.

candidate, were identified in nHH. As shown in Table 3, numerous genes have been found to possess mutations in human nHH/KS. Many are ligand/receptor pairs or are in the same pathway, such as GNRH1/GNRHR, PROK2/PROKR2, and TAC3/TACR3. It is interesting to note that mutations in some genes tend to cause only KS (KAL1) or just nHH (GNRH1, GNRHR, TACR3), while others such as CHD7, WDR11, and PROKR2 cause either nHH or KS. Conclusion Newer molecular genetic techniques and better clinical characterization of patients with reproductive disorders have led the way for advances in understanding their molecular mechanisms. As might be expected, gene mutations have been identified in patients with the least common, but most severe phenotypedhypogonadismdrather than those with more common, less homogenous phenotypes (eugonadal disorders). Genetic diagnosis is possible in many patients with hypergonadotropic and hypogonadotropic hypogonadism. This is important because many of the disorders may have additional nonreproductive deleterious phenotypes, and the inheritance patterns and recurrence risks are known. In contrast, much less is known concerning the genetics of eugonadal disordersdleiomyomata, endometriosis, and PCOS. In fact, no genes are available for clinical testing for these disorders at the time of this writing. Should testing be considered, it should only be considered on a Please cite this article in press as: Trofimova T, et al., Genetic basis of eugonadal and hypogonadal female reproductive disorders, Best Practice & Research Clinical Obstetrics and Gynaecology (2017), http:// dx.doi.org/10.1016/j.bpobgyn.2017.05.003

T. Trofimova et al. / Best Practice & Research Clinical Obstetrics and Gynaecology xxx (2017) 1e12

9

research basis until more definitive data are known. One gene is known for sOHSS (FSHR) and two genes are known for MRKH (WNT5 and HNF1B); so genetic testing is possible for these disorders. Conflict of interest statement TT, DL, LS, WW, YC, and LL have no conflicts of interest to declare. RA is a consultant for Bayer Pharmaceuticals, Ansh labs, and Latitude Capital.

Practice points From the clinical perspective, genetic analysis is a useful tool in the diagnosis of hypogonadism. It is possible to perform targeted DNA sequencing of all the >30 candidate genes for hypogonadotropic hypogonadism, for which the detection rate should be 30e40%. If DNA sequencing is negative, intragenic deletion testing could be considered to pick up deletions missed by PCR-based sequencing. Special attention should be paid to inheritance patterns and associated defects for specific genes because this will affect genetic counseling of recurrence risks. For hypergonadotropic hypogonadism, the detection rate is somewhat less than nHH/KS, but now approaches 15e20% for 46, XX POF/POI women with primary amenorrhea. A karyotype is an important first step in all patients with primary amenorrhea and gonadal failure, as well as those with secondary amenorrhea who are 50 300 or less in stature. If chromosomes are 46, XX, FMR1 DNA analysis is indicated as this is the most frequent genetic cause of hypergonadotropic hypogonadism. Realistically, targeted next generation sequencing with Sanger confirmation can be employed to test all genes for hyper- and hypogonadotropic hypogonadism. For eugonadal disorders such as sOHSS, DNA sequencing may be performed to identify mutations in the FSHR gene. It is probably not practical to perform WNT4 and HNF1B DNA sequencing in MRKH since less than 10 patients worldwide have mutations. Despite all the associations of genes with uterine leiomyomas, endometriosis, and PCOS, clinical testing is not available at this time. However, with the discovery of a growing number of loci for eugonadal disorders, the identification of genetic mutations may facilitate the prediction, diagnosis, and treatment of these disorders in the future.

Research agenda More data are required to support the scientific evidence concerning the molecular basis of eugonadal and hypogonadal disorders. Additional genes need to be identified for the eugonadal disorders, perhaps by whole exome and/or whole genome DNA sequencing in wellcharacterized families. Even though genetic defects are known in some of the hypogonadal disorders, much still need to be learned through mouse, cellular models, and human studies to understand the mechanism of disease.

Acknowledgments LCL was supported by NIH grant HD33004. References [1] Tobet SA, Schwarting GA. Minireview: recent progress in gonadotropin-releasing hormone neuronal migration. Endocrinology 2006;147(3):1159e65. [2] Plant TM. Hypothalamic control of the pituitary-gonadal axis in higher primates: key advances over the last two decades. J Neuroendocrinol 2008;20(6):719e26.

