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Genes predisposing to syndromic and nonsyndromic infertility: a narrative review
Egyptian Journal of Medical Human Genetics volume 21, Article number: 46 (2020)
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.
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.
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.
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 . Infertility affects about 48.5 million couples, representing 15% of couples worldwide . 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 . 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 . An in-depth understanding of these mentioned causes is necessary for the prevention and effective treatment of infertility . 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, GeneCards, 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 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 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 extended to everyone who has the means . 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 . 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 a large number of target and non-target genes . However, the technique has some limitations too, which is its inability to detect haploidies, polyploidies, and mosaicisms .
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 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.
Availability of data and materials
Androgen insufficiency syndrome
Congenital bilateral absence of the vas deferens
Fragile X-associated primary ovarian insufficiency
Genetic home reference
National Center for Biotechnology Information
Ovarian hyperstimulation syndrome
Polycystic ovary syndrome
Premature ovarian failure
Single nucleotide polymorphism
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Yahaya, T.O., Liman, U.U., Abdullahi, H. et al. Genes predisposing to syndromic and nonsyndromic infertility: a narrative review. Egypt J Med Hum Genet 21, 46 (2020). https://doi.org/10.1186/s43042-020-00088-y
- Ovarian Failure