Genes predisposing to syndromic and nonsyndromic infertility: a narrative review
Tajudeen O. Yahaya, Usman U. Liman, Haliru Abdullahi, Yahuza S. Koko, Samuel S. Ribah, Zulkarnain Adamu, Suleiman Abubakar
RR E V I E W Open Access
Genes predisposing to syndromic andnonsyndromic infertility: a narrative review
Tajudeen O. Yahaya , Usman U. Liman , Haliru Abdullahi , Yahuza S. Koko , Samuel S. Ribah ,Zulkarnain Adamu and Suleiman Abubakar Abstract
Background:
Advanced biological techniques have helped produce more insightful findings on the geneticetiology of infertility that may lead to better management of the condition. This review provides an update ongenes predisposing to syndromic and nonsyndromic infertility.
Main body:
The review identified 65 genes linked with infertility and infertility-related disorders. These genesregulate 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, 11cause ovarian failures, and 5 cause sex reversal and puberty delay. Overall, 31 genes (48%) predispose to maleinfertility, 15 genes (23%) cause female infertility, and 19 genes (29%) predispose to both. The common feature ofmale infertility was spermatogenic failure and sperm morphology abnormalities, while ovarian failure has been themost 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 offertility may predispose to syndromic or nonsyndromic infertility via gene-specific mechanisms. A treatmentprocedure that targets the affected gene(s) in individuals expressing infertility may lead to improved treatment.
Keywords:
Genes, Infertility, Mutation, Ovarian Failure, Syndrome
Background
Infertility is generally defined as the inability of an organ-ism to reproduce naturally. In humans, it is complex anddefined as the failure to conceive after a year of regularand unprotected sexual intercourse [1]. Infertility affectsabout 48.5 million couples, representing 15% of couplesworldwide [2]. Males are responsible for 20 –
30% of infer-tility, while females account for 20 – © The Author(s). 2020 Open Access
This article is licensed under a Creative Commons Attribution 4.0 International License,which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you giveappropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate ifchanges were made. The images or other third party material in this article are included in the article's Creative Commonslicence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commonslicence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtainpermission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. * Correspondence: [email protected]; [email protected] Department of Biolog, Federal University Birnin-Kebbi, PMB 1157,Birnin-Kebbi, NigeriaFull list of author information is available at the end of the article
Egyptian Journal of MedicalHuman Genetics
Yahaya et al. Egyptian Journal of Medical Human Genetics (2020) 21:46(2020) 21:46
Yahaya et al. Egyptian Journal of Medical Human Genetics (2020) 21:46(2020) 21:46 https://doi.org/10.1186/s43042-020-00088-y ccounts for 15 –
30% of male infertility alone [10, 11].Fortunately, in the last few decades, technological inno-vations in biological studies have made possible moreinsightful findings on the genetic etiology of infertilitythat may lead to better treatment. This review, therefore,provides an update on genetics and pathophysiology ofsyndromic and nonsyndromic infertility.
Main text
Database searching and search strategy
To identify relevant papers on the topic, academic data-bases such as PubMed, Google Scholar, Uniport, Gene-Cards, Genetics Home Reference (GHR), and NationalCenter for Biotechnology Information (NCBI) weresearched. Key search words used include ‘ infertility ’ , ‘ male infertility ’ , ‘ female infertility ’ , ‘ etiology of infertility ’ ,and ‘ causes of infertility ’ . Others are ‘ genetic etiology ofinfertility ’ , ‘ gene mutations predisposing to infertility ’ , ‘ syndromic and nonsyndromic infertility ’ , and ‘ gene mu-tations causing infertility ’ . Each database was searchedindependently, after which the articles retrieved werepooled together and double citations removed. Inclusion and exclusion criteria
Articles were included if they are available in the Englishlanguage, focused on infertility, genetic etiology of infer-tility, and pathophysiology of infertility. Studies pub-lished before the year 2000 were excluded, exceptsometimes in which the information was vital. This wasdone to ensure up-to-date information.A total of 133 articles were identified from all the da-tabases, of which 120 were retained after removing du-plicates (Fig. 1). Of the 120 articles retained, 110 passedthe relevance test for eligibility. From the eligibility test,101 articles fit the study objectives and were reviewedand included in this study.
Genes predisposing to syndromic and nonsyndromicinfertility
The searches identified several gene mutations linkedwith infertility and infertility-related disorders and syn-dromes. However, it is beyond this study to discuss allthe genes. As such, 65 genes frequently encountered inour searches and with sufficient information were in-cluded in this study. The genes were classified into genespredisposing to syndromic infertility, genes predisposingto nonsyndromic spermatogenic failure and spermmorphology abnormalities, genes predisposing to non-syndromic sex reversal and pubertal delay, and genespredisposing to nonsyndromic ovarian failure.
Genes predisposing to syndromic infertility
Twenty-three (23) genes, representing 35% of thetotal genes collected, were linked with syndromic infertility (Table 1). The most common syndromes as-sociated with infertility identified by this study arepolycystic ovary syndrome (PCOS), Swyer syndrome,and Sertoli cell-only syndrome, respectively. Othersinclude the congenital bilateral absence of the vasdeferens (CBAVD), Wilm ’ s tumour, fibroid, Kallmannsyndrome, Frasier syndrome, Denys-Drash syndrome,and Bordet-Biedl syndrome. Most of the genes causefemale infertility with features such as hypogonado-tropic hypogonadism, ovarian failure, sex reversal,gonad underdevelopment, puberty delay, and men-strual disorders. Some genes also predispose to male Fig. 1
Article selection flow diagram
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Genes predisposing to syndromic infertility
Gene Locus Biological functions Some mutations reported Pathophysiology/disorders
CFTR (cystic fibrosistransmembraneconductance regulator) 7q31.2
CFTR transports chloride ions into andout of cells, controlling the movementof water in tissues, which is necessaryfor the production of mucus thatlubricates and protects the lining of theairways, digestive system, reproductivesystem, and other organs and tissues[12]. A 3-bp deletion named
F508del , 5 T sin-gle nucleotide polymorphism (SNP)within intron 8, 7 T SNP within intron 8,and missense mutation named
R117H within exon 4 were reported [13].Others are
G542X , G551D , R553X , W1282X , and
N1303K [13, 14]. It causes CBAVD, which causes adisconnection between theepididymis and the ejaculatory duct,leading to obstructive azoospermia[13]. Also causes cystic fibrosis (CF),which is associated with menstrualirregularities, including amenorrhea,irregular cycles, and anovulation [15].
NR5A1 (nuclearreceptor subfamily 5group A member 1) 9q33.3
NR5A1 produces a transcription factorcalled the steroidogenic factor 1 (SF1),which helps control the activity ofseveral genes related to thedevelopment of ovaries and testes,particularly the production of sexhormones and sexual differentiation[16]. A missense heterozygous mutationinvolving c. 3G → A transition and twoheterozygous frameshift mutationsnamed c. 666delC and c. 390delG werereported [17]. The following were alsoreported: p. Pro311Leu , p. Arg191Cys , p.Gly121Ser , p . Asp238Asn , and p . Gly123Ala/p. Pro129Leu [18], as well as aheterozygous mutation named c. 195G> A [19]. Predisposes to Swyer syndrome,which disrupts sexual differentiationand prevents affected 46, XY malefrom developing testes and causingthem to develop a uterus andfallopian tubes [16]. Because of thelack of development of the gonads,Swyer syndrome is also called 46, XYcomplete gonadal dysgenesis. Infemales, mutations in the gene causeseveral ovarian anomalies, including46, XX gonadal dysgenesis [16].
