Genes predisposing to syndromic and nonsyndromic infertility: a narrative review

Background: Advanced biological techniques have helped produce more insightful findings on the genetic etiology of infertility that may lead to better management of the condition. This review provides an update on genes predisposing to syndromic and nonsyndromic infertility. Main body: The review identified 65 genes linked with infertility and infertility-related disorders. These genes regulate fertility. However, mutational loss of the functions of the genes predisposes to infertility. Twenty-three (23) genes representing 35% were linked with syndromic infertility, while 42 genes (65%) cause nonsyndromic infertility. Of the 42 nonsyndromic genes, 26 predispose to spermatogenic failure and sperm morphological abnormalities, 11 cause ovarian failures, and 5 cause sex reversal and puberty delay. Overall, 31 genes (48%) predispose to male infertility, 15 genes (23%) cause female infertility, and 19 genes (29%) predispose to both. The common feature of male infertility was spermatogenic failure and sperm morphology abnormalities, while ovarian failure has been the most frequently reported among infertile females. The mechanisms leading to these pathologies are gene-specific, which, if targeted in the affected, may lead to improved treatment. Conclusions: Mutational loss of the functions of some genes involved in the development and maintenance of fertility may predispose to syndromic or nonsyndromic infertility via gene-specific mechanisms. A treatment procedure that targets the affected gene(s) in individuals expressing infertility may lead to improved treatment.


Background
Infertility is generally defined as the inability of an organism to reproduce naturally. In humans, it is complex and defined as the failure to conceive after a year of regular and unprotected sexual intercourse [1]. Infertility affects about 48.5 million couples, representing 15% of couples worldwide [2]. Males are responsible for 20-30% of infertility, while females account for 20-35%, and the remaining is shared by both [2,3]. However, the prevalence of infertility varies worldwide, being highest in South East Asia and West Africa [4,5].
Infertility causes psychological, economic, and health burdens, resulting in trauma and stress, particularly in societies that emphasize childbearing [6]. In some parts of the world such as Africa and Asia, infertile couples, particularly women, face stigmatization, discrimination, and divorce. A variety of pathologies are suspected in infertility, which includes endocrine dysfunction, genetic abnormalities, infection and diseases, and autoimmune disorders [7,8]. These pathologies are triggered by environmental factors, including toxic substance exposure as well as lifestyles, such as delayed marriage, nutrition, obesity, stress, smoking, drug use, and alcohol consumption [9]. An in-depth understanding of these mentioned causes is necessary for the prevention and effective treatment of infertility [7]. The genetic causes, in particular, need more attention and understanding because it accounts for 15-30% of male infertility alone [10,11]. Fortunately, in the last few decades, technological innovations in biological studies have made possible more insightful findings on the genetic etiology of infertility that may lead to better treatment. This review, therefore, provides an update on genetics and pathophysiology of syndromic and nonsyndromic infertility.

Database searching and search strategy
To identify relevant papers on the topic, academic databases such as PubMed, Google Scholar, Uniport, Gene-Cards, Genetics Home Reference (GHR), and National Center for Biotechnology Information (NCBI) were searched. Key search words used include 'infertility', 'male infertility', 'female infertility', 'etiology of infertility', and 'causes of infertility'. Others are 'genetic etiology of infertility', 'gene mutations predisposing to infertility', 'syndromic and nonsyndromic infertility', and 'gene mutations causing infertility'. Each database was searched independently, after which the articles retrieved were pooled together and double citations removed.

Inclusion and exclusion criteria
Articles were included if they are available in the English language, focused on infertility, genetic etiology of infertility, and pathophysiology of infertility. Studies published before the year 2000 were excluded, except sometimes in which the information was vital. This was done to ensure up-to-date information.
A total of 133 articles were identified from all the databases, of which 120 were retained after removing duplicates ( Fig. 1). Of the 120 articles retained, 110 passed the relevance test for eligibility. From the eligibility test, 101 articles fit the study objectives and were reviewed and included in this study.

Genes predisposing to syndromic and nonsyndromic infertility
The searches identified several gene mutations linked with infertility and infertility-related disorders and syndromes. However, it is beyond this study to discuss all the genes. As such, 65 genes frequently encountered in our searches and with sufficient information were included in this study. The genes were classified into genes predisposing to syndromic infertility, genes predisposing to nonsyndromic spermatogenic failure and sperm morphology abnormalities, genes predisposing to nonsyndromic sex reversal and pubertal delay, and genes predisposing to nonsyndromic ovarian failure.

