Genetic abnormalities leading to qualitative defects of sperm morphology or function

Abstract

Infertility, defined by the inability of conceiving a child after 1 year is estimated to concern approximately 50 million couples worldwide. As the male gamete is readily accessible and can be studied by a simple spermogram it is easier to subcategorize male than female infertility. Subjects with a specific sperm phenotype are more likely to have a common origin thus facilitating the search for causal factors. Male infertility is believed to be often multifactorial and caused by both genetic and extrinsic factors, but severe cases of male infertility are likely to have a predominant genetic etiology. Patients presenting with a monomorphic teratozoospermia such as globozoospermia or macrospermia with more than 85% of the spermatozoa presenting this specific abnormality have been analyzed permitting to identify several key genes for spermatogenesis such as AURKC and DPY19L2. The study of patients with other specific sperm anomalies such as severe alteration of sperm motility, in particular multiple morphological anomalies of the sperm flagella (MMAF) or sperm unability to fertilize the oocyte (oocyte activation failure syndrome) has also enable the identification of new infertility genes. Here we review the recent works describing the identification and characterization of gene defects having a direct qualitative effect on sperm morphology or function.

Whole exome sequencing of men with multiple morphological abnormalities of the sperm flagella reveals novel homozygous QRICH2 mutations

“…In the last few years, the emergence and availability of HTS technologies and especially of WES allowed the identification of numerous new genetic causes underlying severe phenotypes of human male infertility such as nonobstructive azoospermia and monomorphic teratozoospermia. 18,19 Among these severe phenotypes, the multiple morphological anomalies of the sperm flagella (MMAF) syndrome showed a high genetic heterogeneity highlighting the abundance of genes involving in flagellum biogenesis and implicated solely in this phenotype. 20 The discovery of new probands harboring QRICH2 mutations in MMAF syndrome by independent research teams is an important step in the validation process of genes involved in human infertility.…”

Interstitial Deletion of 5q22.2q23.1 Including APC and TSSK1B in a Patient with Adenomatous Polyposis and Asthenoteratozoospermia

“…The majority of testicular infertility factors and their genetic background have been linked to genes residing in the Y chromosome and chromosomal aberrations involving the Y chromosome [O'Flynn O'Brien et al, 2010]. There has been progress in the field, as recent research has aimed to relate sperm dysmorphology phenotypes to specific genes, such as DAZL , SYCE1 , SLC26A8 , SEPT12 , and others that have a function related to spermatogenesis [Ray et al, 2017]. Even so, the field of male infertility genetics is still relatively new, and novel contributions are crucial to the ongoing improvement of genetic testing, diagnosis, and counseling [Lamb et al, 2016].…”

DNAH2 is a novel candidate gene associated with multiple morphological abnormalities of the sperm flagella

“…Teratozoospermia, also known as teratospermia, is one of the most common phenotypes of male infertility . It is defined in over 85% of sperm with abnormal morphologies.…”

“…Teratozoospermia, also known as teratospermia, is one of the most common phenotypes of male infertility. 1,2 It is defined in over 85% of sperm with abnormal morphologies. Multiple morphological abnormalities of the sperm flagella (MMAF) is one type of teratozoospermia 1 and are characterized by a variety of flagellar defects, including absent, short, curled, bent or angulated flagella.…”