WT1 (Wilms ’ tumor 1) 11p13 The gene is a transcription factor that isexpressed in the kidneys, ovaries, andtestes [20] and functions ingonadogenesis. Particularly, it plays anactive role in ovarian follicledevelopment [21] and spermatogenesis[22]. A heterozygous point mutation inintron 7 named +2, T → G wasreported [23]. R362Q and
K386R missense mutations among Chinesepopulation [22].Moreover, Seabra et al. [24] reported p.Pro130Leu and pCys350Arg missensemutations among Portuguese. Twoheterozygous missense mutationsnamed p. Pro126Ser in exon1 and p.Arg370His in exon7 were also reportedamong the Chinese women [25]. Avariant named
IVS+4C>T has also beenreported [20]. The +2, T → G mutation causesWilms ’ tumor, characterized bycongenital male genitourinarymalformation [23]. R362Q and
K386R missense mutations cause loss offunction of the
WT1 protein, resultingin non-obstructive azoospermia [22].The p. Pro126Ser and p. Arg370His missense mutations cause prematureovarian follicles (POF) [25]. Some mu-tations also cause Frasier syndromeand Denys-Drash syndrome, both ofwhich often affect the male kidneyand genitalia development [20].
FMR1 (fragile X mentalretardation 1) Xq27.3 The
FMR1 encodes a protein calledFMRP, which is expressed in the brain,testes, and ovaries.
FMR1 transmitsnerve impulses in the brain. In the cell,it transports mRNA from the nucleus tothe sites where proteins are assembled,some of which are necessary for thefunctioning of the nerves, testes, andovaries [26]. A region of the gene contains a
CGG trinucleotide repeat of less than 10 toabout 40. However, the
FMR1 mutationhas been reported in which the
CGG was abnormally repeated from 200 tomore than 1000 times [26]. Abnormal
CGG expansion causesinstability in the region, deactivatingthe gene and making little or noprotein, resulting in a conditioncalled fragile X syndromecharacterized mainly by mentalretardation [26].
CGG elongationbetween 55 and 200 repeats causesPOF [27] and fragile X-associated pri-mary ovarian insufficiency (FXPOI)[26]. FXPOI is characterized by irregu-lar menstrual cycles, early meno-pause, and elevated levels of follicle-stimulating hormone (FSH) [26].
GALT (galactose-1-phosphateuridylyltransferase) 9p13.3 The gene synthesizes galactose-1-phosphate uridylyltransferase, whichconverts galactose obtained from foodinto glucose, the main fuel for all cellu-lar activities. This chemical reaction alsoproduces an active form of galactoseknown as UDP-galactose, which is usedto build galactose-containing proteinsand fats, both which are involved in en-ergy production, chemical signaling, cellstructure building, and molecule trans-port [28]. The SNP called
Gln188Arg or Q188R isprevalent among white Europeans andNorth Americans [28]. Another SNPcalled
Ser135Leu or S135L are foundmostly among the African descent [28].The SNP named
Asn314Asp or N314D was also reported [28]. It represses or stops the activity ofthe galactose-1-phosphate uridylyl-transferase, preventing cells fromconverting galactose into glucose.Consequently, galactose-1-phosphateand related compounds build up totoxic levels in the body, damagingtissues and organs, and leading to acondition known as galactosemia[28]. Women with galactosemia ex-press hypergonadotropic hypogonad-ism and secondary amenorrhea [29],as well as ovarian failure [30].
GDF9 (growth/differentiation factor 9) 5q31.1 This gene encodes a transforminggrowth factor-beta superfamily, which isnecessary for ovarian folliculogenesisand somatic cell function [30, 31]. Several missense mutations reported[32]. It elevates the levels of serumgonadotropins and reduces estradiol,predisposing to premature ovarianfailure 14 (POF14), an ovariandisorder defined as the cessation ofovarian function under the age of 40years. The condition is characterizedby oligomenorrhea or amenorrhea
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Genes predisposing to syndromic infertility (Continued)
Gene Locus Biological functions Some mutations reported Pathophysiology/disorders[33]. Altered expression of the geneis also associated with polycysticovary syndrome (POS) [31].
MED12 (mediatorcomplex subunit 12) Xq13.1 The
MED12 gene codes for a proteincalled mediator complex subunit 12,which regulates gene activity by linkingtranscription factors with an enzymecalled RNA polymerase II. The
MED12 protein is involved in several chemicalsignaling pathways that control manycellular 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, whichare noncancerous growths alsoknown as uterine fibroids. Uterineleiomyomas are common amongadult women and cause pelvic pain,abnormal bleeding, and, in somecases, infertility [34].
MED12 mutations produce nonfunctionalprotein, which disrupts normal cellsignaling and impairs regulation ofcell growth and other cell functions.As a result, certain cells divideuncontrollably, leading to the growthof a tumor [34].
ANOS1 (anosmin 1)/
KAL1
Xp22.31 The gene encodes a protein calledanosmin-1, which is involved in embry-onic development. Anosmin-1 isexpressed in the brain and involved inthe migration of neurons that producegonadotropin-releasing hormone(GnRH), which controls the productionof several hormones that direct sexualdevelopment before birth and duringpuberty, such as the ovaries and testesfunctions [35]. Mutations that delete a part or theentire gene, as well as SNPs that alter orchange amino acids in anosmin-1, havebeen reported [35], among which is c.1267C>T [36]. Alters the synthesis or function ofanosmin-1 during embryonic devel-opment, resulting in the loss of senseof smell and the production of sexhormone, respectively, and the latterinterferes with normal sexual devel-opment causing absence or delay ofpuberty [35]. Mutations in the genealso predispose to Kallmann syn-drome, a disorder characterized byhypogonadotropic hypogonadism[35]. Males expressing hypogonado-tropic hypogonadism often have anunusually small penis (micropenis),undescended testes, and lack of sec-ondary sex characteristic, while fe-males fail to menstruate and developbreast [35].
LEP (leptin) 7q32.1 The gene codes for leptin, which is ahormone that takes part in body weightregulation [37], metabolism, andpuberty [38], as well as cell signalingthat regulates sex developmenthormones [37]. Complete deletion of the gene hasbeen reported in infertile humans andrats [38]. A SNP named rs10244329 wasalso reported [39]. Causes congenital leptin deficiency, adisorder that causes the absence ofleptin, resulting in the loss ofsignaling that triggers feelings ofsatiety, leading to excessive hungerand weight gain, reduced productionof hormones that direct sexualdevelopment, and ultimately endingin hypogonadotropic hypogonadism[37].
LEPR (leptin receptor) 1p31.3 The gene synthesizes a protein calledleptin receptor, which is embedded inmany tissues, including thehypothalamus, and helps regulate bodyweight by providing binding sites forleptin [40]. At least 18
LEPR gene mutations havebeen reported [40]. Results in less receptor proteinreaching the cell surface, causing acondition called leptin receptordeficiency, which reduces
LEPR protein binding and signalingactivities as well as satiety, resultingin excessive hunger and weight andreduced sex hormones, culminatingin hypogonadotropic hypogonadism[40].
NR0B1 (nuclearreceptor subfamily 0group B member 1)/
AHC (adrenalhypoplasia congenital) Xp21.2 The
NR0B1 gene codes for atranscription factor called
DAX1 , whichis involved in the development andfunction of several hormone-producing(endocrine) tissues, including the ad-renal glands, hypothalamus, pituitarygland, as well as the ovaries and testes[41]. Complete and partial deletions of thegene have been reported [41 ] .Abnormally short versions of the DAX1 protein as well as SNPs have also beenreported [41]. Produces inactive
DAX1 protein,disrupting normal development andfunction of hormone-producing tis-sues, particularly the adrenal glands,hypothalamus, pituitary, and gonads,resulting in a condition called X-linked adrenal hypoplasia congenital[41], characterized by male pubertydelay [38]. Mutations in this gene alsocause Swyer syndrome [41].