Please cite this article in press as: Trofimova T, et al., Genetic basis of eugonadal and hypogonadal female reproductive disorders, Best Practice & Research Clinical Obstetrics and Gynaecology (2017), http:// dx.doi.org/10.1016/j.bpobgyn.2017.05.003

10

T. Trofimova et al. / Best Practice & Research Clinical Obstetrics and Gynaecology xxx (2017) 1e12

[3] Layman LC. Human gene mutations causing infertility. J Med Genet 2002;39(3):153e61. [4] Aleksandrovych V, Bereza T, Sajewicz M, et al. Uterine fibroid: common features of widespread tumor (Review article). Folia Med Cracov 2015;55(1):61e75. [5] Tomlinson IP, Alam NA, Rowan AJ, et al. Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer. Nat Genet 2002;30(4):406e10. [6] Zhou J, Mochizuki T, Smeets H, et al. Deletion of the paired alpha 5(IV) and alpha 6(IV) collagen genes in inherited smooth muscle tumors. Science 1993;261(5125):1167e9. €kinen N, Mehine M, Tolvanen J, et al. MED12, the mediator complex subunit 12 gene, is mutated at high frequency in [7] Ma uterine leiomyomas. Science 2011;334(6053):252e5. [8] Cha PC, Takahashi A, Hosono N, et al. A genome-wide association study identifies three loci associated with susceptibility to uterine fibroids. Nat Genet 2011;43(5):447e50. [9] Eggert SL, Huyck KL, Somasundaram P, et al. Genome-wide linkage and association analyses implicate FASN in predisposition to Uterine Leiomyomata. Am J Hum Genet 2012;91(4):621e8. [10] Aissani B, Zhang K, Wiener H. Evaluation of GWAS candidate susceptibility loci for uterine leiomyoma in the multi-ethnic NIEHS uterine fibroid study. Front Genet 2015;6:241. [11] Bulun SE. Endometriosis. N Engl J Med 2009;360(3):268e79. re J, Telvi L, et al. Detection of DNA copy number changes in human endometriosis by [12] Gogusev J, Bouquet de Jolinie comparative genomic hybridization. Hum Genet 1999;105(5):444e51. [13] Treloar SA, Wicks J, Nyholt DR, et al. Genomewide linkage study in 1,176 affected sister pair families identifies a significant susceptibility locus for endometriosis on chromosome 10q26. Am J Hum Genet 2005;77(3):365e76. [14] Painter JN, Anderson CA, Nyholt DR, et al. Genome-wide association study identifies a locus at 7p15.2 associated with endometriosis. Nat Genet 2011;43(1):51e4. [15] Uno S, Zembutsu H, Hirasawa A, et al. A genome-wide association study identifies genetic variants in the CDKN2BAS locus associated with endometriosis in Japanese. Nat Genet 2010;42(8):707e10. [16] Bulun SE, Monsivais D, Kakinuma T, et al. Molecular biology of endometriosis: from aromatase to genomic abnormalities. Semin Reprod Med 2015;33(3):220e4. [17] Lizneva D, Suturina L, Walker W, et al. Criteria, prevalence, and phenotypes of polycystic ovary syndrome. Fertil Steril 2016;106(1):6e15. [18] Azziz R, Carmina E, Dewailly D, et al. Positions statement: criteria for defining polycystic ovary syndrome as a predominantly hyperandrogenic syndrome: an Androgen Excess Society guideline. J Clin Endocrinol Metab 2006;91(11): 4237e45. [19] Kadowaki T, Bevins CL, Cama A, et al. Two mutant alleles of the insulin receptor gene in a patient with extreme insulin resistance. Science 1988;240(4853):787e90. [20] Garg