Testing for genetic contributions to infertility: potential clinical impact

Abstract

Male infertility affects about 7% of the general male population, and it is a multifactorial, polygenic pathological condition. Known genetic factors, accounting for about 20-25% of male factor infertility, are present in each etiological category: i) hypothalamic-pituitary axis dysfunction; ii) quantitative and qualitative alterations of spermatogenesis; iii) ductal obstruction/dysfunction. Areas covered: All routinely available genetic tests are described. Indication for testing for chromosomal anomalies and Y chromosome microdeletions is based on sperm count (severe oligozoospermia/azoospermia). Mutation screening in candidate genes is indicated in specific semen/testis phenotypes. In about 40% of infertile patients, the aetiology remains unknown ('idiopathic cases') and whole exome sequencing may reveal novel genetic causes. Expert commentary: Genetic testing is essential for its relevance in clinical decision-making. For instance, it helps to avoid unnecessary surgical or medical treatments and it may provide prediction for testicular sperm retrieval. The highest frequency of genetic anomalies is observed in severe spermatogenic impairment, which can be treated with in vitro fertilization (IVF). Given the risk of transmitting genetic disorders to the future offspring through IVF, the diagnosis of known and the discovery of novel genetic factors in idiopathic infertility is of outmost clinical importance.

Genetics of ncHH: from a peculiar inheritance of a novel GNRHR mutation to a comprehensive review of the literature

“…Gonadotropin‐releasing hormone (GnRH) stimulates gonadotropins (FSH and LH) which are crucial for both reproductive and endocrine function of the testis. A deficit in LH and FSH secretion might be caused by congenital or acquired factors and these can be related to a primary lesion in the pituitary gland or secondary to insufficient hypothalamic GnRH production or action (Boehm et al ., ; Krausz et al ., ). This pathological condition is referred as hypogonadotropic hypogonadism, and its clinical manifestation depends on the timing of onset of the disease.…”

“…Congenital hypogonadotropic hypogonadism is a rare genetic form of hypogonadism with a higher prevalence in male subjects (1 : 8000). It typically manifests with absent or delayed puberty, but the phenotypic presentation of this disease and its genetic background are highly heterogeneous (Krausz et al ., ). The first gene defect found to be responsible for isolated normosmic congenital hypogonadotropic hypogonadism (ncHH) was described in the GNRHR (de Roux et al ., ).…”

Clinical and molecular characterization of Y microdeletions and X‐linked CNV67 implications in male fertility: a 20‐year experience

“…Many genetic alterations have been identified, some with putative direct or indirect implications in fertility and others with unknown precise effects (Wosnitzer, ). With tests such as karyotype and Yq microdeletion analyses, cystic fibrosis transmembrane conductance regulator (CFTR) gene and congenital hypogonadotropic hypogonadism mutation screenings, half of the cases of male infertility remains idiopathic (Krausz et al ., ). Additional investigations on still unknown factors involved are required to identify the potential contribution of genome alterations in this disorder (Benkhalifa et al ., ) and its short‐ and long‐term consequences on the offspring in those who have assisted reproductive techniques as a therapeutic option (Krausz et al ., ).…”

“…Approximately 15% of couples worldwide are affected with infertility, attributed to a male co-factor in about half of the cases (de Kretser, 1997;Tuttelmann et al, 2011b). Although many genetic mutations and polymorphisms linked to spermatogenesis have been identified during the last years and despite full clinical workup (including karyotype, Y chromosome microdeletion testing, cystic fibrosis transmembrane conductance regulator (CFTR) gene screening and hypogonadotropic hypogonadism mutation screening in some cases) (Wosnitzer, 2014), the aetiopathogenesis of male infertility remains unclear in around 50% of cases (Jungwirth et al, 2012;Krausz et al, 2018). The aetiology of most of these 'idiopathic infertility' cases is likely to be related to genetic abnormalities ) as more than one thousand genes are now thought to be functionally required to spermatogenesis, some of them specifically expressed on the male gonads and consequently strong candidates to explain spermatogenic failure (Matzuk & Lamb, 2008;Krausz, 2011).…”

Male Infertility is a Women’s Health Issue—Research and Clinical Evaluation of Male Infertility Is Needed

“…Of note, in this manuscript, we focus on the sperm's role in male infertility; however, similar arguments can be made about other contributing elements. For example, the male genital tract [2], seminal fluids [3,4], hormonal regulation [5,6], non-germ line testicular cells [7,8], and his genetic constitution can all contribute to male infertility [9]. Finally, we focus on how investing in the identification of new male infertility mechanisms will improve the treatment outcomes and lives of women in the future.…”