Genes predisposing to syndromic infertility
Twenty-three (23) genes, representing 35% of the total genes collected, were linked with syndromic infertility ( Table 1). The most common syndromes associated with infertility identified by this study are polycystic ovary syndrome (PCOS), Swyer syndrome, and Sertoli cell-only syndrome, respectively. Others include the congenital bilateral absence of the vas deferens (CBAVD), Wilm's tumour, fibroid, Kallmann syndrome, Frasier syndrome, Denys-Drash syndrome, and Bordet-Biedl syndrome. Most of the genes cause female infertility with features such as hypogonadotropic hypogonadism, ovarian failure, sex reversal, gonad underdevelopment, puberty delay, and menstrual disorders. Some genes also predispose to male  7q31.2 CFTR transports chloride ions into and out of cells, controlling the movement of water in tissues, which is necessary for the production of mucus that lubricates and protects the lining of the airways, digestive system, reproductive system, and other organs and tissues [12].
It causes CBAVD, which causes a disconnection between the epididymis and the ejaculatory duct, leading to obstructive azoospermia [13]. Also causes cystic fibrosis (CF), which is associated with menstrual irregularities, including amenorrhea, irregular cycles, and anovulation [15].
NR5A1 (nuclear receptor subfamily 5 group A member 1) 9q33.3 NR5A1 produces a transcription factor called the steroidogenic factor 1 (SF1), which helps control the activity of several genes related to the development of ovaries and testes, particularly the production of sex hormones and sexual differentiation [16].
Predisposes to Swyer syndrome, which disrupts sexual differentiation and prevents affected 46, XY male from developing testes and causing them to develop a uterus and fallopian tubes [16]. Because of the lack of development of the gonads, Swyer syndrome is also called 46, XY complete gonadal dysgenesis. In females, mutations in the gene cause several ovarian anomalies, including 46, XX gonadal dysgenesis [16].
The gene is a transcription factor that is expressed in the kidneys, ovaries, and testes [20] and functions in gonadogenesis. Particularly, it plays an active role in ovarian follicle development [21] and spermatogenesis [22].
The +2, T → G mutation causes Wilms' tumor, characterized by congenital male genitourinary malformation [23]. R362Q and K386R missense mutations cause loss of function of the WT1 protein, resulting in non-obstructive azoospermia [22]. The p. Pro126Ser and p. Arg370His missense mutations cause premature ovarian follicles (POF) [25]. Some mutations also cause Frasier syndrome and Denys-Drash syndrome, both of which often affect the male kidney and genitalia development [20].
FMR1 (fragile X mental retardation 1) Xq27. 3 The FMR1 encodes a protein called FMRP, which is expressed in the brain, testes, and ovaries. FMR1 transmits nerve impulses in the brain. In the cell, it transports mRNA from the nucleus to the sites where proteins are assembled, some of which are necessary for the functioning of the nerves, testes, and ovaries [26].
A region of the gene contains a CGG trinucleotide repeat of less than 10 to about 40. However, the FMR1 mutation has been reported in which the CGG was abnormally repeated from 200 to more than 1000 times [26].
Abnormal CGG expansion causes instability in the region, deactivating the gene and making little or no protein, resulting in a condition called fragile X syndrome characterized mainly by mental retardation [26]. CGG elongation between 55 and 200 repeats causes POF [27] and fragile X-associated primary ovarian insufficiency (FXPOI) [26]. FXPOI is characterized by irregular menstrual cycles, early menopause, and elevated levels of folliclestimulating hormone (FSH) [26].
9p13. 3 The gene synthesizes galactose-1phosphate uridylyltransferase, which converts galactose obtained from food into glucose, the main fuel for all cellular activities. This chemical reaction also produces an active form of galactose known as UDP-galactose, which is used to build galactose-containing proteins and fats, both which are involved in energy production, chemical signaling, cell structure building, and molecule transport [28].
The SNP called Gln188Arg or Q188R is prevalent among white Europeans and North Americans [28]. Another SNP called Ser135Leu or S135L are found mostly among the African descent [28]. The SNP named Asn314Asp or N314D was also reported [28].
It represses or stops the activity of the galactose-1-phosphate uridylyltransferase, preventing cells from converting galactose into glucose. Consequently, galactose-1-phosphate and related compounds build up to toxic levels in the body, damaging tissues and organs, and leading to a condition known as galactosemia [28]. Women with galactosemia express hypergonadotropic hypogonadism and secondary amenorrhea [29], as well as ovarian failure [30].
MED12 (mediator complex subunit 12) Xq13. 1 The MED12 gene codes for a protein called mediator complex subunit 12, which regulates gene activity by linking transcription factors with an enzyme called RNA polymerase II. The MED12 protein is involved in several chemical signaling pathways that control many cellular activities, such as cell growth, cell movement, and cell differentiation [34].
Several somatic mutations in the MED12 gene have been reported [34].
It causes uterine leiomyomas, which are noncancerous growths also known as uterine fibroids. Uterine leiomyomas are common among adult women and cause pelvic pain, abnormal bleeding, and, in some cases, infertility [34]. MED12 mutations produce nonfunctional protein, which disrupts normal cell signaling and impairs regulation of cell growth and other cell functions. As a result, certain cells divide uncontrollably, leading to the growth of a tumor [34].
