Population variation in Y-chromosome microdeletion and its role in the evaluation of male infertility management: a systematic review

Background: Infertility has been a significantly growing problem worldwide, affecting approximately 10-15% of couples within reproductive age. Among the many causes of male infertility, Y-chromosome microdeletion is considered one of the most frequent genetic causes. Thus, this systematic review was constructed to determine the prevalence of Y-chromosome microdeletion and the population variations in the different types of Y-chromosome microdeletions. Methods: We searched the PubMed, Scielo, and Science Direct databases to obtain articles that addressed the frequency of Y-chromosome microdeletion and male infertility. We identified 14 articles that originated from China, India, Iran, Brazil, Indonesia, North America, South Korea, and Slovakia, and the vital information collected included the year of publication, authors, number of patients with different types of Y-chromosome microdeletions, and the proportion of microdeletion in the major affected sub-regions of the Y-chromosome. Results: In this review, we attempted to highlight the variation in the frequency of Y-chromosome microdeletion in different geographical populations. The highest and lowest frequencies of Y-chromosome microdeletion were found in Indonesian (23.94%) and Slovakian (3.5%) populations, respectively. Conclusion: In conclusion, Y-chromosome microdeletion was undeniably found to be one of the leading genetic causes of male infertility. Azoospermic factor c (AZFc) microdeletion was the most frequent type of Y-chromosome microdeletion, typically presenting in patients with various clinical manifestations that ranged from oligozoospermia to azoospermia and exhibiting the highest chance for sperm retrieval. This review will undoubtedly help clinicians in providing a more accurate consultation to their patients and determining the success rates of assisted reproductive technology.

Genetic Factors of Non-Obstructive Azoospermia: Consequences on Patients’ and Offspring Health

Non-Obstructive Azoospermia (NOA) affects about 1% of men in the general population and is characterized by clinical heterogeneity implying the involvement of several different acquired and genetic factors. NOA men are at higher risk to be carriers of known genetic anomalies such as karyotype abnormalities and Y-chromosome microdeletions in respect to oligo-normozoospermic men. In recent years, a growing number of novel monogenic causes have been identified through Whole Exome Sequencing (WES). Genetic testing is useful for diagnostic and pre-TESE prognostic purposes as well as for its potential relevance for general health. Several epidemiological observations show a link between azoospermia and higher morbidity and mortality rate, suggesting a common etiology for NOA and some chronic diseases, including cancer. Since on average 50% of NOA patients has a positive TESE outcome, the identification of genetic factors in NOA patients has relevance also to the offspring’s health. Although still debated, the observed increased risk of certain neurodevelopmental disorders, as well as impaired cardiometabolic and reproductive health profile in children conceived with ICSI from NOA fathers may indicate the involvement of transmissible genetic factors. This review provides an update on the reproductive and general health consequences of known genetic factors causing NOA, including offspring’s health.

CAG polymorphism of the Androgen Receptor gene and semen parameters in pathozoospermic patients with and without Y chromosome microdeletions, and in normozoospermic men

Introduction. The effect of polymorphic variants of the androgen receptor gene (AR) on spermatogenesis and semen parameters in men with different genotypes for other loci has not been sufficiently studied.The aim of this work was to study the effect of the (CAG)n polymorphism of the AR gene on semen parameters in men with impaired fertility, with and without partial deletions of the AZFс region from the Y chromosome.Materials and methods. The study included 988 unrelated Russian patients with pathozoospermia, including 591 patients without Y chromosome microdeletions and 397 patients with partial deletions of the AZFc region of the Y chromosome. The control group consisted of 131 normozoospermic men. All men who participated in the study underwent semen analysis and genetic testing. Genomic DNA was isolated from peripheral venous blood lymphocytes and ejaculate. The analysis of the polymorphism of (GAG)n repeat in exon 1 of the AR gene was performed using a polymerase chain reaction by the amplified fragment length polymorphism method.Results. Three groups were studied: patients with pathozoospermia with (n = 32) and without (n = 541) Y chromosome microdeletions, and normozoospermic men (control, n = 131). The median and quartiles of the number of CAG repeats in the groups were 22 and 20-25, respectively. According to the number of trinucleotide repeats of the AR gene, all patients were divided into subgroups: carriers of short ((GAG)n ≤18), medium ((GAG)n = 19-25) and long ((GAG)n ≥26) alleles. Medium alleles prevailed in all groups; in men without AZFc deletions and with microdeletions, their frequency was 79.3 and 81.4 %, respectively, in controls - 81.7 %.Conclusion. No correlation was found in examined cohort for semen parameters (sperm concentration and total number, number of live, progressively motile and morphologically normal spermatozoa) from the number of trinucleotide repeats. However, a statistically significant difference (p ≤0.045; FDR correction) was found in concentration and total number, number of live, progressively motile and morphologically normal spermatozoa when comparing men with nomrozoospermia (control) with patients with pathozoospermia with and without partial AZFc deletions in subgroups of carriers of short, medium and long alleles.