HESX1 (HESXhomeobox 1) 3p14.3 The
HESX1 gene encodes a transcriptionfactor that regulates the earlyembryonic development of severalbody structures, particularly the pituitary SNPs as well as insertion and deletionmutations have been reported in thisgene [42]. Alters the function of the
HESX1 protein and represses the activity ofother genes, disrupting the formationand early development of the
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Genes predisposing to syndromic infertility (Continued)
Gene Locus Biological functions Some mutations reported Pathophysiology/disordersgland [42]. pituitary gland, optic nerves, andother brain structures, resulting ingonadotropin deficiency and acondition known as septo-optic dys-plasia [42]. Septo-optic dysplasia ischaracterized by hypogonadotropichypogonadism [38]. LH β (luteinizinghormone beta-subunit) 19q13.33 It encodes the beta subunit ofluteinizing hormone (LH), which isexpressed in the pituitary gland andpromotes spermatogenesis andovulation by stimulating the testes andovaries to synthesize steroids [43]. The SNP named G1052A has beenreported [44]. Six other SNPs were alsoidentified and are gC356090A , gC356113T , gA356701G , gG355869A , gG356330C , and gG356606T [45]. Causes defective LH, leading to lowtestosterone and gonadotropins,culminating in pubertal delay,bilaterally small descended testes,and infertility [38]. Also increasessusceptibility to PCOS, characterizedby pubertal delay [38]. LHCGR (luteinizinghormone/choriogonadotropinreceptor) 2p16.3 The gene synthesizes the luteinizinghormone/chorionic gonadotropinreceptor which is a receptor forluteinizing hormone and chorionicgonadotropin. In males, chorionicgonadotropin stimulates thedevelopment of Leydig cells in thetestis, which are also stimulated byluteinizing hormone to produceandrogens, such as testosterone thatcontrols male sexual development andreproduction. In females, luteinizinghormone triggers ovulation, whilechorionic gonadotropins ensure normalprogression of pregnancy [46]. A SNP called
G935A has been reported[44]. At least 17 other SNPs werereported [46]. Impairs the development of
LHCGR protein, preventing chorionicgonadotropin binding, and resultingin the absence, or poorly developedLeydig cells, a condition calledLeydig cell hypoplasia, characterizedby low testosterone, which interfereswith male sexual developmentbefore and after birth [46]. ExtremeLeydig cell hypoplasia causes 46, XYmale to develop female externalgenitalia and small undescendedtestes [46]. Mild Leydig cellhypoplasia results in an externalgenital that is not clearly male orfemale [46]. Mutations in the genealso cause polycystic ovary syndrome(POS) [46]. AR (androgen receptor) Xq12 The AR gene produces an androgenreceptor, which is expressed in manytissues, where it binds to androgen toform an androgen-receptor complex,which in turn binds to DNA and regu-lates the activity of certain genes in-volved in male sexual development [47]. Abnormal elongation of a DNAsegment in the AR gene known as CAG ,which is normally repeated betweenless than 10 and 36, has been reported[47]. Some SNPs, as well as deletionsand insertions, were also reported [47]. Results in the receptors that areunable to bind androgens or DNA,causing androgen insensitivitysyndrome (AIS), a condition thatcauses male sexual dysfunctionbefore birth and at puberty. Thecondition also causes 46, XY male sexreversal also known as gonadaldysgenesis [47]. Mutations in thegene also cause polycystic ovarysyndrome [47].
SRY (sex-determiningregion Y) Yp11.2 The gene encodes a transcription factorcalled the sex-determining region Y pro-tein, which is located on the Y chromo-some and regulates genes involved inmale sexual activities, directing a fetusto develop testes and preventing uterusand fallopian tube formation [48]. Absence and rearrangement thatwrongly placed the gene on the Xchromosome have been reported [48]. Prevents production of SRY proteinor hampers it, resulting in Swyersyndrome, characterized by 46, XYmale sex reversal [48]. Sometimes themutation may misplace the gene onthe X chromosome from the father,causing 46, XX female to developboth ovarian and testicular tissues, acondition called ovotesticulardisorder [48].
VDR (vitamin Dreceptor) 12q13.11 The gene is expressed in male andfemale reproductive tissues [49] andsynthesizes a protein called vitamin Dreceptor, which forms a complex withan active form of vitamin D, known ascalcitriol, and another protein calledretinoid X receptor, which then binds toparticular regions of DNA, where itregulates the activity of some genesthat control several processes,particularly calcium and phosphateabsorption [50]. In mice,
VDR signalingplays a role in folliculogenesis andfertility [51]. The SNP in exon 9 named rs731236 wasreported by Bagheri et al. [52].Szczepa ń sk et al. [53] also reported twoSNPs named rs1544410 and rs222857 . Reduces follicle number, resulting inPCOS [51, 52] or endometriosis-associated infertility [53]. VDR knock-out in female mice disrupts
VDR sig-naling and ovarian response tostimulation, causing defective follicu-logenesis and infertility [51]. Malemice deficient of
VDR showed go-nadal insufficiency and decreasedsperm count and motility as well ashistological abnormalities of the testis[49].
FKBP4 (FKBP prolylisomerase 4) 6p21.3 The gene encodes
FKBP52 , which playsan important role in potentiating Deletions and two SNPs, known as rs2968909 and rs4409904 , were reported Causes azoospermia [54] as well asimplantation failure and recurrent
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Page 5 of 17 nfertility with phenotypic presentations, includinghypogonadotropic hypogonadism, sex reversal, pubertydelay or absence, gonad underdevelopment, and sper-matogenic failure.
Genes predisposing to nonsyndromic spermatogenic failureand sperm morphology abnormalities
Twenty-six (26) genes, representing 40% of the totalgenes collected, predispose to nonsyndromic spermato-genic failure and sperm morphology abnormalities(Table 2). Most often, mutations in the genes cause mei-otic arrest, resulting in acrosome malformation or ab-sence, ultimately ending in sperm head abnormalitiessuch as azoospermia, globozoospermia, oligospermia,and oligozoospermia. In some cases, the meiotic arrestmay result in polyploidy spermatozoa, characterized byan enlarged sperm cell head called macrozoospermia. Ameiotic arrest may also decrease sperm motility and hy-peractivation needed to push spermatozoa through theuterus. Sometimes, mutations in the genes may causechromatin damage or DNA fragmentation, disrupting spermatogenesis and causing sperm cell structural de-fects and loss.
Genes predisposing to nonsyndromic sex reversal andpubertal delay
Five (5) of the genes collected, representing 7.69% of thetotal genes, predispose to sex reversal and puberty delayor absence (Table 3). Most mutations in the genes causereduced circulating levels of gonadotropins and testos-terone, resulting in hypogonadotropic hypogonadism,characterized by the absence or incomplete sexual mat-uration. Mutations in the genes may also cause completeor partial gonadal dysgenesis, characterized by under-developed 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 ovarianfailure (Table 4). Some mutations in the genes may re-duce the sensitivity of fully grown immature oocytes toprogestin hormone, resulting in a reduced number of
Table 1
Genes predisposing to syndromic infertility (Continued)
Gene Locus Biological functions Some mutations reported Pathophysiology/disordersandrogen receptor ( AR ) signaling in theprostate and accessory glands [54]. [55]. pregnancy [56]. Also predisposes toPCOS [55]. DBY (DEAD-box Y RNAhelicase)/
DDX3Y (DEAD-box helicase 3Y-linked) Yq11.21 The gene resides in the
AZFa region onthe Y chromosome and is expressed inmany tissues, but mostly in thespermatogonia of the testis tissue andtranslated only in the male germline[57]. Deletion mutations were reported [57]. Causes severe testicular pathologyknown as Sertoli cell-only (SCO) syn-drome, a condition that disruptsspermatogenesis [57].
USP9Y (ubiquitinspecific peptidase 9 Y-linked) Yq11.221
USP9Y resides in the azoospermia factora (
AZFa ) region of the Y chromosomeand encodes an enzyme calledubiquitin-specific peptidase 9, Y-linked,which is necessary for sperm production[58].
AZFa deletions resulting in completeloss of
USP9Y have been reported [59]. Predisposes to Sertoli cell-only syn-drome, characterized by the absenceof germ cells in the seminiferous tu-bules, leading to azoospermia [59].Also causes spermatogenic failure Y-linked 2 (SPGFY2), resulting in azoo-spermia or oligozoospermia [59].
PLK4 (Polo-like kinase 4) 4q28.1
PLK4 protein resides in the centriolesand plays an active role in centriolarduplication that is necessary for normalcell division [60, 61]. A heterozygous mutation called p.Ile242Asn was observed in mice [62]. Aheterozygous 13 bp deletion called c.201_213delGAAACATCCTTCT was alsoreported [62]. Causes mitotic error in mice, resultingin patchy germ cell loss in the testessimilar to the human Sertoli cell-onlysyndrome (SCOS) [62, 63].