Xp22. 31 The gene encodes a protein called anosmin-1, which is involved in embryonic development. Anosmin-1 is expressed in the brain and involved in the migration of neurons that produce gonadotropin-releasing hormone (GnRH), which controls the production of several hormones that direct sexual development before birth and during puberty, such as the ovaries and testes functions [35].
Mutations that delete a part or the entire gene, as well as SNPs that alter or change amino acids in anosmin-1, have been reported [35], among which is c.1267C>T [36].
Alters the synthesis or function of anosmin-1 during embryonic development, resulting in the loss of sense of smell and the production of sex hormone, respectively, and the latter interferes with normal sexual development causing absence or delay of puberty [35]. Mutations in the gene also predispose to Kallmann syndrome, a disorder characterized by hypogonadotropic hypogonadism [35]. Males expressing hypogonadotropic hypogonadism often have an unusually small penis (micropenis), undescended testes, and lack of secondary sex characteristic, while females fail to menstruate and develop breast [35].
LEP (leptin) 7q32. 1 The gene codes for leptin, which is a hormone that takes part in body weight regulation [37], metabolism, and puberty [38], as well as cell signaling that regulates sex development hormones [37].
Complete deletion of the gene has been reported in infertile humans and rats [38]. A SNP named rs10244329 was also reported [39].
Causes congenital leptin deficiency, a disorder that causes the absence of leptin, resulting in the loss of signaling that triggers feelings of satiety, leading to excessive hunger and weight gain, reduced production of hormones that direct sexual development, and ultimately ending in hypogonadotropic hypogonadism [37].
LEPR (leptin receptor) 1p31. 3 The gene synthesizes a protein called leptin receptor, which is embedded in many tissues, including the hypothalamus, and helps regulate body weight by providing binding sites for leptin [40].
At least 18 LEPR gene mutations have been reported [40].
Results in less receptor protein reaching the cell surface, causing a condition called leptin receptor deficiency, which reduces LEPR protein binding and signaling activities as well as satiety, resulting in excessive hunger and weight and reduced sex hormones, culminating in hypogonadotropic hypogonadism [40].
NR0B1 (nuclear receptor subfamily 0 group B member 1)/ AHC (adrenal hypoplasia congenital) Xp21. 2 The NR0B1 gene codes for a transcription factor called DAX1, which is involved in the development and function of several hormone-producing (endocrine) tissues, including the adrenal glands, hypothalamus, pituitary gland, as well as the ovaries and testes [41].
Complete and partial deletions of the gene have been reported [41]. Abnormally short versions of the DAX1 protein as well as SNPs have also been reported [41].
Produces inactive DAX1 protein, disrupting normal development and function of hormone-producing tissues, particularly the adrenal glands, hypothalamus, pituitary, and gonads, resulting in a condition called Xlinked adrenal hypoplasia congenital [41], characterized by male puberty delay [38]. Mutations in this gene also cause Swyer syndrome [41].
3p14. 3 The HESX1 gene encodes a transcription factor that regulates the early embryonic development of several body structures, particularly the pituitary SNPs as well as insertion and deletion mutations have been reported in this gene [42].
Alters the function of the HESX1 protein and represses the activity of other genes, disrupting the formation and early development of the   [42]. pituitary gland, optic nerves, and other brain structures, resulting in gonadotropin deficiency and a condition known as septo-optic dysplasia [42]. Septo-optic dysplasia is characterized by hypogonadotropic hypogonadism [38].
LHβ (luteinizing hormone beta-subunit) 19q13.33 It encodes the beta subunit of luteinizing hormone (LH), which is expressed in the pituitary gland and promotes spermatogenesis and ovulation by stimulating the testes and ovaries to synthesize steroids [43].
Causes defective LH, leading to low testosterone and gonadotropins, culminating in pubertal delay, bilaterally small descended testes, and infertility [38]. Also increases susceptibility to PCOS, characterized by pubertal delay [38].
2p16. 3 The gene synthesizes the luteinizing hormone/chorionic gonadotropin receptor which is a receptor for luteinizing hormone and chorionic gonadotropin. In males, chorionic gonadotropin stimulates the development of Leydig cells in the testis, which are also stimulated by luteinizing hormone to produce androgens, such as testosterone that controls male sexual development and reproduction. In females, luteinizing hormone triggers ovulation, while chorionic gonadotropins ensure normal progression of pregnancy [46].
Impairs the development of LHCGR protein, preventing chorionic gonadotropin binding, and resulting in the absence, or poorly developed Leydig cells, a condition called Leydig cell hypoplasia, characterized by low testosterone, which interferes with male sexual development before and after birth [46]. Extreme Leydig cell hypoplasia causes 46, XY male to develop female external genitalia and small undescended testes [46]. Mild Leydig cell hypoplasia results in an external genital that is not clearly male or female [46]. Mutations in the gene also cause polycystic ovary syndrome (POS) [46].

AR (androgen receptor) Xq12
The AR gene produces an androgen receptor, which is expressed in many tissues, where it binds to androgen to form an androgen-receptor complex, which in turn binds to DNA and regulates the activity of certain genes involved in male sexual development [47].