The genetic causes of infertility in patients with oligozoospermia and azoospermia in Turkish population

Objective: Advances in the science of genetics and the development of assisted reproductive techniques focus on the genetic causes of infertility. The aim of this research is to reveal genetic abnormalities in terms of sex chromosome aneuploidy and Y chromosome microdeletions. Material and Methods: A total of 350 patients with azoospermia or severe oligozoospermia were selected. After general examination of the patients and laboratory investigations were performed, cartoypes and Y chromosome microdeletions were examined. Results: A total of 225 infertile men with non-obstructive azoospermia (NOA) and 125 infertile men with oligozoospermia were enrolled into the study. The overall cytogenetic anomaly rate was 16%. Chromosomal changes were detected in 32 of 350 (9.1%) cases. The most common genetic anomaly was 47, XXY (Klinefelter syndrome) and the incidence was 11.5% in NOA group. This rate was 3.2% in oligozoospermia group. Y chromosome microdeletions were detected in 24 (6.8%) patients and similarly, it was observed more frequently in the NOA group than in the oligozoospermia group. Conclusion: The incidence of genetic causes have been increasing with the severity of infertility. As a result, genetic screening and appropriate genetic counseling are needed before the use of assisted reproductive techniques. Keywords: azospermia, chromosome, infertility, microdeletion, oligozoospermiaage

The Spectrum of Common Mutations in CFTR, AR Gene, and the Y Chromosome Microdeletions and Karyotyping Abnormalities in Phenotypic Male with Very Severe Oligozoospermia

Male infertility due to very severe oligozoospermia has been associated with a number of genetic risk factors.This association in patients with sperm concentration lower than 1× 106 ml are not yet fully studied.The present study aims to investigate the distribution of the mutations in the CFTR gene, the CAG repeat expansion of the AR gene as well as Y chromosome microdeletions and karyotyping abnormalities in very severe oligozoospermia patients from the Iranian population. In the present case-control study 200 severe oligozoospermia and 200 fertile males were enrolled. All patients karyotyped for diagnosis of the chromosomal abnormalities using routine. Microdeletions were evaluated using multiplex PCR. Five common CFTR mutations were genotyped using the ARMS-PCR technique. The CAG repeat expansion in the AR gene was evaluated for the number of repeats in each patient using sequencing. Overall, 4% of cases have a numerical and structural abnormality. 7.5% of patients had a deletion in one of the AZF regions on Yq, and 3.5% had a deletion in two regions. F508del was the most common (4.5%) CFTR gene mutation, G542X, and W1282X were detected with 1.5% and 1% respectively. One patient was found to have AZFa microdeletion and F508del in heterozygote form; one patient had AZFb microdeletion with F508del. F508del was seen as compound heterozygous with G542X in one patient and with W1282X in the other patient. The difference in the mean of the CAG repeat in the AR gene in patients and controls were statistically significant (P = 0.04). Our study shows that ICSI in couples with very severe oligozoospermia can lead to an increase in children who are at risk of unbalanced chromosomal complement, male infertility due to transmission of Y-chromosomal microdeletion , AR- CAG repeat and cystic fibrosis if both partners carry the CFTR gene mutation. Genetic testing and counseling before considering ICSI is suggested for these couples.

Novel Variants in HFM1 Lead to Male Infertility Due to Non-obstructive Azoospermia

Background Non-obstructive azoospermia (NOA) is the most severe form of male infertility. More than half of the NOA patients were idiopathic for their etiology, in whom it’s difficult to retrieve sperm despite the application of microsurgical testicular sperm extraction (microTESE). Therefore, we conducted to this study to identify the potential genetic factors responsible for NOA, and investigate the sperm retrieval rate of microTESE for the genetic defected NOA.Methods One NOA patient from a consanguineous family (F1-II-1) and fifty NOA patients from non-consanguineous families were included in the study. Semen analyses, chromosome karyotypes, screening of Y chromosome microdeletions, sex hormone testing, and subsequent testicular biopsy were performed to categorize NOA or obstructive azoospermia. Potentialgenetic variants were identified by whole exome sequencing (WES),and confirmed by Sanger sequencing in F1 II-1. The candidate genes were screened in the other fifty NOA patients. Further experiments including quantitative real time-polymerase chain reaction and western blotting were performed to verify the effects of gene variation on gene expression.Results Normal somatic karyotypes and Y chromosome microdeletions were examined in all patients. Hematoxylin and eosin staining (H&E) of the testicular tissues suggested meiotic arrest, and a novel homozygous HFM1 variant (c.3490C>T: p.Q1164X) was identified in F1 II-1. Furthermore, another homozygous HFM1 variant (c.3470G>A: p.C1157Y) was also verified in F2 II-1 from the fifty NOA patients. Significantly decreased expression levels of HFM1 mRNA and protein were observed in the testicular tissues of these two mutants compared with controls. MicroTESE was performed in these two patients, while no sperm were retrieved. Conclusions Our study identified two novel homozygous variants of HFM1 that are responsible for spermatogenic failure and NOA, even microTESE can not contribute to retrieve sperm in these patients.

Evaluation of Y chromosome microdeletions and chromosomal anomalies in infertile men

Objectives Chromosome anomalies and Y chromosome microdeletions are one of the reasons that can be seen in infertile patients and affect fertility. In this study, it was aimed to determine the frequencies of chromosomal anomalies and Y chromosome microdeletions in primary infertile male patients. Methods We included 374 patients with primary infertility in this study. Cytogenetic analysis was performed with the GTG banding technique by using trypsin and Giemsa stain. Y microdeletion analysis was studied by multiplex polymerase chain reaction using 28 Y chromosome-specific sequence-tagged sites. Results Chromosomal irregularities were detected in 27 (7.22%) of infertile cases. It was observed that 7 (25.92%) of chromosomal irregularities detected in cases were in autosomal and 20 (%74.08) were in gonosomal chromosomes. The incidence of Y chromosome microdeletion was 1.07% (4/374) and the microdeletions were observed in AZFb, AZFc and AZFd regions. AZFc + AZFd deletion was detected in three patients (0.81%) and AZFb + AZFc + AZFd deletion in one patient (0.26%). Conclusions In conclusion, gonosomal chromosome irregularity was higher than autosomal chromosome irregularity in infertile men. The frequency of Y microdeletion has different rates according to some factors such as ethnic differences of patients, patient selection criteria, differences in the number of cases, and methodological aspects.