BBS9 (Bardet-Biedlsyndrome 9)
PTHB1 (parathyroidhormone responsive-B1) 7p14 The specific role of the protein releasedby this gene has not been determined[64]. A haplotype named
GAAAG as well asthree SNPs named rs3884597 , rs6944723 ,and rs11773504 were reported [65]. Causes Bardet-Biedl syndrome, char-acterized by many features, includingPOF [65]. FSHR (follicle-stimulating hormonereceptor) 2p16.3 The gene secretes a receptor for thefollicle-stimulating hormone, whichfunctions in the ovary and testis devel-opment [66]. A SNP in exon 7 named
C566T andinvolving Ala to Val substitution atresidue 189 was reported by Aittomäk[67]. Predisposes to ovarian dysgenesis 1(ODG1), characterized by primaryamenorrhea, poorly developed streakovaries, and high serum levels of FSHand LH. May also cause ovarianhyperstimulation syndrome (OHSS),characterized by massive ovarianenlargement as well as multipleserous and hemorrhagic follicularcysts lined by luteinized cells [68].
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Genes predisposing to nonsyndromic spermatogenic failure and sperm morphological abnormalities
SPATA16 (spermatogenesis-associated 16, also known as NYD-SP12) 3q26.32 The gene is expressed mainly inthe Golgi apparatus of the cellsof testis [69] and activelyinvolved in the formation ofsperm acrosome, which plays arole in spermatogenesis andfusion of sperms and eggs [70]. A homozygous SNP in exon 4named c.848G → A wasreported [17]. Causes acrosome malformationwhich can be absent in severecases, resulting in sperm headabnormality characterized byround-headed sperms knownas globozoospermia [71]. Alsopredisposes spermatogenic fail-ure 6 (SPGF6), an infertility dis-order caused byspermatogenesis defects [70]. AURKC (aurora kinase C) 19q13.43 The
AURKC codes for a proteincalled aurora kinase, whichhelps dividing cells separatefrom each other and ensuresthe accurate distribution ofgenetic materials(chromosomes). Aurora kinase Cis most abundant in maletestes, where it regulates thedivision of sperm cells, ensuringthat every new sperm celldivides accurately and containsone copy of each chromosome[72]. A homozygous deletion called c. 144delC and frequently foundamong North African descentwas reported [72]. Produces a nonfunctionalaurora kinase C or a proteinthat breaks down quickly,preventing sperm cell division.Consequently, the sperm cellscarry extra chromosomes(polyploidy spermatozoa),usually four copies of eachinstead of the usual one. Theincrease in chromosomenumber enlarges the sperm cellhead and leads to the presenceof multiple tails (flagella), acondition calledmacrozoospermia. Theadditional genetic materialsmay prevent any of the spermcells from fusing with an egg ormay result in miscarriage [72].
CATSPER (cation channel spermassociated 1) 11q13.1 The gene encodes a proteinlocalized in the tail of spermcells and transport calciumcations into the cells for normalsperm motility and a type ofsperm cell motility calledhyperactivation, which is arigorous movement necessaryto push the sperm cellsthrough the cell membrane ofthe egg cell during fertilization[73]. Two insertion mutationsnamed c.539-540insT and c.948-949insATGGC , leading toframeshifts and premature stopcodons known as p.Lys180LysfsX8 and p.Asp317MetfsX18 , have beenreported [74]. Alters or malfunctions
CATSPER1 protein or produces a proteinthat is degraded quickly by thecell. This impairs calcium entryinto the sperm cell, decreasingthe motility and preventinghyperactivation, ultimatelyresulting in
CATSPER1 -relatednon-syndromic male infertility.Affected men may also producea smaller than the usual num-ber of sperm cells or spermcells that are abnormallyshaped [73].
MTHFR (methylenetetrahydrofolatereductase) 1p36.22 The
MTHFR gene synthesizes anenzyme calledmethylenetetrahydrofolatereductase, which converts aform of folate called 5, 10-methylenetetrahydrofolate toan another form called 5-methyltetrahydrofolate. The lat-ter is the primary form of folatein the blood, where it helpsconverts the amino acid homo-cysteine to another amino acidcalled methionine. The bodyuses methionine to make pro-teins and other important com-pound as well as vital in DNAmethylation and spermatogen-esis [75, 76]. A SNP named andinvolving the substitution of analanine for a valine is the mostcommon in infertile men with
MTHFR deficiency [13]. Thesecond mutation involved an Ato C transition at nucleotide1298 (
A1298C ), resulting inglutamate to alaninesubstitution in the
MTHFR protein [77]. Loss of
MTHFR decreases theactivity of its enzyme,disrupting folic acidmetabolism, resulting in DNAhypo-methylation, ultimatelyending in the absence of ger-minal cells and spermatogen-esis arrest [13, 75, 78].
SYCP3 (synaptonemal complexprotein 3) 12q23.2
SYCP3 is embedded in the testisand encoded an essentialstructural component of thesynaptonemal complex, whichis involved in synapsis,recombination, and segregationof meiotic chromosomes [79]. A heterozygous deletion called , and a heterozygousgenetic change known as
T657C was identified amongIranian women with recurrentpregnancy losses [17]. Causes early meiotic arrest,disrupting the spermatogenicprocess in males [17], resultingin spermatogenic failure 4(SPGF4), a disordercharacterized by azoospermia.In females, early meiotic arrest
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Page 7 of 17 able 2
Genes predisposing to nonsyndromic spermatogenic failure and sperm morphological abnormalities (Continued)
The gene ensures centromerepairing during meiosis in malegerm cells, thus important fornormal spermatogenesis [80]. causes recurrent pregnancy loss[79].
HSF2 (heat-shock transcription factor2) 6q22.31
HSF2 is expressed in the testisand encodes heat-shock tran-scription factor 2, which bindsspecifically to the heat-shockpromoter element to activateheat-shock response genesunder conditions of heat orother stresses [81]. Heterozygous missensemutations have been reported[82].
HSF2 -null male mice showedembryonic lethality, neuronaldefects, and reducedspermatogenesis that relates tomeiotic arrest, increased spermapoptosis, and seminiferoustubule dysgenesis [83]. Malehumans showed azoospermia[82].
SYCP2 (synaptonemal complexprotein 2) 20q13.33 The gene codes for a majorcomponent of thesynaptonemal complex, whichis required for normal meioticchromosome synapsis duringoocyte and spermatocytedevelopment and for normalmale and female fertility [84]. Heterozygous frameshiftmutation and deletion havebeen reported in the gene [85]. Alters synaptonemal complex,disrupting spermatogenesis andresulting in cryptozoospermiaand azoospermia [85, 86].
A-MYB/MYBL1 (myeloblastosisoncogene-like 1) 8q13.1
MYBL1 protein is a male-specificmaster regulator of meioticgenes that are involved in mul-tiple processes in spermato-cytes, particularly processesinvolved in cell cycle progres-sion through pachynema [87]. A variant named repro9 involving a C to A transversionat nucleotide 893 of the
MYBL1 mRNA was reported [87].
MYBL1 − / − , showing meioticarrest similar to repro9 , has alsobeen reported [87]. Causes meiotic arrest inspermatocytes, characterized bydefects in autosome synapsis inpachynema, unsynapsed sexchromosomes, incompletedouble-strand break repair onsynapsed pachytene chromo-somes and a lack of crossingover [87]. TEX11 (testis expressed 11) Xq13.1
TEX11 protein is required forspermatogenesis; particularlycertain levels of the protein arerequired for meioticprogression. The protein is alsonecessary for normal genome-wide meiotic recombinationrates in both sexes [88]. Frameshift mutations wereobserved, so also missensemutations, particularly amissense mutation tagged
V748A was observed amongtransgenic mice [88]. Causes meiotic arrest in malemice, resulting inspermatogenic failure, X-linked,2 (SPGFX2), a disorder charac-terized by mixed testicular atro-phy and azoospermia [89].Among humans, meiotic arrestleads to non-obstructive azoo-spermia [88].
KIT (v-kit Hardy-Zuckerman 4 felinesarcoma viral oncogene homolog) 4q12 The gene is embedded in thereproductive cells and encodedreceptor tyrosine kinases, whichis involved in signaltransduction. The protein takespart in phosphorylation thatactivates a series of proteins inmultiple signaling pathways,which are necessary for normalcell growth, proliferation,survival, and movement in thereproductive cells and certainother cell types [90]. A SNP in which Asp-816 is re-placed with a Val or His residueat exon 17 has been reported[91]. Causes seminomas andtesticular carcinoma [91].