Abnormal elongation of a DNA segment in the AR gene known as CAG, which is normally repeated between less than 10 and 36, has been reported [47]. Some SNPs, as well as deletions and insertions, were also reported [47].
Results in the receptors that are unable to bind androgens or DNA, causing androgen insensitivity syndrome (AIS), a condition that causes male sexual dysfunction before birth and at puberty. The condition also causes 46, XY male sex reversal also known as gonadal dysgenesis [47]. Mutations in the gene also cause polycystic ovary syndrome [47].
Yp11. 2 The gene encodes a transcription factor called the sex-determining region Y protein, which is located on the Y chromosome and regulates genes involved in male sexual activities, directing a fetus to develop testes and preventing uterus and fallopian tube formation [48].
Absence and rearrangement that wrongly placed the gene on the X chromosome have been reported [48].
Prevents production of SRY protein or hampers it, resulting in Swyer syndrome, characterized by 46, XY male sex reversal [48]. Sometimes the mutation may misplace the gene on the X chromosome from the father, causing 46, XX female to develop both ovarian and testicular tissues, a condition called ovotesticular disorder [48].
12q13. 11 The gene is expressed in male and female reproductive tissues [49] and synthesizes a protein called vitamin D receptor, which forms a complex with an active form of vitamin D, known as calcitriol, and another protein called retinoid X receptor, which then binds to particular regions of DNA, where it regulates the activity of some genes that control several processes, particularly calcium and phosphate absorption [50]. In mice, VDR signaling plays a role in folliculogenesis and fertility [51].
Reduces follicle number, resulting in PCOS [51,52] or endometriosisassociated infertility [53]. VDR knockout in female mice disrupts VDR signaling and ovarian response to stimulation, causing defective folliculogenesis and infertility [51]. Male mice deficient of VDR showed gonadal insufficiency and decreased sperm count and motility as well as histological abnormalities of the testis [49].
6p21. 3 The gene encodes FKBP52, which plays an important role in potentiating Deletions and two SNPs, known as rs2968909 and rs4409904, were reported Causes azoospermia [54] as well as implantation failure and recurrent infertility with phenotypic presentations, including hypogonadotropic hypogonadism, sex reversal, puberty delay or absence, gonad underdevelopment, and spermatogenic failure.
Genes predisposing to nonsyndromic spermatogenic failure and sperm morphology abnormalities Twenty-six (26) genes, representing 40% of the total genes collected, predispose to nonsyndromic spermatogenic failure and sperm morphology abnormalities ( Table 2). Most often, mutations in the genes cause meiotic arrest, resulting in acrosome malformation or absence, ultimately ending in sperm head abnormalities such as azoospermia, globozoospermia, oligospermia, and oligozoospermia. In some cases, the meiotic arrest may result in polyploidy spermatozoa, characterized by an enlarged sperm cell head called macrozoospermia. A meiotic arrest may also decrease sperm motility and hyperactivation needed to push spermatozoa through the uterus. Sometimes, mutations in the genes may cause chromatin damage or DNA fragmentation, disrupting spermatogenesis and causing sperm cell structural defects and loss.
Genes predisposing to nonsyndromic sex reversal and pubertal delay Five (5) of the genes collected, representing 7.69% of the total genes, predispose to sex reversal and puberty delay or absence (Table 3). Most mutations in the genes cause reduced circulating levels of gonadotropins and testosterone, resulting in hypogonadotropic hypogonadism, characterized by the absence or incomplete sexual maturation. Mutations in the genes may also cause complete or partial gonadal dysgenesis, characterized by underdeveloped or presence of both gonads.
Genes predisposing to nonsyndromic ovarian failure Eleven (11) of the genes collected, representing 16.92% of the total genes, predispose to nonsyndromic ovarian failure (Table 4). Some mutations in the genes may reduce the sensitivity of fully grown immature oocytes to progestin hormone, resulting in a reduced number of  [54]. [55]. pregnancy [56]. Also predisposes to PCOS [55].
Yq11. 21 The gene resides in the AZFa region on the Y chromosome and is expressed in many tissues, but mostly in the spermatogonia of the testis tissue and translated only in the male germline [57].
USP9Y (ubiquitin specific peptidase 9 Ylinked) Yq11.221 USP9Y resides in the azoospermia factor a (AZFa) region of the Y chromosome and encodes an enzyme called ubiquitin-specific peptidase 9, Y-linked, which is necessary for sperm production [58].
AZFa deletions resulting in complete loss of USP9Y have been reported [59].
PLK4 (Polo-like kinase 4) 4q28.1 PLK4 protein resides in the centrioles and plays an active role in centriolar duplication that is necessary for normal cell division [60,61].
A heterozygous mutation called p.Ile242Asn was observed in mice [62]. A heterozygous 13 bp deletion called c.201_213delGAAACATCCTTCT was also reported [62].