A. Clinical review: Lipodystrophies: genetic and acquired body fat disorders. J Clin Endocrinol Metab 2011;96(11): 3313e25. [21] Jones MR, Goodarzi MO. Genetic determinants of polycystic ovary syndrome: progress and future directions. Fertil Steril 2016;106(1):25e32. [22] Azziz R. PCOS in 2015: New insights into the genetics of polycystic ovary syndrome. Nat Rev Endocrinol 2016;12(2):74e5. [23] McAllister JM, Modi B, Miller BA, et al. Overexpression of a DENND1A isoform produces a polycystic ovary syndrome theca phenotype. Proc Natl Acad Sci U S A 2014;111(15):E1519e27. [24] Vink JM, Sadrzadeh S, Lambalk CB, et al. Heritability of polycystic ovary syndrome in a Dutch twin-family study. J Clin Endocrinol Metab 2006;91(6):2100e4. [25] Siegel ET, Kim HG, Nishimoto HK, et al. The molecular basis of impaired follicle-stimulating hormone action: evidence from human mutations and mouse models. Reprod Sci 2013;20(3):211e33. [26] Reindollar RH, Byrd JR, McDonough PG. Delayed sexual development: a study of 252 patients. Am J Obstet Gynecol 1981; 140(4):371e80. [27] Fontana L, Gentilin B, Fedele L, et al. Genetics of Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome. Clin Genet 2016. [28] Sultan C, Biason-Lauber A, Philibert P. Mayer-Rokitansky-Kuster-Hauser syndrome: recent clinical and genetic findings. Gynecol Endocrinol 2009;25(1):8e11. [29] Biason-Lauber A, Konrad D, Navratil F, et al. A WNT4 mutation associated with Müllerian-duct regression and virilization in a 46,XX woman. N Engl J Med 2004;351(8):792e8. [30] Nik-Zainal S, Strick R, Storer M, et al. High incidence of recurrent copy number variants in patients with isolated and syndromic Müllerian aplasia. J Med Genet 2011;48(3):197e204. [31] Gottlieb B, Pinsky L, Beitel LK, et al. Androgen insensitivity. Am J Med Genet 1999;89(4):210e7. [32] Smith EP, Boyd J, Frank GR, et al. Estrogen resistance caused by a mutation in the estrogen-receptor gene in a man. N Engl J Med 1994;331(16):1056e61. [33] Quaynor SD, Stradtman EW, Kim HG, et al. Delayed puberty and estrogen resistance in a woman with estrogen receptor a variant. N Engl J Med 2013;369(2):164e71. [34] Bernard V, Kherra S, Francou B, et al. Familial multiplicity of estrogen insensitivity associated with a loss-of-function ESR1 mutation. J Clin Endocrinol Metab 2017;102(1):93e9. [35] Layman LC. Genetics of human hypogonadotropic hypogonadism. Am J Med Genet 1999;89(4):240e8. [36] Reindollar RH, Novak M, Tho SP, et al. Adult-onset amenorrhea: a study of 262 patients. Am J Obstet Gynecol 1986; 155(3):531e43. [37] Zhong Q, Layman LC. Genetic considerations in the patient with Turner syndromee45,X with or without mosaicism. Fertil Steril 2012;98(4):775e9. [38] Sim H, Argentaro A, Harley VR. Boys, girls and shuttling of SRY and SOX9. Trends Endocrinol Metab 2008;19(6):213e22. [39] Conway GS, Payne NN, Webb J, et al. Fragile X premutation screening in women with premature ovarian failure. Hum Reprod 1998;13(5):1184e7. [40] Bhagavath B, Podolsky RH, Ozata M, et al. Clinical and molecular characterization of a large sample of patients with hypogonadotropic hypogonadism. Fertil Steril 2006;85(3):706e13.