ADGRG2 (adhesion G protein-coupled receptor G2) Xp22.13 This gene encodes anepididymis-specific transmem-brane protein, which is involvedin a signal transduction path-way controlling epididymalfunction and male fertility. Mayparticularly regulate fluid ex-change within the epididymis[92]. Three protein-truncating hemi-zygous mutations, named c.1545dupT ( p.Glu516Ter ), c.2845delT ( p.Cys949AlafsTer81 ),and c.2002_2006delinsAGA ( p.Leu668ArgfsTer21 ), have beenreported [93]. Predisposes to congenitalbilateral aplasia of the vasdeferens, X-linked (CBAVDX), adisease characterized by bilat-eral absence of vas deferensand obstructive azoospermia[92]. FKBP6 (FKBP prolylisomerase 6) 7q11.23 Encodes a protein thatfunctions in immunoregulation,homologous chromosomepairing in meiosis duringspermatogenesis and cellular Deletion in the exon 8 of thegene has been reported [95]. Causes spermatogenic failure,resulting in azoospermia orsevere oligozoospermia [96].
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Genes predisposing to nonsyndromic spermatogenic failure and sperm morphological abnormalities (Continued) processes involving proteinfolding and trafficking [94].
PRM1 (protamine 1) 16p13.13 It encodes a protein calledprotamine 1, which replaceshistone during developmentalstages of elongating spermatidsand compact sperm DNA into ahighly condensed, stable, andinactive complex to ensure thatquality spermatozoa areproduced and as well protectspermatozoa from thedegrading effects of freeradicals [97]. A c.102G>T transversion thatresults in the SNP named p.Arg34Ser , a missensemutation named c.119G>A ( p.Cys40Tyr ), a heterozygousmutation named c.-107G>C ,and a variant named c.*51G>C have been reported [98]. Increases sperm DNAfragmentation, resulting inoligozoospermia [98]. PRM2 (protamine 2) 16p13.13
PRM2 secretes protamine 2,which replaces histone duringspermatid development,condensing chromatin, andcompacting the DNA to ensureproduction of qualityspermatozoa and preventdegradation by free radicals[97]. A SNP, known as - ( rs2301365 ), was identified inboth PRM1 and 2 [99]. Causes chromatin damage andDNA breaks, resulting in spermstructural defects, reducedmotility, and defectivespermatogenesis due tohaploinsufficiency [100].
TNP1 (nuclear transition protein 1) 2q35 The gene encodes nuclearproteins, which replace nuclearhistones and in turn substitutedby protamine 1 and 2 duringspermatogenesis [101]. A SNP named g.IVS1+75T>C was reported by Heidan et al[102]. A deletion of 15nucleotides in the 5 ′ -promoterregion of the gene was alsoreported [101]. Disrupts the highly condensedstructure of the sperm nuclearchromatin, resulting inabnormal spermatogenesis[102]. Also causes varicocele,due to the failure of ipsilateraltesticular growth anddevelopment [102]. TNP2 (nuclear transition protein 2) 16p13.13
TNP2 participates in theremoval of the nucleohistonesand in the initial condensationof the spermatid nucleus, thuscontributes to the densepacking of spermatid chromatinduring spermatogenesis [103]. A variant named
G1272C wasreported [98].
TNP2 − / − in mice affects spermchromatin structure, causingsperm head abnormalities,acrosome abnormalities inwhich the acrosomes do notattach to the nuclear envelope,and reduced sperm motility,resulting in tetrazoospermia[103]. DAZ1 (deleted in azoospermia 1) Yq11.223 The gene encodes azoospermiaprotein 1, which is necessary forspermatogenesis. It binds to the3 ′ -UTR of mRNAs, regulatingtheir translation, and promotinggerm cell progression tomeiosis and the formation ofhaploid germ cells [104]. DAZ1 deletions were reported[105]. Causes Y chromosome infertilityknown as spermatogenic failureY-linked 2 (SPGFY2), a disorderresulting in azoospermia or oli-gozoospermia [104]. Also causessperm structural abnormalitiesand reduced motility [106].
XRCC2 (X-ray repair crosscomplementing 2) 7q36.1
XRCC2 protein was shown inmice to be required for geneticstability, embryonicneurogenesis and viability [107]. A SNP in the gene involving c.41T>C substitution wasreported [108]. Causes meiotic arrest, resultingin azoospermia [108].
CCDC62 (coiled-coil domaincontaining 62) 12q24.31 Encodes a nuclear receptor co-activator that enhances estro-gen receptor transactivation[109]. The gene is expressed inthe acrosome of developingspermatids and mature sperms,showing that it is necessary forspermatogenesis [110]. A nonsense mutation in theexon 6, which results in theformation of a premature stopcodon and a truncated protein,was reported by Li et al. [110]. Causes defective spermmorphology and reducedmotility [110].
EFCAB9 (EF-hand calcium21 bindingdomain-containing protein 9) 5q35.1 Encodes sperm-specific EF-banddomain protein, which is essen-tial for activation of
CATSPER channel that regulates spermmotility [111].
EFCAB9 deletions werereported [111]. Disrupts
CATSPER channelsignaling, which affects spermmotility [111].
Yahaya et al. Egyptian Journal of Medical Human Genetics (2020) 21:46
Page 9 of 17 ocytes undergoing meiotic maturation. Mutations inthe genes may also cause ovarian dysgenesis, character-ized by absence or puberty delay, primary amenorrhea,uterine hypoplasia, and hypogonadotropic hypogonad-ism. Some mutations prevent the formation of primor-dial follicles, resulting in reduced oocyte numbers afterbirth.In summary, 23 genes, representing 35%, were linkedwith syndromic infertility, while 42 genes, accounting for65% cause nonsyndromic infertility. Of the 42 nonsyn-dromic genes, 26 predispose to spermatogenic failureand sperm morphology abnormalities, 11 cause ovarianfailures, and 5 cause sex reversal and puberty delay.Overall, 31 genes (48%) predispose to male infertility, 15genes (23%) cause female infertility, and 19 genes (29%)predispose to both. The common features of male infertility were spermatogenic failure and sperm morph-ology abnormalities, while ovarian failure has been themost frequently reported among infertile females. Thisanalysis infers that male genetic infertility was moreprevalent than female, with spermatogenic failure andsperm morphology abnormalities being most prevalent.
Genetic testing for infertility disorders
Knowing the exact cause of infertility allows for betterdiagnostic decisions and enables enhanced counselingfor parents with regard to risks to their children. For thisreason, when there is a means, testing of embryos shouldbe recommended for a family with a history of geneticinfertility disorders discussed above. Moreover, everyhealthy-looking individual is a carrier of between 5 to 8recessive 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 cell-specific protein essential forspermatogenesis [63]. Two missense mutationsnamed
A313T and
Q216P werereported [112]. Impairs homodimerization,resulting in germ cell loss,abnormal spermatids, andsevere oligozoospermia [112].
SEPT12 (septin 12) 16p13.3 The gene codes for septin 12,which is expressed exclusivelyin the testis and involved inspermatogenesis, especiallymorphogenesis of sperm headsand the elongation of spermtails [63]. Two missense mutationsnamed c.266C>T/p.Thr8 Met and c.589G>A/p.Asp197Asn were reported by Kuo et al.[113]. Disrupts the structural integrityof sperm by perturbing septinfilament formation, causingvarious sperm abnormalities,including immotility, bent tails,acrosome breakage, roundheads, and significantspermatozoa DNA damage, aswell as oligoasthenozoospermand asthenoteratozoospermia[63, 113].
TAF4B (TATA-box binding proteinassociated factor 4b) 18q11.2
TAF4B encodes a transcriptionalcoactivator and involved infolliculogenesis,spermatogenesis, andoogenesis [114]. A nonsense mutation in exon 9named p.R611X was reported[115]. Causes spermatogenic failure13 (SPGF13), a disorder resultingin azoospermia oroligozoospermia [114].
