The current issue of the Croatian Medical Journal features 
two interesting articles on reproductive health. Sengun et 
al (1) present their findings of novel mutations in the gene 
coding for FK506 binding protein-like (FKBPL) associated 
with male infertility, while Bilić et al (2) discuss the benefits of ovarian tissue cryopreservation. In spite of tremendous advances in the field, various aspects of reproductive 
health, particularly infertility, still necessitate further study 
and development of novel diagnostic and therapeutic approaches

Calogero, Aldo E.

Cannarella, Rossella

Condorelli, Rosita A.

Vignera, Sandro  La

English

PubMed

HRČAK - Portal of Croatian Scientific and Professional Journals

201www.cmj.hrRossella Cannarella, Rosita A. Condorelli, Sandro La Vignera, Aldo E. CalogeroDepartment of Clinical and Experimental Medicine, University of Catania, Catania, Italyaldo.calogero@unict.itNew perspectives in the genetic diagnosis of male infertilityThe current issue of the Croatian Medical Journal features two interesting articles on reproductive health. Sengun et al (1) present their findings of novel mutations in the gene coding for FK506 binding protein-like (FKBPL) associated with male infertility, while Bilić et al (2) discuss the ben-efits of ovarian tissue cryopreservation. In spite of tremen-dous advances in the field, various aspects of reproductive health, particularly infertility, still necessitate further study and development of novel diagnostic and therapeutic ap-proaches.Infertility, defined by the World Health Organization as the failure to achieve conception after 12-24 months of unpro-tected sexual intercourse (3), affects about one out of six couples of childbearing age in Western countries (4). Male factor infertility is identified in about half of the cases (5) and most of the times presents as spermatogenesis fail-ure (SPGF). Spermatogenesis is a 74-day-long process in-volving up to 2000 genes. Among them, 600 to 900 are ex-clusively expressed by the male germ-line (6-8). Despite a comprehensive diagnostic workup, in the majority of cases the etiology of SPGF remains elusive. A monocentric study on 1737 infertile patients reported idiopathic oligozoo-spermia in ~ 75% of cases (9). Classic genetic screening can identify the cause of male infertility in only 5% of unselect-ed patients and in 20% of patients with non-obstructive azoospermia (NOA) (10). In the remaining cases, the etiol-ogy of infertility is elusive.In recent years, several mutations of genes involved in dif-ferent steps of spermatogenesis, such as spermatogonia proliferation or meiotic division of primary spermatocytes, have been reported capable of interfering with murine spermatogenesis (11). Interestingly, many of them have been validated in infertile patients, as shown in case re-ports or case series. Thus, the inclusion of a comprehensive gene panel in the diagnostic algorithm of male infertility could raise the diagnostic yields (11). The first study ad-dressing this issue analyzed a panel of three genes: NR5A1, DMRT1, and TEX11, in a cohort of 80 patients with NOA. NR5A1 (9q33.3) encodes for a transcription factor involved in the regulation of genes playing a role in steroidogene-sis. Its mutation has been associated with a wide spectrum of phenotypes, ranging from 46,XY partial and complete gonadal dysgenesis, to hypospadias, micropenis, anorchia, and, in otherwise healthy men, oligozoospermia or NOA. DMRT1 (9p24.3) encodes for a testis-specific transcription factor acting in testis differentiation, whose mutations have been reported in patients with NOA. Finally, TEX11 (Xq13.1) encodes for a meiosis-specific factor, involved in double-strand breaks DNA repair, which may play a role in NOA pathogenesis due to meiotic arrest (11). Out of 80 pa-tients with NOA investigated for NR5A1, DMRT1, and