Causes mitotic error in mice, resulting in patchy germ cell loss in the testes similar to the human Sertoli cell-only syndrome (SCOS) [62,63].
The specific role of the protein released by this gene has not been determined [64].
FSHR (folliclestimulating hormone receptor) 2p16. 3 The gene secretes a receptor for the follicle-stimulating hormone, which functions in the ovary and testis development [66].
A SNP in exon 7 named C566T and involving Ala to Val substitution at residue 189 was reported by Aittomäk [67].  3q26. 32 The gene is expressed mainly in the Golgi apparatus of the cells of testis [69] and actively involved in the formation of sperm acrosome, which plays a role in spermatogenesis and fusion of sperms and eggs [70].
Causes acrosome malformation which can be absent in severe cases, resulting in sperm head abnormality characterized by round-headed sperms known as globozoospermia [71]. Also predisposes spermatogenic failure 6 (SPGF6), an infertility disorder caused by spermatogenesis defects [70].
AURKC (aurora kinase C) 19q13. 43 The AURKC codes for a protein called aurora kinase, which helps dividing cells separate from each other and ensures the accurate distribution of genetic materials (chromosomes). Aurora kinase C is most abundant in male testes, where it regulates the division of sperm cells, ensuring that every new sperm cell divides accurately and contains one copy of each chromosome [72].
A homozygous deletion called c. 144delC and frequently found among North African descent was reported [72].
Produces a nonfunctional aurora kinase C or a protein that breaks down quickly, preventing sperm cell division. Consequently, the sperm cells carry extra chromosomes (polyploidy spermatozoa), usually four copies of each instead of the usual one. The increase in chromosome number enlarges the sperm cell head and leads to the presence of multiple tails (flagella), a condition called macrozoospermia. The additional genetic materials may prevent any of the sperm cells from fusing with an egg or may result in miscarriage [72].
CATSPER (cation channel sperm associated 1) 11q13. 1 The gene encodes a protein localized in the tail of sperm cells and transport calcium cations into the cells for normal sperm motility and a type of sperm cell motility called hyperactivation, which is a rigorous movement necessary to push the sperm cells through the cell membrane of the egg cell during fertilization [73].
Alters or malfunctions CATSPER1 protein or produces a protein that is degraded quickly by the cell. This impairs calcium entry into the sperm cell, decreasing the motility and preventing hyperactivation, ultimately resulting in CATSPER1-related non-syndromic male infertility. Affected men may also produce a smaller than the usual number of sperm cells or sperm cells that are abnormally shaped [73].

MTHFR (methylenetetrahydrofolatereductase)
1p36. 22 The MTHFR gene synthesizes an enzyme called methylenetetrahydrofolate reductase, which converts a form of folate called 5, 10methylenetetrahydrofolate to an another form called 5methyltetrahydrofolate. The latter is the primary form of folate in the blood, where it helps converts the amino acid homocysteine to another amino acid called methionine. The body uses methionine to make proteins and other important compound as well as vital in DNA methylation and spermatogenesis [75,76].
A SNP named 677C/T and involving the substitution of an alanine for a valine is the most common in infertile men with MTHFR deficiency [13]. The second mutation involved an A to C transition at nucleotide 1298 (A1298C), resulting in glutamate to alanine substitution in the MTHFR protein [77].
Loss of MTHFR decreases the activity of its enzyme, disrupting folic acid metabolism, resulting in DNA hypo-methylation, ultimately ending in the absence of germinal cells and spermatogenesis arrest [13,75,78].
SYCP3 (synaptonemal complex protein 3) 12q23.2 SYCP3 is embedded in the testis and encoded an essential structural component of the synaptonemal complex, which is involved in synapsis, recombination, and segregation of meiotic chromosomes [79].
A heterozygous deletion called 643delA, and a heterozygous genetic change known as T657C was identified among Iranian women with recurrent pregnancy losses [17].
Causes early meiotic arrest, disrupting the spermatogenic process in males [17], resulting in spermatogenic failure 4 (SPGF4), a disorder characterized by azoospermia. In females, early meiotic arrest  Table 2 Genes predisposing to nonsyndromic spermatogenic failure and sperm morphological abnormalities (Continued) The gene ensures centromere pairing during meiosis in male germ cells, thus important for normal spermatogenesis [80].
HSF2 (heat-shock transcription factor 2) 6q22.31 HSF2 is expressed in the testis and encodes heat-shock transcription factor 2, which binds specifically to the heat-shock promoter element to activate heat-shock response genes under conditions of heat or other stresses [81].
SYCP2 (synaptonemal complex protein 2) 20q13. 33 The gene codes for a major component of the synaptonemal complex, which is required for normal meiotic chromosome synapsis during oocyte and spermatocyte development and for normal male and female fertility [84].
Heterozygous frameshift mutation and deletion have been reported in the gene [85].