ZMYND15 (zinc finger mynd-containing protein 15) 17p22.1
ZMYND15 codes for atranscription repressor, which inmice is expressed exclusively inthe haploid germ cells,particularly during latespermatogenesis [116]. A mutation in exon 9 of thegene named p.K507Sfs*3 wasreported by Ayhan et al. [115]. Causes spermatogenic failure14 (SPGF14), a disorder resultingin azoospermia oroligozoospermia [117].
NANOS1 (nanos C2HC-type zinc fin-ger 1) 10q26.11 This gene encodes a CCHC-typezinc finger protein that is specif-ically expressed in the germcells of adult men and regulatesthe translation by acting as apost-transcriptional repressor[118]. Two deletion mutations called p.Pro77_Ser78delinsPro and p.Ala173del have been reported[119]. Results in spermatogenic failure12 (SPGF12), an infertilitydisorder caused byspermatogenesis defects,characterized by decreasedsperm motility andconcentration, sperm structuraldefects, non-obstructive azoo-spermia, oligozoospermia, andoligo-astheno-teratozoospermia[120].
GALNTL5 (polypeptide N-acetylgalactosaminyltransferase Like5) 7q36.1
GALNTL5 encodes an inactiveprotein, which is expressed inthe testis and is required duringspermatid development inwhich it participates in proteinloading into the acrosomes[121]. Heterozygous single nucleotidedeletion of maternalinheritance was reported [63,122]. Decreases glycolytic enzymes,which disrupts protein loadinginto acrosomes, resulting inasthenozoospermia and poorsperm motility [122].
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Page 10 of 17 xtended to everyone who has the means [157]. It is spe-cifically recommended for embryos of couples who arerecessive for a gene infertility disorder.The conventional method used in genetic testing ofembryos is the whole sequence amplification. Afterfertilization, the embryo undergoes mitotic divisions for5 to 7 days, ending with the development of the blasto-cyst stage. A biopsy of some blastocysts is done, afterwhich a whole genome amplification of the cells is con-ducted, usually using polymerase chain reaction [157,158]. This technique is laborious, time-consuming, andexpensive, so recently, a new technique known as thenext-generation sequencing is being used for testinggenetic disorders in infertile couples and embryos [159].The protocol is based on an enlarged panel of disease-associated genes (approximately 5000 genes). The large panel of marker genes allows the identifications of alarge number of target and non-target genes [157]. How-ever, the technique has some limitations too, which is itsinability to detect haploidies, polyploidies, and mosai-cisms [157].
Conclusion
Several studies reviewed showed that certain genes em-bedded in the hypothalamus, pituitary gland, gonads,and gonadal outflow regulate fertility in both males andfemales. However, mutational inactivation of these genesmay cause syndromic or nonsyndromic infertility. Thecommon features of male infertility include spermato-genic failure, resulting in azoospermia, oligospermia, andchromosome structural abnormalities. Most females ex-press ovarian failure, resulting in menstrual dysfunction
Table 3
Genes predisposing to nonsyndromic sex reversal and pubertal delay
GNRHR (gonadotropin-releasinghormonereceptor) 4q13.2 This gene encodes the receptor for type1 gonadotropin-releasing hormone, a re-ceptor that is expressed on the surface ofpituitary gonadotrope cells, lymphocytes,breast, ovary, and prostate.
GNRHR be-comes activated after binding withgonadotropin-releasing hormone, andthe complex formed causes the releaseof gonadotropic luteinizing hormones(LH) and follicle-stimulating hormones(FSH) [123]. At least 19 different mutations havebeen identified, includingheterozygous mutations named
Gln106Arg/Arg262Gln and
Arg262Gln/Tyr28Cys [17] as well as homozygousmissense mutation named g. G7167A;p. Arg139His [124]. Causes low levels of circulatinggonadotropins and testosterone,resulting in hypogonadotropichypogonadism 7 (HH7), a disordercharacterized by absent or incompletesexual maturation by the age of 18years [125].
PROP1 (PROPpaired-likehomeobox 1) 5q35.3 The gene produces a transcription factorembedded only in the pituitary glandand releases hormones for growth,reproduction, and cell differentiation inthe pituitary gland [126]. At least 25 mutations had beenreported, the most common of whichdeletes two amino acids, written as [126]. Reduces pituitary cell differentiationand prevents the release of hormonesfrom the pituitary gland, causing acondition called combined pituitaryhormone deficiency, with features likeshort stature and delayed or absentpuberty [126].
DMRT1 (doublesex- andMAB3-relatedtranscription fac-tor 1) 9p24.3 The gene encodes a transcription factorexpressed in the testis and involved inmale sex determination anddifferentiation before and after birth bypromoting male-specific genes andrepressing female-specific genes. Mayalso play a minor role in oogenesis [127]. Deletions in the gene had beenreported [127]. Predisposes to male-to-female sex re-versal in the presence of a normal 46,XY karyotype, referred to as 46, XY sexreversal 4 (SRXY4), characterized bycomplete or partial gonadal dysgene-sis. The mutation may also cause tes-ticular germ cell tumors [127].
SOX3 (SRY-boxtranscriptionfactor 3) Xq27.1 The gene codes for a transcription factorembedded in the hypothalamus andpituitary gland where it regulatesneuronal development anddifferentiation, and as well promote malesex development [128]. Copy number variations includingtwo duplications of about 123 kb and85 kb, a 343 kb deletion immediatelyupstream of
SOX3 , and a largeduplication of approximately 6 Mbthat encompasses
SOX3 have beenreported [128]. Causes 46, XX sex reversal 3 (SRXX3),characterized by XX male reversal anda complex phenotype that includesscrotal hypoplasia, microcephaly,developmental delay, and growthretardation [128]. Also causes 46, XXtesticular disorder of sex development[128].
RSPO1 (R-spondin 1) 1p34.3 Produces a protein that is essential inovary determination through regulationof Wnt signaling [129]. c.286+1G>A [130]. Causes oocytes depletion andmasculinized ovaries, resulting in XXtrue hermaphroditism, also known asan ovotesticular disorder of sexualdevelopment, a disorder of gonadaldevelopment characterized by thepresence of both ovarian andtesticular tissue in 46, XX individuals[130].
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Genes predisposing to nonsyndromic ovarian failure
BMP15 (bonemorphogeneticprotein 15)/
GDF9B (growth/differentiation factor9B) Xp11.22 The gene encodes a member oftransforming growth factor-betasuperfamily, which plays a role in oo-cyte maturation and follicular develop-ment, through activation of granulosacells [131]. Several missense mutations reported[131]. Causes ovarian dysgenesis 2(ODG2), a disorder characterized bylack of spontaneous pubertaldevelopment, primary amenorrhea,uterine hypoplasia, andhypergonadotropic hypogonadismas a result of streak gonads [132].May also cause premature ovarianfailure 4 (POF4), a disorder in whichthe ovarian function stops beforethe age of 40 years and ischaracterized by oligomenorrhea oramenorrhea, in the presence ofelevated levels of serumgonadotropins and low estradiol[131, 132].
FIGLA (factor ingermline alpha) 2p13.3
FIGLA encodes a germ cell-specificbasic helix-loop-helix transcription fac-tor that regulates the expression ofthe zona pellucida- and oocyte-specific genes, particularly genes in-volved in folliculogenesis [30, 133]. Missense mutations and deletionsthat resulted in a frameshift had beenreported [134].
FIGLA knockout in female miceprevents formation of primordialfollicles, and oocyte numbers droprapidly after birth [135]. May alsocause haploinsufficiency,predisposing to premature ovarianfailure 6 (POF6), an ovarian disorderdefined as the cessation of ovarianfunction under the age of 40 yearsand is characterized byoligomenorrhea or amenorrhea, inthe presence of elevated levels ofserum gonadotropins and lowestradiol [134, 136].
NOBOX (newbornovary homeobox) 7q35
NOBOX encodes a transcriptionalregulator with a homeobox motif andis important for early folliculogenesis[137]. Missense mutations in the homeoboxdomain were observed in infertileCaucasian or African descent [138]. Predisposes to POF [139].
