Is BRD7 associated with spermatogenesis impairment and male infertility in humans? A case-control study in a Han Chinese population

Background Bromodomain-containing protein 7 (BRD7), a member of the bromodomain-containing protein family, plays important roles in chromatin modification and transcriptional regulation. A recent model of Brd7-knockout mice presented azoospermia and male infertility, implying the potential role of BRD7 in spermatogenic failure in humans. This case-control study aimed to explore the association of the BRD7 gene with spermatogenic efficiency and the risk of spermatogenic defects in humans. Results A total of six heterozygous variants were detected in the coding and splicing regions of the BRD7 gene in patients with azoospermia. For each of four rare variants predicted to potentially damage BRD7 function, we further identified these four variants in oligozoospermia and normozoospermia as well. However, no difference in the allele and genotype frequencies of rare variants were observed between cases with spermatogenic failure and controls with normozoospermia; the sperm products of variant carriers were similar to those of noncarriers. Moreover, similar distribution of the alleles, genotypes and haplotypes of seven tag single nucleotide polymorphisms (tagSNPs) was observed between the cases with azoospermia and oligozoospermia and controls with normozoospermia; associations of tagSNP-distinguished BRD7 alleles with sperm products were not identified. Conclusions The lack of an association of BRD7-linked rare and common variants with spermatogenic failure implied a limited contribution of the BRD7 gene to spermatogenic efficiency and susceptibility to male infertility in humans.

Nonobstructive azoospermia, when we can find spermatozoa, is FSH as a marker of succes?

Azoospermia is the absence of spermatozoa in ejaculate even after semen centrifugation at least two times. Azoospermia due to spermatogenic failure – non-obstructive azoospermia (NOA) observed in 1% of population and in 10–15% of infertile men. Predictive factors for the presence of spermatozoa in testis are still under debate. The development of ICSI revolutionized management of azoospermia. In our practice we advised TESA as a first step and FSH can predict the success. According serum FSH levels we divided our men in three groups: FSH < 10 mU/ml, 10–15 mU/ml and > 15 mU/ml. We tried to evaluated SRR in accordance serum FSH level and find significant difference. In 117 men with FSH < 10 mU/ml SRR was 66% (in 77 cases), in 89 men which FSH was 10–15 mU/ml SRR was 27 % and finally SRR was 35% when FSH was > 15 mU/ml (45 cases from 131). At the same time, we make embryologist personal assessment (EPA) and try to show embryologist crucial role in tissue assessment after TESA. Another crucial point of discussion – histomorphology within the testis in NOA and indications for re – TESA after 3–6 months.

A common 1.6 mb Y-chromosomal inversion predisposes to subsequent deletions and severe spermatogenic failure in humans

Male infertility is a prevalent condition, affecting 5–10% of men. So far, few genetic factors have been described as contributors to spermatogenic failure. Here, we report the first re-sequencing study of the Y-chromosomal Azoospermia Factor c (AZFc) region, combined with gene dosage analysis of the multicopy DAZ, BPY2, and CDYgenes and Y-haplogroup determination. In analysing 2324 Estonian men, we uncovered a novel structural variant as a high-penetrance risk factor for male infertility. The Y lineage R1a1-M458, reported at >20% frequency in several European populations, carries a fixed ~1.6 Mb r2/r3 inversion, destabilizing the AZFc region and predisposing to large recurrent microdeletions. Such complex rearrangements were significantly enriched among severe oligozoospermia cases. The carrier vs non-carrier risk for spermatogenic failure was increased 8.6-fold (p=6.0×10−4). This finding contributes to improved molecular diagnostics and clinical management of infertility. Carrier identification at young age will facilitate timely counselling and reproductive decision-making.

Male Infertility Diagnosis: Improvement of Genetic Analysis Performance by the Introduction of Pre-Diagnostic Genes in a Next-Generation Sequencing Custom-Made Panel

BackgroundInfertility affects about 7% of the general male population. The underlying cause of male infertility is undefined in about 50% of cases (idiopathic infertility). The number of genes involved in human spermatogenesis is over two thousand. Therefore, it is essential to analyze a large number of genes that may be involved in male infertility. This study aimed to test idiopathic male infertile patients negative for a validated panel of “diagnostic” genes, for a wide panel of genes that we have defined as “pre-diagnostic.”MethodsWe developed a next-generation sequencing (NGS) gene panel including 65 pre-diagnostic genes that were used in 12 patients who were negative to a diagnostic genetic test for male infertility disorders, including primary spermatogenic failure and central hypogonadism, consisting of 110 genes.ResultsAfter NGS sequencing, variants in pre-diagnostic genes were identified in 10/12 patients who were negative to a diagnostic test for primary spermatogenic failure (n = 9) or central hypogonadism (n = 1) due to mutations of single genes. Two pathogenic variants of DNAH5 and CFTR genes and three uncertain significance variants of DNAI1, DNAH11, and CCDC40 genes were found. Moreover, three variants with high impact were found in AMELY, CATSPER 2, and ADCY10 genes.ConclusionThis study suggests that searching for pre-diagnostic genes may be of relevance to find the cause of infertility in patients with apparently idiopathic primary spermatogenic failure due to mutations of single genes and central hypogonadism.

E2F1 regulates testicular descent and controls spermatogenesis by influencing WNT4 signaling

ABSTRACTCryptorchidism is the most common urologic birth defect in men and is a predisposing factor of male infertility and testicular cancer, yet the etiology remains largely unknown. E2F1 microdeletions and microduplications contribute to cryptorchidism, infertility and testicular tumors. Although E2f1 deletion or overexpression in mice causes spermatogenic failure, the mechanism by which E2f1 influences testicular function is unknown. This investigation revealed that E2f1-null mice develop cryptorchidism with severe gubernacular defects and progressive loss of germ cells resulting in infertility and, in rare cases, testicular tumors. It was hypothesized that germ cell depletion resulted from an increase in WNT4 levels. To test this hypothesis, the phenotype of a double-null mouse model lacking both Wnt4 and E2f1 in germ cells was analyzed. Double-null mice are fertile. This finding indicates that germ cell maintenance is dependent on E2f1 repression of Wnt4, supporting a role for Wnt4 in germ cell survival. In the future, modulation of WNT4 expression in men with cryptorchidism and spermatogenic failure due to E2F1 copy number variations may provide a novel approach to improve their spermatogenesis and perhaps their fertility potential after orchidopexy.

A common 1.6 Mb Y-chromosomal inversion predisposes to subsequent deletions and severe spermatogenic failure in humans

Male infertility is a prevalent condition, concerning 5-10% of men. So far, only some recurrent genetic factors have been described as confident contributors to spermatogenic failure. Here, we report the first re-sequencing study of the Y-chromosomal Azoospermia Factor c (AZFc) region combined with gene dosage and Y-haplogroup determination. In analysing 2,324 Estonian men, we uncovered a novel structural variant as a high-penetrant risk factor to male infertility. The Y lineage R1a1-M458, reported at >20% frequency in several European populations, carries a fixed ∼1.6 Mb long r2/r3 inversion destabilizing the AZFc region and predisposing to recurrent microdeletions. Such complex rearrangements were significantly enriched among severe oligozoospermia cases. The carrier vs non-carrier risk to spermatogenic failure was increased 8.6-fold (p = 6.0 × 10−4). The finding contributes to improved molecular diagnostics and clinical management of infertility. Carrier identification in young age will facilitate timely counselling and reproductive decision-making.