Please cite this article in press as: Trofimova T, et al., Genetic basis of eugonadal and hypogonadal female reproductive disorders, Best Practice & Research Clinical Obstetrics and Gynaecology (2017), http:// dx.doi.org/10.1016/j.bpobgyn.2017.05.003

T. Trofimova et al. / Best Practice & Research Clinical Obstetrics and Gynaecology xxx (2017) 1e12

11

[41] Pitteloud N, Acierno JS, Meysing AU, et al. Reversible kallmann syndrome, delayed puberty, and isolated anosmia occurring in a single family with a mutation in the fibroblast growth factor receptor 1 gene. J Clin Endocrinol Metab 2005;90(3):1317e22. [42] Kim SH. Congenital hypogonadotropic hypogonadism and kallmann syndrome: past, present, and future. Endocrinol Metab (Seoul) 2015;30(4):456e66. [43] Franco B, Guioli S, Pragliola A, et al. A gene deleted in Kallmann's syndrome shares homology with neural cell adhesion and axonal path-finding molecules. Nature 1991;353(6344):529e36. [44] Louwers YV, Stolk L, Uitterlinden AG, et al. Cross-ethnic meta-analysis of genetic variants for polycystic ovary syndrome. J Clin Endocrinol Metab 2013;98(12):E2006e12. [45] Chen ZJ, Zhao H, He L, et al. Genome-wide association study identifies susceptibility loci for polycystic ovary syndrome on chromosome 2p16.3, 2p21 and 9q33.3. Nat Genet 2011;43(1):55e9. [46] El-Shal AS, Zidan HE, Rashad NM, et al. Association between genes encoding components of the Leutinizing hormone/ Luteinizing hormone-choriogonadotrophin receptor pathway and polycystic ovary syndrome in Egyptian women. IUBMB Life 2016;68(1):23e36. [47] Shi Y, Zhao H, Cao Y, et al. Genome-wide association study identifies eight new risk loci for polycystic ovary syndrome. Nat Genet 2012;44(9):1020e5. [48] Day FR, Hinds DA, Tung JY, et al. Causal mechanisms and balancing selection inferred from genetic associations with polycystic ovary syndrome. Nat Commun 2015;6:8464. [49] Hayes MG, Urbanek M, Ehrmann DA, et al. Genome-wide association of polycystic ovary syndrome implicates alterations in gonadotropin secretion in European ancestry populations. Nat Commun 2015;6:7502. ~ alver Bernabe  B, et al. Evidence for chromosome 2p16.3 polycystic ovary syndrome [50] Mutharasan P, Galdones E, Pen susceptibility locus in affected women of European ancestry. J Clin Endocrinol Metab 2013;98(1):E185e90. [51] Almawi WY, Hubail B, Arekat DZ, et al. Leutinizing hormone/choriogonadotropin receptor and follicle stimulating hormone receptor gene variants in polycystic ovary syndrome. J Assist Reprod Genet 2015;32(4):607e14. [52] Brower MA, Jones MR, Rotter JI, et al. Further investigation in europeans of susceptibility variants for polycystic ovary syndrome discovered in genome-wide association studies of Chinese individuals. J Clin Endocrinol Metab 2015;100(1): E182e6. [53] Saxena R, Georgopoulos NA, Braaten TJ, et al. Han Chinese polycystic ovary syndrome risk variants in women of European ancestry: relationship to FSH levels and glucose tolerance. Hum Reprod 2015;30(6):1454e9. [54] Tian Y, Zhao H, Chen H, et al. Variants in FSHB are associated with polycystic ovary syndrome and luteinizing hormone level in Han Chinese Women. J Clin Endocrinol Metab 2016;101(5):2178e84. [55] Li T, Zhao H, Zhao X, et