SALL4 (SAL-like 4) 20q13.2 The gene is expressed in the testisand oocytes and secretes putative zincfinger transcription factor that plays arole in the pluripotency of oocytesand maintenance of undifferentiatedspermatogonia [38, 140]. Deletions [140]. Predisposes to nonsyndromic POF[140, 141].
FSH β (follicle-stimulating hormonesubunit beta) 11p14.1 This gene encodes the beta subunit ofthe follicle-stimulating hormone whichin association with luteinizing hor-mone induces egg and sperm produc-tion [38, 142]. Tyr76X , Cys51Gly , and
Val61X werereported [38]. Causes low FSH and estradiol, andhigh LH among females, resultingin the absence or incompletebreast development and sterility[143]. Males produce low androgen,leading to low testosterone andazoospermia, but puberty may benormal or absent [38].
HCG β (humanchorionicgonadotrophin) 19q13.3 HCG β encodes a hormone called HCGwhich is secreted mainly by theplacenta and is important for normalprogression of pregnancy bymaintaining the production of steroidhormones and other growth factors inthe corpus luteum [144]. SNPs named CGB5 p.Val56Leu ( rs72556325 ) and CGB8 p.Pro73Arg ( rs72556345 ) had been reported [145]. Causes low levels of HCG duringthe first trimester of pregnancy,resulting in miscarriage and ectopicpregnancy [146]. SOHLH1 (spermatogenesisand oogenesis-specific basic helix-loop-helix 1) 9q34.3 This gene encodes one of the testis-specific transcription factors which areessential for spermatogenesis, oogen-esis, and folliculogenesis. The proteinis necessary for spermatogonial prolif-eration and differentiation as well asregulates both male and female germ-line differentiation [147]. Alternatively spliced transcript variantsencoding different isoforms havebeen found for this gene [147]. Causes ovarian dysgenesis 5(ODG5), a disorder characterized bylack of spontaneous pubertaldevelopment, primary amenorrhea,uterine hypoplasia, andhypergonadotropic hypogonadism[147]. May also result inspermatogenic failure 32 (SPGF32),a condition that is characterized bynon-obstructive azoospermia [148].
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Page 12 of 17 nd pregnancy loss. Males and females may also expresssex reversal, pubertal delay or absence, and genital ab-normalities such as micro-penis and absence of thebreast. Male genetic infertility was more prevalent thanfemale, with spermatogenic failure and sperm morph-ology abnormalities being most prevalent. The mecha-nisms leading to these pathologies are gene-specific,which, if targeted in the affected, may lead to improvedtreatment. Medical practitioners are advised to targetthese genes in the affected.
Abbreviations
AIS: Androgen insufficiency syndrome; BBS: Bordet-Biedl syndrome;CBAVD: Congenital bilateral absence of the vas deferens; CF: Cystic fibrosis;FSH: Follicle-stimulating hormone; FXPOI: Fragile X-associated primary ovar-ian insufficiency; GHR: Genetic home reference; HH: Hypogonadotropichypogonadism; LH: Luteinizing hormone; NCBI: National Center forBiotechnology Information; OHSS: Ovarian hyperstimulation syndrome;ODG: Ovarian dysgenesis; PCOS: Polycystic ovary syndrome; POF: Prematureovarian failure; SCOS: Sertoli cell-only; SNP: Single nucleotide polymorphism;SPGF: Spermatogenic failure
Acknowledgments
Not applicable.
Authors ’ contributions TOY conceptualized and did literature searches, article writing, and correspondence.UUL, HA, YSK, SSR, ZA, and SA did literature searches, sorting, and referencing. Allauthors proofread and approved the final manuscript.
Funding
Not applicable.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
Author details Department of Biolog, Federal University Birnin-Kebbi, PMB 1157,Birnin-Kebbi, Nigeria. Department of Biochemistry and Molecular Biology,Federal University Birnin-Kebbi, Birnin-Kebbi, Nigeria.
Received: 12 June 2020 Accepted: 7 August 2020
References
1. Venkatesh T, Suresh PS, Tsutsumi R (2014) New insights into the geneticbasis of infertility. Appl Clin Genet. 7:235 – – Table 4
Genes predisposing to nonsyndromic ovarian failure (Continued)
SOHLH2 (spermatogenesisand oogenesisspecific basic helix-loop-helix 2) 13q13.3 The
SOHLH2 is expressed specifically inspermatogonia and oocytes and isrequired for early spermatogonial andoocyte differentiation [149].
SOHLH2 isa transcription regulator of both maleand female germline differentiationand together with
SOHLH1 regulatesoocyte growth and differentiation[150]. At least 11 mutant variants of
SOHLH2 gene have been reported [151]. Inparticular, two variants, named rs6563386 and rs1328626 , werereported by Song et al. [152].
SOHLH2 knockout causes defects inspermatogenesis and oogenesissimilar to those in
SOHLH1 -nullmice [149]. May also predispose toPO [151]. Some mutant variantsmay increase the risk of non-obstructive azoospermia [152], aswell as the small testis and testicu-lar atrophy [153].
PGRMC1 (progesteronereceptor membranecomponent 1) Xq24 The gene codes for progestin receptormembrane component 1, whichassociates with and transports a widerange of molecules, including steroids,and the gene has been demonstratedin zebrafish to function in oocytematuration and meiosis resumption[154]. Mutant alleles named ecu4 , f21 , and sa37360 were reported in zebrafish(ZFIN) [154]. PGRMC1 knockout in zebrafishreduces both spawning frequencyand the number of embryosproduced by females. It alsoreduces the sensitivity of fullygrown immature oocytes toprogestin hormone, resulting in areduced number of oocytesundergoing meiotic maturation[154].
ESR1 (estrogenreceptor 1) 6q25.1-q25.2 Estrogen receptor alpha regulatesestrogen action in all reproductivetissues. Estrogen signaling mediatesleukemia inhibitory factor expression,which is a cytokine critical forblastocyst implantation [155]. A SNP named r s9340799 was reported[155]. Causes estrogen resistance,resulting in absence of pubertalgrowth and endometriosis-relatedinfertility [155].
HES1 (Hes familybHLH transcriptionfactor 1) 3q29
Hes is expressed in the ovary andencodes transcriptional factorsnecessary for oocyte survival andmaturation [156]. Deletions were reported [156].
HES1 knockout reduces notchsignaling and elevates apoptosis,decreasing the number, size, andmaturation of oocytes [156].