A-MYB/MYBL1 (myeloblastosis oncogene-like 1) 8q13.1 MYBL1 protein is a male-specific master regulator of meiotic genes that are involved in multiple processes in spermatocytes, particularly processes involved in cell cycle progression through pachynema [87].
A variant named repro9 involving a C to A transversion at nucleotide 893 of the MYBL1 mRNA was reported [87]. MYBL1−/−, showing meiotic arrest similar to repro9, has also been reported [87].
Causes meiotic arrest in spermatocytes, characterized by defects in autosome synapsis in pachynema, unsynapsed sex chromosomes, incomplete double-strand break repair on synapsed pachytene chromosomes and a lack of crossing over [87].
TEX11 (testis expressed 11) Xq13.1 TEX11 protein is required for spermatogenesis; particularly certain levels of the protein are required for meiotic progression. The protein is also necessary for normal genomewide meiotic recombination rates in both sexes [88].
Frameshift mutations were observed, so also missense mutations, particularly a missense mutation tagged V748A was observed among transgenic mice [88].
KIT (v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog) 4q12 The gene is embedded in the reproductive cells and encoded receptor tyrosine kinases, which is involved in signal transduction. The protein takes part in phosphorylation that activates a series of proteins in multiple signaling pathways, which are necessary for normal cell growth, proliferation, survival, and movement in the reproductive cells and certain other cell types [90].
A SNP in which Asp-816 is replaced with a Val or His residue at exon 17 has been reported [91].
ADGRG2 (adhesion G proteincoupled receptor G2) Xp22.13 This gene encodes an epididymis-specific transmembrane protein, which is involved in a signal transduction pathway controlling epididymal function and male fertility. May particularly regulate fluid exchange within the epididymis [92].
Predisposes to congenital bilateral aplasia of the vas deferens, X-linked (CBAVDX), a disease characterized by bilateral absence of vas deferens and obstructive azoospermia [92].
FKBP6 (FKBP prolylisomerase 6) 7q11. 23 Encodes a protein that functions in immunoregulation, homologous chromosome pairing in meiosis during spermatogenesis and cellular Deletion in the exon 8 of the gene has been reported [95].
PRM1 (protamine 1) 16p13.13 It encodes a protein called protamine 1, which replaces histone during developmental stages of elongating spermatids and compact sperm DNA into a highly condensed, stable, and inactive complex to ensure that quality spermatozoa are produced and as well protect spermatozoa from the degrading effects of free radicals [97].
A c.102G>T transversion that results in the SNP named p.Arg34Ser, a missense mutation named c.119G>A (p.Cys40Tyr), a heterozygous mutation named c.-107G>C, and a variant named c.*51G>C have been reported [98].
Causes chromatin damage and DNA breaks, resulting in sperm structural defects, reduced motility, and defective spermatogenesis due to haploinsufficiency [100].

TNP1 (nuclear transition protein 1) 2q35
The gene encodes nuclear proteins, which replace nuclear histones and in turn substituted by protamine 1 and 2 during spermatogenesis [101].
A SNP named g.IVS1+75T>C was reported by Heidan et al [102]. A deletion of 15 nucleotides in the 5′-promoter region of the gene was also reported [101].
Disrupts the highly condensed structure of the sperm nuclear chromatin, resulting in abnormal spermatogenesis [102]. Also causes varicocele, due to the failure of ipsilateral testicular growth and development [102].
TNP2 (nuclear transition protein 2) 16p13.13 TNP2 participates in the removal of the nucleohistones and in the initial condensation of the spermatid nucleus, thus contributes to the dense packing of spermatid chromatin during spermatogenesis [103].
TNP2−/− in mice affects sperm chromatin structure, causing sperm head abnormalities, acrosome abnormalities in which the acrosomes do not attach to the nuclear envelope, and reduced sperm motility, resulting in tetrazoospermia [103].
DAZ1 (deleted in azoospermia 1) Yq11. 223 The gene encodes azoospermia protein 1, which is necessary for spermatogenesis. It binds to the 3′-UTR of mRNAs, regulating their translation, and promoting germ cell progression to meiosis and the formation of haploid germ cells [104].
XRCC2 (X-ray repair cross complementing 2) 7q36.1 XRCC2 protein was shown in mice to be required for genetic stability, embryonic neurogenesis and viability [107].
A SNP in the gene involving c.41T>C substitution was reported [108].
CCDC62 (coiled-coil domain containing 62) 12q24.31 Encodes a nuclear receptor coactivator that enhances estrogen receptor transactivation [109]. The gene is expressed in the acrosome of developing spermatids and mature sperms, showing that it is necessary for spermatogenesis [110].
A nonsense mutation in the exon 6, which results in the formation of a premature stop codon and a truncated protein, was reported by Li et al. [110].
Disrupts CATSPER channel signaling, which affects sperm motility [111]. oocytes undergoing meiotic maturation. Mutations in the genes may also cause ovarian dysgenesis, characterized by absence or puberty delay, primary amenorrhea, uterine hypoplasia, and hypogonadotropic hypogonadism. Some mutations prevent the formation of primordial follicles, resulting in reduced oocyte numbers after birth.