al. Identification of YAP1 as a novel susceptibility gene for polycystic ovary syndrome. J Med Genet 2012;49(4):254e7. [56] Di Pasquale E, Beck-Peccoz P, Persani L. Hypergonadotropic ovarian failure associated with an inherited mutation of human bone morphogenetic protein-15 (BMP15) gene. Am J Hum Genet 2004;75(1):106e11. [57] Aittom€ aki K, Lucena JL, Pakarinen P, et al. Mutation in the follicle-stimulating hormone receptor gene causes hereditary hypergonadotropic ovarian failure. Cell 1995;82(6):959e68. [58] Consortium F-GA. An autoimmune disease, APECED, caused by mutations in a novel gene featuring two PHD-type zincfinger domains. Nat Genet 1997;17(4):399e403. [59] Yanase T, Simpson ER, Waterman MR. 17 alpha-hydroxylase/17,20-lyase deficiency: from clinical investigation to molecular definition. Endocr Rev 1991;12(1):91e108. [60] Ito Y, Fisher CR, Conte FA, et al. Molecular basis of aromatase deficiency in an adult female with sexual infantilism and polycystic ovaries. Proc Natl Acad Sci U S A 1993;90(24):11673e7. [61] Lourenço D, Brauner R, Lin L, et al. Mutations in NR5A1 associated with ovarian insufficiency. N Engl J Med 2009;360(12): 1200e10. [62] Kaufman FR, Devgan S, Donnell GN. Results of a survey of carrier women for the galactosemia gene. Fertil Steril 1993; 60(4):727e8. [63] Fogli A, Rodriguez D, Eymard-Pierre E, et al. [eIF2B and Cree Indian leukodystrophies]. Med Sci (Paris) 2003;19(3):283e4. [64] Fogli A, Gauthier-Barichard F, Schiffmann R, et al. Screening for known mutations in EIF2B genes in a large panel of patients with premature ovarian failure. BMC Womens Health 2004;4(1):8. [65] Crisponi L, Deiana M, Loi A, et al. The putative forkhead transcription factor FOXL2 is mutated in blepharophimosis/ ptosis/epicanthus inversus syndrome. Nat Genet 2001;27(2):159e66. [66] Laissue P, Lakhal B, Benayoun BA, et al. Functional evidence implicating FOXL2 in non-syndromic premature ovarian failure and in the regulation of the transcription factor OSR2. J Med Genet 2009;46(7):455e7. [67] Zhao H, Chen ZJ, Qin Y, et al. Transcription factor FIGLA is mutated in patients with premature ovarian failure. Am J Hum Genet 2008;82(6):1342e8. [68] Qin Y, Choi Y, Zhao H, et al. NOBOX homeobox mutation causes premature ovarian failure. Am J Hum Genet 2007;81(3): 576e81. [69] Qin Y, Shi Y, Zhao Y, et al. Mutation analysis of NOBOX homeodomain in Chinese women with premature ovarian failure. Fertil Steril 2009;91(4 Suppl):1507e9. [70] de Vries L, Behar DM, Smirin-Yosef P, et al. Exome sequencing reveals SYCE1 mutation associated with autosomal recessive primary ovarian insufficiency. J Clin Endocrinol Metab 2014;99(10):E2129e32.  [STAG3 in premature ovarian failure]. Med Sci (Paris) 2015;31(2):129e31. [71] Caburet S, Vilain E. [72] Le Quesne Stabej P, Williams HJ, James C, et al. STAG3 truncating variant as the cause of primary ovarian insufficiency. Eur J Hum Genet 2016;24(1):135e8. [73] Pu D, Wang C, Cao J, et al. Association analysis between HFM1 variation and primary ovarian insufficiency in Chinese women. Clin Genet 2016;89(5):597e602. [74] Wang J, Zhang W, Jiang H, et al., Collaboration POI. Mutations in HFM1 in recessive primary ovarian insufficiency. N Engl J Med 2014;370(10):972e4.