Yahaya et al. Egyptian Journal of Medical Human Genetics (2020) 21:46
Page 13 of 17 . Kumar N, Singh AK (2015) Trends of male factor infertility, an importantcause of infertility: a review of literature. J Hum Reprod Sci. 8:191 – – –
53. https://doi.org/10.1016/s1472-6483(10)62187-69. Durairajanayagam D (2018) Lifestyle causes of male infertility. Arab J Urol.16(1):10 –
20. https://doi.org/10.1016/j.aju.2017;12:00410. Ferlin A, Raicu F, Gatta V et al (2007) Male infertility: role of geneticbackground. Reprod Biomed Online. 14:734 – –
12. https://doi.org/10.1016/j.fertnstert.2009.10.04512. Genetic Home Reference. 2020. CFTR gene. Available at https://ghr.nlm.nih.gov/gene/CFTR. .13. Tahmasbpour E, Balasubramanian D, Agarwal A (2014) A multi-facetedapproach to understanding male infertility: gene mutations, moleculardefects and assisted reproductive techniques (ART) J. Assist Reprod Genet.31:1115 – –
56. https://doi.org/10.2174/187425560110301004215. Ajonuma LC, Ng EH, Chow PH et al (2005) Increased cystic fibrosistransmembrane conductance regulator (CFTR) expression in the humanhydrosalpinx. Hum Reprod. 20(5):1228 – – – – ’ Tumor and congenital male genitourinarymalformation. Pediatr Res. 50:337 – – – – – – –
57. https://doi.org/10.1111/andr.1243237. Genetic Home Reference. 2020. LEP gene. Available at https://ghr.nlm.nih.gov/gene/LEP – ž i ć AM, Ristanovi ć B, Zorn C et al (2017) Genetic variation in leptin andleptin receptor genes as a risk factor for idiopathic male infertility. Androl.5(1):70 –
74. https://doi.org/10.1111/andr.1229540. Genetic Home Reference. 2020. LEPR gene. Available at https://ghr.nlm.nih.gov/gene/LEPR –
36. https://doi.org/10.1002/iub.145745. Reen JK, Kerekoppa R, Deginal R et al (2018) Luteinizing hormone betagene polymorphism and its effect on semen quality traits and luteinizinghormone concentrations in Murrah buffalo bulls. Asian-Australas J Anim Sci.31(8):1119 – – – ń sk M, Mostowska A, Wirstlein P, Skrzypczak J. Matthew MM,Jagodzi ń ski PP. Polymorphic variants in vitamin D signaling pathway genesand the risk of endometriosis-associated infertility. Mol Med Rep. 2015; 12(5): 7109-7115. https://doi.org/10.3892/mmr.2015.4309.54. Sunnotel O, Hiripi L, Lagan K et al (2010) Alterations in the steroid hormonereceptor co-chaperone FKBPL are associated with male infertility: a case-control study. Reprod Biol Endocrinol. 8:22. https://doi.org/10.1186/1477-7827-8-2255. Ketefian A, Jones MR, Krauss RM. Association study of androgen signalingpathway genes in polycystic ovary syndrome. Fertil Steril. 2016; 105(2):467-73.e4. DOI: 10.1016/j.fertnstert.2015;09: 043.56. Demetriou C, Chanudet E, Joseph A et al (2019) Exome sequencing identifiesvariants in FKBP4 that are associated with recurrent fetal loss in humans. HumMol Genet. 28(20):3466 – Yahaya et al. Egyptian Journal of Medical Human Genetics (2020) 21:46(2020) 21:46
36. https://doi.org/10.1002/iub.145745. Reen JK, Kerekoppa R, Deginal R et al (2018) Luteinizing hormone betagene polymorphism and its effect on semen quality traits and luteinizinghormone concentrations in Murrah buffalo bulls. Asian-Australas J Anim Sci.31(8):1119 – – – ń sk M, Mostowska A, Wirstlein P, Skrzypczak J. Matthew MM,Jagodzi ń ski PP. Polymorphic variants in vitamin D signaling pathway genesand the risk of endometriosis-associated infertility. Mol Med Rep. 2015; 12(5): 7109-7115. https://doi.org/10.3892/mmr.2015.4309.54. Sunnotel O, Hiripi L, Lagan K et al (2010) Alterations in the steroid hormonereceptor co-chaperone FKBPL are associated with male infertility: a case-control study. Reprod Biol Endocrinol. 8:22. https://doi.org/10.1186/1477-7827-8-2255. Ketefian A, Jones MR, Krauss RM. Association study of androgen signalingpathway genes in polycystic ovary syndrome. Fertil Steril. 2016; 105(2):467-73.e4. DOI: 10.1016/j.fertnstert.2015;09: 043.56. Demetriou C, Chanudet E, Joseph A et al (2019) Exome sequencing identifiesvariants in FKBP4 that are associated with recurrent fetal loss in humans. HumMol Genet. 28(20):3466 – Yahaya et al. Egyptian Journal of Medical Human Genetics (2020) 21:46(2020) 21:46
Page 14 of 17
7. Ditton HJ, Zimmer J, Kamp C, Rajpert-De ME, Vogt PH (2004) The AZFagene DBY (DDX3Y) is widely transcribed but the protein is limited to themale germ cells by translation control. Hum Mol Genet. 13(19):2333 – – – – –
88. https://doi.org/10.1002/rmb2.1201764. Veleri S, Bishop K, Dalle Nogare DE et al (2012) Knockdown of Bardet-Biedlsyndrome gene
BBS9/PTHB1 leads to cilia defects. PLoS ONE. 7(3):e34389.https://doi.org/10.1371/journal.pone.003438965. HyunJun K, Seung KL, Min-Ho K et al (2008) Parathyroid hormone-responsive B1 gene is associated with premature ovarian failure. HumReprod. 23(6):1457 – – – –
510 https://doi.org/10.1016/j.ajhg.2009.03.00475. Nuti F, Krausz C (2008) Gene polymorphisms/mutations relevant toabnormal spermatogenesis. Reprod Biomed Online. 16:504 – – – –
165 83. Wang G, Ying Z, Jin X et al (2004) Essential requirement for both hsf1 andhsf2 transcriptional activity in spermatogenesis and male fertility. Genesis.38(2):66 – –
57. https://doi.org/10.1016/j.ajhg.2019.11.01386. Takemoto K, Imai Y, Saito K et al (2020) Sycp2 is essential for synaptonemalcomplex assembly, early meiotic recombination and homologous pairing inzebrafish spermatocytes. PLoS Genet. 16(2):e1008640. https://doi.org/10.1371/journal.pgen.100864087. Bolcun-Filas E, Bannister LA, Barash A et al (2011) A-MYB (MYBL1)transcription factor is a master regulator of male meiosis. Develop. 138:3319 – – – – – ’ am A, Widodo MA, Sumitro SB, Purnomo BB (2016) Theimportant role of protamine in spermatogenesis and quality of sperm: amini review. Asian Pac J Reprod. 5:357 – – – – – – – Yahaya et al. Egyptian Journal of Medical Human Genetics (2020) 21:46(2020) 21:46
57. https://doi.org/10.1016/j.ajhg.2019.11.01386. Takemoto K, Imai Y, Saito K et al (2020) Sycp2 is essential for synaptonemalcomplex assembly, early meiotic recombination and homologous pairing inzebrafish spermatocytes. PLoS Genet. 16(2):e1008640. https://doi.org/10.1371/journal.pgen.100864087. Bolcun-Filas E, Bannister LA, Barash A et al (2011) A-MYB (MYBL1)transcription factor is a master regulator of male meiosis. Develop. 138:3319 – – – – – ’ am A, Widodo MA, Sumitro SB, Purnomo BB (2016) Theimportant role of protamine in spermatogenesis and quality of sperm: amini review. Asian Pac J Reprod. 5:357 – – – – – – – Yahaya et al. Egyptian Journal of Medical Human Genetics (2020) 21:46(2020) 21:46
Page 15 of 17
08. Yang Y, Guo J, Dai L (2018) XRCC2 mutation causes meiotic arrest,azoospermia and infertility. J Med Genet. 55:628 – –
597 https://doi.org/10.1095/biolreprod.116.141408111. Hwang JY, Mannowetz N, Zhang Y. EFCAB9 is a pH-Dependent Ca2+ sensorthat regulates CatSper channel activity and sperm motility. BioRxiv. 2018;Article no 459487. doi: https://doi.org/10.1101/459487.112. Yatsenko AN, Roy A, Chen R (2006) Non-invasive genetic diagnosis of maleinfertility using spermatozoal RNA: KLHL10 mutations in oligozoospermicpatients impair homodimerization. Hum Mol Genet. 15:3411 – – – – – – – – – – – – – β -subunit gene. NEngl J Med. 337:607 – β -subunit of human chorionic gonadotropingenes during the normal and failed pregnancy. Hum Reprod. 2005; 20(12):3360 – β -subunit. MolHum Reprod. 18(8):379 – – Homosapiens – – –
52. https://doi.org/10.1016/j.ejogrb.2014.11.003153. Hao J, Yamamoto M, Richardson TE et al (2008) Sohlh2 knockout mice aremale-sterile because of degeneration of differentiating type Aspermatogonia. Stem Cells 26(6):1587 – – – Yahaya et al. Egyptian Journal of Medical Human Genetics (2020) 21:46(2020) 21:46
52. https://doi.org/10.1016/j.ejogrb.2014.11.003153. Hao J, Yamamoto M, Richardson TE et al (2008) Sohlh2 knockout mice aremale-sterile because of degeneration of differentiating type Aspermatogonia. Stem Cells 26(6):1587 – – – Yahaya et al. Egyptian Journal of Medical Human Genetics (2020) 21:46(2020) 21:46
Page 16 of 17
57. Cariati F, D ’ – Publisher ’ s Note Springer Nature remains neutral with regard to jurisdictional claims inpublished maps and institutional affiliations.
Yahaya et al. Egyptian Journal of Medical Human Genetics (2020) 21:46(2020) 21:46