TEX11 gene mutations, the authors reported pathogenic vari-ants in four, thus raising the diagnostic yield by 25% (10). A subsequent study has developed a gene panel includ-ing 15 genes (Table 1) involved in germ-cell proliferation and meiotic division. Interestingly, pathogenic mutations of NR5A1 and TEX11 genes were reported in 3/25 patients, increasing the diagnostic rate by 12%. Noteworthy, 11 likely pathogenic variants meriting functional analysis or segregation studies were also observed.EDITORIAL  Croat Med J. 2021;62:201-3 https://doi.org/10.3325/cmj.2021.62.201EDITORIAL202 Croat Med J. 2021;62:201-3www.cmj.hrThese data highlight the importance of designing a com-prehensive and accurate gene panel to be used in patients with otherwise unexplained SPGF. Furthermore, next-gen-eration sequencing makes this analysis widely accessible from both an economic and a geographic point of view. An appropriate gene panel for SPGF could facilitate the identification of the genetic cause of infertility (when pres-ent), but in the future it may also represent a diagnostic test predicting sperm recovery after testicular sperm extraction (TESE). Accordingly, a study matching the results of testicu-lar histology with those of genetic testing has been pub-lished and others are currently ongoing. Interestingly, mu-tations (eg, deletions, missense, stop-gain) of specific genes involved in meiosis (eg, M1AP, ADAD2, TERB1, SHOC1, MSH4, RAD21L1, TEX14, DMRT1, TEX11, SYCE1, MEIOB, MEI1, STAG3-a) have been reported in patients with meiotic arrest (13,14). If validated, these gene variations may be included in a pre-TESE prognostic gene panel, which may help to determine the chance of sperm recovery. Finally, another challenge in this field is to understand the implications of the transmis-sion of these gene mutations to the offspring.In conclusion, the evidence favoring the inclusion of SPGF monogenic mutation assessment in the diagnos-tic workup of male infertility is accumulating. Despite this, a comprehensive panel has not yet been validated, although some gene mutations are more frequently pres-ent than others (eg, NR5A1 or TEX11), and others have re-cently been discovered. Since more than 2000 genes are involved in spermatogenesis, we are still far from a com-prehensive view of the monogenic etiology of SPGF. How-ever, in the near future, this evidence is likely to practically affect the diagnostic workup and decision-making algo-rithms of male infertility.TAbLE 1. Genes whose mutations cause spermatogenic failure characterized by a decreased sperm number (12)*Gene InheritanceOMIM numberOMIM phenotypeSpermatogenic defectMutation detection frequency HGNC gene numberNR5A1 AR 184757 SF8 AzoospermiaOligozoospermia2% (7/315) Nuclear receptor subfamily 5, group A, member 1SYCP3 AD 604759 SF4 AzoospermiaOligozoospermia10.5% (2/19) Synaptonemal complex protein 3ZMYND15 AR 614312 SF14 AzoospermiaOligozoospermia1 consanguineous family Zinc finger, MYND-type contain-ing 15TAF4B AR 601689 SF13 AzoospermiaOligozoospermia1 consanguineous family TAF4b RNA polymerase II, TATA box binding protein (TBP)-associ-ated factorTEX11 XLR 300311 SF, X-linked, 2 Azoospermia 1%-2.4% (7/289) azoo-spermia; 15% azoospermia with meiotic arrestTestis expressed 11NANOS1 AD 608226 SF12 AzoospermiaOligozoospermiaOAT2.6% (5/195) Nanos homologue 1 (Drosophila)PLK4 AD 605031 - Azoospermia (Sertoli cell-only syndrome)1.2% (1/81) Polo like kinase 4MEIOB AR 617670 SF22 NOA 1 consanguineous family Meiosis specific with OB domainsSYCE1 AR 611486 SF15 NOA 1 consanguineous family Synaptonemal complex central element protein 1USP9Y YL 400005 SF, Y-linked, 2 NOA 3 probands (4-db DEL; DEL incl. entire gene)Ubiquitin specific peptidase 9, Y-linkedSOHLH1 - 610224 - NOA 2% (2/100) Spermatogenesis and oogenesis specific basic helix-loop-helix 1RHOXF2 - 300447 - Severe oligozoospermia <1% (1/250) Rhox homeobox family member 2TEX15 AR 605795 - AzoospermiaOligozoospermia2 family; 1 proband Testis expressed 15, meiosis and synapsis associatedHSF2 AD 140581 - Azoospermia <1%(1/766) Heat shock transcription factor 2KLHL10 AD 608778 SF11 OAT 1.3% (7/556) Kelch-like family member 10*Abbreviations: OMIM – Online Mendelian Inheritance in Man; HGNC – Hugo Gene Nomenclature Committee; AD – autosomal dominant; AR – auto-somal recessive; NOA – non-obstructive azoospermia; OAT – oligo-astheno-teratozoospermia; SF – spermatogenic failure.203Cannarella et al:  New perspectives in the genetic diagnosis of male infertilitywww.cmj.hrReferences1 Sengun DA, Tanoglu EG, Ulucan H. A novel mutation in FK506 binding protein-like (FKbPL) causes male infertility. Croat Med J. 2021;62:227-32.2 bilić K, Vilaj M, Golubić-Ćepulić b, Ježek D. Ovarian tissue bank. Croat Med J. 2021;62:297-9.3 World Health Organization. Report of the meeting on the prevention of infertility at the primary health care levels. Geneva: WHO; 1983).4 Agarwal A, Mulgund A, Hamada A, Chyatte MR. A unique view on male infertility around the globe. Reprod biol Endocrinol. 2015;13:37. Medline:25928197 doi:10.1186/s12958-015-0032-15 Valenti D, La Vignera S, Condorelli RA, Rago R, barone N, Vicari E, et al. Follicle-stimulating hormone treatment in normogonadotropic infertile men. Nat Rev Urol. 2013;10:55-62. Medline:23229508 doi:10.1038/nrurol.2012.2346 Schultz N, Hamra FK, Garbers DL. A multitude of genes expressed solely in meiotic or postmeiotic spermatogenic cells offers a myriad of contraceptive targets. Proc Natl Acad Sci U S A. 2003;100:12201-6. Medline:14526100 doi:10.1073/pnas.16350541007 Matzuk MM, Lamb DJ. The biology of infertility: research advances and clinical challenges. Nat Med. 2008;14:1197-213. Medline:18989307 doi:10.1038/nm.f.18958 Yan W. Male infertility caused by spermiogenic defects: lessons from gene knockouts. Mol Cell Endocrinol. 2009;306:24-32. Medline:19481682 doi:10.1016/j.mce.2009.03.0039 Punab M, Poolamets O, Paju P, Vihljajev V, Pomm K, Ladva R, et al. Causes of male infertility: a 9-year prospective monocentre study on 1737 patients with reduced total sperm counts. Hum Reprod. 2017;32:18-31. Medline:2786436110 Tüttelmann F, Ruckert C, Röpke A. Disorders of spermatogenesis: Perspectives for novel genetic diagnostics after 20 years of unchanged routine. Med Genetik. 2018;30:12-20. Medline:29527098 doi:10.1007/s11825-018-0181-711 Cannarella R, Condorelli RA, Duca Y, La Vignera S, Calogero AE. New insights into the genetics of spermatogenic failure: a review of the literature. Hum Genet. 2019;138:125-40. Medline:30656449 doi:10.1007/s00439-019-01974-112 Cannarella R, Condorelli RA, Paolacci S, barbagallo F, Guerri G, bertelli M, et al. Next-generation sequencing: toward an increase in the diagnostic yield in patients with apparently idiopathic spermatogenic failure. Asian J Androl. 2021;23:24-9. Medline:32655042 doi:10.4103/aja.aja_25_2013 Wyrwoll MJ, Temel ŞG, Nagirnaja L, Oud MS, Lopes AM, van der Heijden GW, et al. bi-allelic mutations in M1AP are a frequent cause of meiotic arrest and severely impaired spermatogenesis leading to male infertility. Am J Hum Genet. 2020;107:342-51. Medline:32673564 doi:10.1016/j.ajhg.2020.06.01014 Krausz C, Riera-Escamilla A, Moreno-Mendoza D, Holleman K, Cioppi F, Algaba F, et al. Genetic dissection of spermatogenic arrest through exome analysis: clinical implications for the management of azoospermic men. Genet Med. 2020;22:1956-66. Medline:32741963 doi:10.1038/s41436-020-0907-1

New perspectives in the genetic diagnosis of male infertility

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http://dx.doi.org/10.3325/cmj.2021.62.201

New perspectives in the genetic diagnosis of male infertility

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