Please cite this article in press as: Trofimova T, et al., Genetic basis of eugonadal and hypogonadal female reproductive disorders, Best Practice & Research Clinical Obstetrics and Gynaecology (2017), http:// dx.doi.org/10.1016/j.bpobgyn.2017.05.003

12

T. Trofimova et al. / Best Practice & Research Clinical Obstetrics and Gynaecology xxx (2017) 1e12

[75] Dou X, Guo T, Li G, et al. Minichromosome maintenance complex component 8 mutations cause primary ovarian insufficiency. Fertil Steril 2016;106(6). 1485e9.e2. [76] Desai S, Wood-Trageser M, Matic J, et al. MCM8 and MCM9 Nucleotide variants in women with primary ovarian insufficiency. J Clin Endocrinol Metab 2017;102(2):576e82. [77] Wood-Trageser MA, Gurbuz F, Yatsenko SA, et al. MCM9 mutations are associated with ovarian failure, short stature, and chromosomal instability. Am J Hum Genet 2014;95(6):754e62. [78] Coppieters F, Ascari G, Dannhausen K, et al. Isolated and syndromic retinal dystrophy caused by biallelic mutations in RCBTB1, a gene implicated in ubiquitination. Am J Hum Genet 2016;99(2):470e80. [79] Faridi R, Rehman AU, Morell RJ, et al. Mutations of SGO2 and CLDN14 collectively cause coincidental Perrault syndrome. Clin Genet 2017;91(2):328e32. [80] Norling A, Hirschberg AL, Karlsson L, et al. No mutations in the PSMC3IP gene identified in a Swedish cohort of women with primary ovarian insufficiency. Sex Dev 2014;8(4):146e50. [81] Weinberg-Shukron A, Renbaum P, Kalifa R, et al. A mutation in the nucleoporin-107 gene causes XX gonadal dysgenesis. J Clin Invest 2015;125(11):4295e304. [82] Lin H, Matzuk MM. Poreless eggshells. J Clin Invest 2015;125(11):4005e7. [83] Muscatelli F, Strom TM, Walker AP, et al. Mutations in the DAX-1 gene give rise to both X-linked adrenal hypoplasia congenita and hypogonadotropic hypogonadism. Nature 1994;372(6507):672e6. [84] Zanaria E, Muscatelli F, Bardoni B, et al. An unusual member of the nuclear hormone receptor superfamily responsible for X-linked adrenal hypoplasia congenita. Nature 1994;372(6507):635e41. [85] Woods KS, Cundall M, Turton J, et al. Over- and underdosage of SOX3 is associated with infundibular hypoplasia and hypopituitarism. Am J Hum Genet 2005;76(5):833e49. [86] Kelberman D, Rizzoti K, Lovell-Badge R, et al. Genetic regulation of pituitary gland development in human and mouse. Endocr Rev 2009;30(7):790e829. [87] Pingault V, Bodereau V, Baral V, et al. Loss-of-function mutations in SOX10 cause Kallmann syndrome with deafness. Am J Hum Genet 2013;92(5):707e24.  C, Levilliers J, Dupont JM, et al. Loss-of-function mutations in FGFR1 cause autosomal dominant Kallmann syn[88] Dode drome. Nat Genet 2003;33(4):463e5. [89] Pitteloud N, Quinton R, Pearce S, et al. Digenic mutations account for variable phenotypes in idiopathic hypogonadotropic hypogonadism. J Clin Invest 2007;117(2):457e63. [90] Kim HG, Kurth I, Lan F, et al. Mutations in CHD7, encoding a chromatin-remodeling protein, cause idiopathic hypogonadotropic hypogonadism and Kallmann syndrome. Am J Hum Genet 2008;83(4):511e9. [91] Dattani MT, Martinez-Barbera JP, Thomas PQ, et al. Mutations in the homeobox gene HESX1/Hesx1 associated with septooptic dysplasia in human and mouse. Nat Genet 1998;19(2):125e33. [92] Kelberman D, Rizzoti K, Avilion A, et al. Mutations within Sox2/SOX2 are associated with abnormalities in the hypothalamo-pituitary-gonadal axis in mice and humans. J Clin Invest 2006;116(9):2442e55. [93] Machinis K, Pantel J, Netchine I, et al. Syndromic short stature in patients with a germline mutation in the LIM homeobox LHX4. Am J Hum Genet 2001;69(5):961e8. [94] Farooqi IS, Bullmore E, Keogh J, et al. Leptin regulates striatal regions and human eating behavior. Science 2007; 317(5843):1355. [95] Gianetti E, Tusset C, Noel SD, et al. TAC3/TACR3 mutations reveal preferential activation of gonadotropin-releasing hormone release by neurokinin B in neonatal life followed by reversal in adulthood. J Clin Endocrinol Metab 2010; 95(6):2857e67. [96] Topaloglu AK, Reimann F, Guclu M, et al. TAC3 and TACR3 mutations in familial hypogonadotropic hypogonadism reveal a key role for Neurokinin B in the central control of reproduction. Nat Genet 2009;41(3):354e8. [97] Quaynor SD, Bosley ME, Duckworth CG, et al. Targeted next generation sequencing approach identifies eighteen new candidate genes in normosmic hypogonadotropic hypogonadism and Kallmann syndrome. Mol Cell Endocrinol 2016; 437:86e96. [98] Layman LC, Cohen DP, Jin M, et al. Mutations in gonadotropin-releasing hormone receptor gene cause hypogonadotropic hypogonadism. Nat Genet 1998;18(1):14e5. [99] Bhagavath B, Ozata M, Ozdemir IC, et al. The prevalence of gonadotropin-releasing hormone receptor mutations in a large cohort of patients with hypogonadotropic hypogonadism. Fertil Steril 2005;84(4):951e7. [100] de Roux N, Young J, Misrahi M, et al. A family with hypogonadotropic hypogonadism and mutations in the gonadotropinreleasing hormone receptor. N Engl J Med 1997;337(22):1597e602.

Please cite this article in press as: Trofimova T, et al., Genetic basis of eugonadal and hypogonadal female reproductive disorders, Best Practice & Research Clinical Obstetrics and Gynaecology (2017), http:// dx.doi.org/10.1016/j.bpobgyn.2017.05.003