A de novo paradigm for male infertility

De novo mutations are known to play a prominent role in sporadic disorders with reduced fitness. We hypothesize that de novo mutations play an important role in severe male infertility and explain a portion of the genetic causes of this understudied disorder. To test this hypothesis, we utilize trio-based exome sequencing in a cohort of 185 infertile males and their unaffected parents. Following a systematic analysis, 29 of 145 rare (MAF < 0.1%) protein-altering de novo mutations are classified as possibly causative of the male infertility phenotype. We observed a significant enrichment of loss-of-function de novo mutations in loss-of-function-intolerant genes (p -value = 1.00 × 10 −5) in infertile men compared to controls. Additionally, we detected a significant increase in predicted pathogenic de novo missense mutations affecting missense-intolerant genes (p -value = 5.01 × 10 −4) in contrast to predicted benign de novo mutations. One gene we identify, RBM5, is an essential regulator of male germ cell pre-mRNA splicing and has been previously implicated in male infertility in mice. In a follow-up study, 6 rare pathogenic missense mutations affecting this gene are observed in a cohort of 2,506 infertile patients, whilst we find no such mutations in a cohort of 5,784 fertile men (p -value = 0.03). Our results provide evidence for the role of de novo mutations in severe male infertility and point to new candidate genes affecting fertility. Germline de novo mutations can impact individual fitness, but their role in human male infertility is understudied. Trio-based exome sequencing identifies many new candidate genes affecting male fertility, including an essential regulator of male germ cell pre-mRNA splicing

Cervical determinants of anal HPV infection and high-grade anal lesions in women: a collaborative pooled analysis

Cervical cancer screening might contribute to the prevention of anal cancer in women. We aimed to investigate if routine cervical cancer screening results-namely high-risk human papillomavirus (HPV) infection and cytohistopathology-predict anal HPV16 infection, anal high-grade squamous intraepithelial lesions (HSIL) and, hence, anal cancer.International Agency for Research on Cance

Informational needs of couples undergoing intracytoplasmic sperm injection with surgical sperm retrieval: A qualitative study

OBJECTIVE: Infertile couples consider patient information a very important dimension of patient-centred care. Although testicular sperm extraction (TESE) followed by intracytoplasmic sperm injection (ICSI) has long been offered to infertile couples, little is known about couples' informational needs. The aim of this study was to identify the informational needs of couples undergoing TESE and ICSI, including information content and the channels providing the information as a first step to improve patient-centred care. STUDY DESIGN: We conducted a qualitative study consisting of semi-structured interviews with 11 couples. The topic guide was based on a literature review and interviews with an expert panel. The number of interviews was determined with data saturation. The data were analysed using a constant comparative method. RESULTS: The couples needed information about many topics. They considered information about the success rates of the treatment, an explanation of the treatment procedure, and other patient experiences the most important. Regarding information channels, the couples preferred face-to-face information, but they also valued a leaflet, website, or an online application, especially when it is personalized or providing interactive functionalities. CONCLUSION: We obtained in-depth insight into the information needs of couples undergoing TESE and ICSI. The results of this study give fertility clinics an opportunity to develop patient information that meets the needs of their patients and thus improve patient-centred fertility care

Improved detection of CFTR variants by targeted next-generation sequencing in male infertility: a case series

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Klinefelter syndrome and fertilityImpact of X-chromosomal inheritance on spermatogenesis

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A comparative study of british and south african 12yr old rugby players, in relation to game-specific, physical, motor and anthropometric variables

Most of the non-obstructive azoospermia (NOA)-patients have only focal spermatogenesis which results in insufficient numbers of spermatozoa to reach the ejaculate. In approximately 50% of these NOA-patients testicular sperm extraction (TESE) is successful and intracytoplasmic sperm injection (ICSI) is pursued. We studied whether (i) spermatogenesis can be evaluated by defining the ratios between Sertoli cells, pachytene spermatocytes and spermatozoa in a testicular cell suspension, and (ii) these ratios are associated with the outcome of fertility treatment. A retrospective cohort study was conducted between June 2007 and August 2012. In this period, 441 consecutive ICSI-TESE cycles were performed in 212 couples. For each TESE biopsy, the ratios between Sertoli cells, pachytene spermatocytes and spermatozoa were calculated. A control population of 32 vasectomized men was used to define cut-off values for complete spermatogenesis. Based on the pachytene to sperm ratio (P/Sp) and number of spermatozoa per 100 Sertoli cells (#Sp/100SC) groups were defined as complete spermatogenesis, hypospermatogenesis and partial maturation arrest (MA). Validation of the cytological diagnoses was performed by comparing the results of cytology to the histological evaluation of spermatogenesis in 40 cases. In 92.5%, a perfect match was observed and in the three remaining cases cytology corresponded well with the results of TESE. Couples with complete spermatogenesis have a higher ongoing pregnancy rate after the first treatment cycle compared to couples with hypospermatogenesis (34 vs. 16%; p = 0.02) and partial MA (34 vs. 19%; p = 0.11). In conclusion, pachytene spermatocytes, spermatozoa and Sertoli cells can be easily identified and counted in a cell suspension and their ratios can be successfully used to diagnose the level of spermatogenic impairment. This pilot study indicates that once successful spermatozoa retrieval is achieved, treatment outcome declines when spermatogenesis is impaired in NOA. The predictive value of cytological evaluation of spermatogenesis has to be established in a future prospective trial