In summary, 23 genes, representing 35%, were linked with syndromic infertility, while 42 genes, accounting for 65% cause nonsyndromic infertility. Of the 42 nonsyndromic genes, 26 predispose to spermatogenic failure and sperm morphology abnormalities, 11 cause ovarian failures, and 5 cause sex reversal and puberty delay. Overall, 31 genes (48%) predispose to male infertility, 15 genes (23%) cause female infertility, and 19 genes (29%) predispose to both. The common features of male infertility were spermatogenic failure and sperm morphology abnormalities, while ovarian failure has been the most frequently reported among infertile females. This analysis infers that male genetic infertility was more prevalent than female, with spermatogenic failure and sperm morphology abnormalities being most prevalent.

Genetic testing for infertility disorders
Knowing the exact cause of infertility allows for better diagnostic decisions and enables enhanced counseling for parents with regard to risks to their children. For this reason, when there is a means, testing of embryos should be recommended for a family with a history of genetic infertility disorders discussed above. Moreover, every healthy-looking individual is a carrier of between 5 to 8 recessive genetic disorders; so the test should be Table 2 Genes predisposing to nonsyndromic spermatogenic failure and sperm morphological abnormalities (Continued) KLHL10 (Kelch-like family member 10) 17q21 KLHL10 encodes a germ cellspecific protein essential for spermatogenesis [63].
SEPT12 (septin 12) 16p13. 3 The gene codes for septin 12, which is expressed exclusively in the testis and involved in spermatogenesis, especially morphogenesis of sperm heads and the elongation of sperm tails [63].
Disrupts the structural integrity of sperm by perturbing septin filament formation, causing various sperm abnormalities, including immotility, bent tails, acrosome breakage, round heads, and significant spermatozoa DNA damage, as well as oligoasthenozoosperm and asthenoteratozoospermia [63,113].
ZMYND15 (zinc finger myndcontaining protein 15) 17p22.1 ZMYND15 codes for a transcription repressor, which in mice is expressed exclusively in the haploid germ cells, particularly during late spermatogenesis [116].
A mutation in exon 9 of the gene named p.K507Sfs*3 was reported by Ayhan et al. [115].
NANOS1 (nanos C2HC-type zinc finger 1) 10q26.11 This gene encodes a CCHC-type zinc finger protein that is specifically expressed in the germ cells of adult men and regulates the translation by acting as a post-transcriptional repressor [118].
Two deletion mutations called p.Pro77_Ser78delinsPro and p.Ala173del have been reported [119].
GALNTL5 (polypeptide Nacetylgalactosaminyltransferase Like 5) 7q36.1 GALNTL5 encodes an inactive protein, which is expressed in the testis and is required during spermatid development in which it participates in protein loading into the acrosomes [121].
Heterozygous single nucleotide deletion of maternal inheritance was reported [63,122].
Decreases glycolytic enzymes, which disrupts protein loading into acrosomes, resulting in asthenozoospermia and poor sperm motility [122]. extended to everyone who has the means [157]. It is specifically recommended for embryos of couples who are recessive for a gene infertility disorder.
The conventional method used in genetic testing of embryos is the whole sequence amplification. After fertilization, the embryo undergoes mitotic divisions for 5 to 7 days, ending with the development of the blastocyst stage. A biopsy of some blastocysts is done, after which a whole genome amplification of the cells is conducted, usually using polymerase chain reaction [157,158]. This technique is laborious, time-consuming, and expensive, so recently, a new technique known as the next-generation sequencing is being used for testing genetic disorders in infertile couples and embryos [159]. The protocol is based on an enlarged panel of diseaseassociated genes (approximately 5000 genes). The large panel of marker genes allows the identifications of a large number of target and non-target genes [157]. However, the technique has some limitations too, which is its inability to detect haploidies, polyploidies, and mosaicisms [157].

Conclusion
Several studies reviewed showed that certain genes embedded in the hypothalamus, pituitary gland, gonads, and gonadal outflow regulate fertility in both males and females. However, mutational inactivation of these genes may cause syndromic or nonsyndromic infertility. The common features of male infertility include spermatogenic failure, resulting in azoospermia, oligospermia, and chromosome structural abnormalities. Most females express ovarian failure, resulting in menstrual dysfunction p. Arg139His [124].
Causes low levels of circulating gonadotropins and testosterone, resulting in hypogonadotropic hypogonadism 7 (HH7), a disorder characterized by absent or incomplete sexual maturation by the age of 18 years [125].
5q35. 3 The gene produces a transcription factor embedded only in the pituitary gland and releases hormones for growth, reproduction, and cell differentiation in the pituitary gland [126].
At least 25 mutations had been reported, the most common of which deletes two amino acids, written as 301-302delAG [126].
Reduces pituitary cell differentiation and prevents the release of hormones from the pituitary gland, causing a condition called combined pituitary hormone deficiency, with features like short stature and delayed or absent puberty [126].

DMRT1
(doublesex-and MAB3-related transcription factor 1) 9p24. 3 The gene encodes a transcription factor expressed in the testis and involved in male sex determination and differentiation before and after birth by promoting male-specific genes and repressing female-specific genes. May also play a minor role in oogenesis [127].
Deletions in the gene had been reported [127].
Predisposes to male-to-female sex reversal in the presence of a normal 46, XY karyotype, referred to as 46, XY sex reversal 4 (SRXY4), characterized by complete or partial gonadal dysgenesis. The mutation may also cause testicular germ cell tumors [127].
SOX3 (SRY-box transcription factor 3) Xq27. 1 The gene codes for a transcription factor embedded in the hypothalamus and pituitary gland where it regulates neuronal development and differentiation, and as well promote male sex development [128].
Copy number variations including two duplications of about 123 kb and 85 kb, a 343 kb deletion immediately upstream of SOX3, and a large duplication of approximately 6 Mb that encompasses SOX3 have been reported [128].
1p34.3 Produces a protein that is essential in ovary determination through regulation of Wnt signaling [129].
c.286+1G>A [130]. Causes oocytes depletion and masculinized ovaries, resulting in XX true hermaphroditism, also known as an ovotesticular disorder of sexual development, a disorder of gonadal development characterized by the presence of both ovarian and testicular tissue in 46, XX individuals [130].  FIGLA knockout in female mice prevents formation of primordial follicles, and oocyte numbers drop rapidly after birth [135]. May also cause haploinsufficiency, predisposing to premature ovarian failure 6 (POF6), an ovarian disorder defined as the cessation of ovarian function under the age of 40 years and is characterized by oligomenorrhea or amenorrhea, in the presence of elevated levels of serum gonadotropins and low estradiol [134,136].
NOBOX encodes a transcriptional regulator with a homeobox motif and is important for early folliculogenesis [137].
Missense mutations in the homeobox domain were observed in infertile Caucasian or African descent [138].
SALL4 (SAL-like 4) 20q13. 2 The gene is expressed in the testis and oocytes and secretes putative zinc finger transcription factor that plays a role in the pluripotency of oocytes and maintenance of undifferentiated spermatogonia [38,140].
FSHβ (folliclestimulating hormone subunit beta) 11p14.1 This gene encodes the beta subunit of the follicle-stimulating hormone which in association with luteinizing hormone induces egg and sperm production [38,142].
Causes low FSH and estradiol, and high LH among females, resulting in the absence or incomplete breast development and sterility [143]. Males produce low androgen, leading to low testosterone and azoospermia, but puberty may be normal or absent [38].
HCGβ (human chorionic gonadotrophin) 19q13.3 HCGβ encodes a hormone called HCG which is secreted mainly by the placenta and is important for normal progression of pregnancy by maintaining the production of steroid hormones and other growth factors in the corpus luteum [144].
Causes low levels of HCG during the first trimester of pregnancy, resulting in miscarriage and ectopic pregnancy [146]. and pregnancy loss. Males and females may also express sex reversal, pubertal delay or absence, and genital abnormalities such as micro-penis and absence of the breast. Male genetic infertility was more prevalent than female, with spermatogenic failure and sperm morphology abnormalities being most prevalent. The mechanisms leading to these pathologies are gene-specific, which, if targeted in the affected, may lead to improved treatment. Medical practitioners are advised to target these genes in the affected.  13q13. 3 The SOHLH2 is expressed specifically in spermatogonia and oocytes and is required for early spermatogonial and oocyte differentiation [149]. SOHLH2 is a transcription regulator of both male and female germline differentiation and together with SOHLH1 regulates oocyte growth and differentiation [150].

SOHLH1
At least 11 mutant variants of SOHLH2 gene have been reported [151]. In particular, two variants, named rs6563386 and rs1328626, were reported by Song et al. [152].
SOHLH2 knockout causes defects in spermatogenesis and oogenesis similar to those in SOHLH1-null mice [149]. May also predispose to PO [151]. Some mutant variants may increase the risk of nonobstructive azoospermia [152], as well as the small testis and testicular atrophy [153].

Xq24
The gene codes for progestin receptor membrane component 1, which associates with and transports a wide range of molecules, including steroids, and the gene has been demonstrated in zebrafish to function in oocyte maturation and meiosis resumption [154].
PGRMC1 knockout in zebrafish reduces both spawning frequency and the number of embryos produced by females. It also reduces the sensitivity of fully grown immature oocytes to progestin hormone, resulting in a reduced number of oocytes undergoing meiotic maturation [154].
Causes estrogen resistance, resulting in absence of pubertal growth and endometriosis-related infertility [155].
HES1 (Hes family bHLH transcription factor 1) 3q29 Hes is expressed in the ovary and encodes transcriptional factors necessary for oocyte survival and maturation [156].