Large-scale analyses of the X chromosome in 2,354 infertile men discover recurrently affected genes associated with spermatogenic failure.

Although the evolutionary history of the X chromosome indicates its specialization in male fitness, its role in spermatogenesis has largely been unexplored. Currently only three X chromosome genes are considered of moderate-definitive diagnostic value. We aimed to provide a comprehensive analysis of all X chromosome-linked protein-coding genes in 2,354 azoospermic/cryptozoospermic men from four independent cohorts. Genomic data were analyzed and compared with data in normozoospermic control individuals and gnomAD. While updating the clinical significance of known genes, we propose 21 recurrently mutated genes strongly associated with and 34 moderately associated with azoospermia/cryptozoospermia not previously linked to male infertility (novel). The most frequently affected prioritized gene, RBBP7, was found mutated in ten men across all cohorts, and our functional studies in Drosophila support its role in germ stem cell maintenance. Collectively, our study represents a significant step towards the definition of the missing genetic etiology in idiopathic severe spermatogenic failure and significantly reduces the knowledge gap of X-linked genetic causes of azoospermia/cryptozoospermia contributing to the development of future diagnostic gene panels.

Efecto del tadalafilo 5mg/día en la hemodinámica peniana en pacientes con disfunción eréctil / Effect of tadalafil 5mg daily treatment on penile haemodynamics in patients with erectile dysfunction

Antecedentes y objetivo: Los inhibidores de la fosfodiesterasa 5 son los fármacos más utilizados para tratar a los pacientes con disfunción eréctil (DE). Los métodos para diagnosticar y evaluar la DE así como la respuesta al tratamiento son básicamente clínicos, es decir, la percepción del paciente sobre la calidad de su erección y la realización de cuestionarios validados. Actualmente aun es necesario identificar marcadores que puedan predecir la respuesta al tratamiento farmacológico. Este estudio pretende evaluar si la toma diaria de tadalafilo 5mg es capaz de inducir cambios en la hemodinámica peniana (midiendo la velocidad del pico sistólico (VPS) y la aceleración sistólica (AS) mediante ecografía doppler, sin utilizar alprostadilo) y estudiar si estos cambios tienen una correlación clínica. El objetivo es identificar un factor predictivo hemodinámico de respuesta al tratamiento farmacológico.Materiales y métodos: Se realizó un estudio prospectivo a 40 pacientes con DE a los que se inició tratamiento con tadalafilo 5mg/día. Estos respondieron a los cuestionarios IIEF-6, EHS, SEP-2 y SEP-3, y se les realizó una ecografía doppler peniana en 3 momentos distintos: antes de comenzar el tratamiento, a los 3 y a los 6 meses (estando previamente 30 días sin medicación).Resultados y conclusiones: El tratamiento durante 3 meses no modificó de forma significativa la VPS y la AS. Sí hubo una mejoría clínica tras 3 meses de tratamiento de acuerdo a los cuestionarios, que no se mantuvo a los 6 meses. No se pudo establecer una correlación clínico-radiológica ni encontramos un valor hemodinámico predictor de respuesta al tratamiento. (AU)

Introduction and objective: Phosphodiesterase-5 inhibitors (PDE-5) are the first-line treatment. ED diagnostic and evaluation methods are clinical: erection self-perception and evaluation questionnaires. It is necessary to identify predictive markers to choose the best drug and the best dose for each individual patient. This study seeks to evaluate the effect of tadalafil 5mg daily treatment on penile haemodynamics (penis in flaccidity, using doppler ultrasound, without using alprostadil) and to study if these changes are clinically associated.Material and methods: 40 patients who started treatment with tadalafil 5mg daily were consecutively selected in a prospective study. Each patient underwent a penile doppler ultrasound and completed questionnaires (IIEF-6, EHS, SEP-2, SEP-3) at three different times: before starting the treatment, at 3 months and at 6 months (within the last 30 days without treatment).Results and conclusions: Tadalafil 5mg daily treatment for 3 months did not result in significant modifications to VPS and AS. There was clinical improvement according to the questionnaires after three months of treatment, which was not maintained at 6 months. Neither a clinical-radiological correlation nor a haemodynamic value predicting response to treatment could be established. (AU)

[Effect of tadalafil 5mg daily treatment on penile haemodynamics in patients with erectile dysfunction]. / Efecto del tadalafilo 5mg/día en la hemodinámica peniana en pacientes con disfunción eréctil.

INTRODUCTION AND OBJECTIVE: Phosphodiesterase-5 inhibitors (PDE-5) are the first-line treatment. ED diagnostic and evaluation methods are clinical: erection self-perception and evaluation questionnaires. It is necessary to identify predictive markers to choose the best drug and the best dose for each individual patient. This study seeks to evaluate the effect of tadalafil 5mg daily treatment on penile haemodynamics (penis in flaccidity, using doppler ultrasound, without using alprostadil) and to study if these changes are clinically associated. MATERIAL AND METHODS: 40 patients who started treatment with tadalafil 5mg daily were consecutively selected in a prospective study. Each patient underwent a penile doppler ultrasound and completed questionnaires (IIEF-6, EHS, SEP-2, SEP-3) at three different times: before starting the treatment, at 3 months and at 6 months (within the last 30 days without treatment). RESULTS AND CONCLUSIONS: Tadalafil 5mg daily treatment for 3 months did not result in significant modifications to VPS and AS. There was clinical improvement according to the questionnaires after three months of treatment, which was not maintained at 6 months. Neither a clinical-radiological correlation nor a haemodynamic value predicting response to treatment could be established.

Ten-year experience with penile prosthetic surgery for the treatment of erectile dysfunction: outcomes of a tertiary referral center and predictors of early prosthetic infection.

We aimed to evaluate ten-year outcomes of penile prosthesis (PP) implantation for the treatment of erectile dysfunction and to assess predictors of early prosthetic infection (EPI). We identified 549 men who underwent 576 PP placements between 2008 and 2018. Univariate and multivariate analyses were used to identify potential predictors of EPI. An EPI predictive nomogram was developed. Thirty-five (6.1%) cases of EPI were recorded with an explant rate of 3.1%. In terms of satisfaction, 82.0% of the patients defined themselves as "satisfied," while partner's satisfaction was 88.3%. Diabetes (P = 0.012), longer operative time (P = 0.032), and reinterventions (P = 0.048) were associated with EPI risk, while postoperative ciprofloxacin was inversely associated with EPI (P = 0.014). Rifampin/gentamicin-coated 3-piece inflatable PP (r/g-c 3IPP) showed a higher EPI risk (P = 0.019). Multivariate analyses showed a two-fold higher risk of EPI in diabetic patients, redo surgeries, or when a r/g-c 3IPP was used (all P < 0.03). We showed that diabetes, longer operative time, and secondary surgeries were the risk factors for EPI. Postoperative ciprofloxacin was associated with a reduced risk of EPI, while r/g-c 3IPP had higher EPI rates without an increased risk of PP explant. After further validation, the proposed nomogram could be a useful tool for the preoperative counseling of PP implantation.

Peyronie's Disease Questionnaire (PDQ): Spanish translation and validation.

The Peyronie's Disease Questionnaire (PDQ) is a 15-question self-reported questionnaire that evaluates the severity and physical and psychosexual issues of Peyronie's disease (PD) symptoms in three scales: "psychological and physical symptoms," "penile pain," and "symptom bother." Previous studies validated the PDQ US version and confirmed its test-retest reliability and responsiveness. The aim is to translate and validate the Spanish version of the PDQ to be used in the clinical practice and in PD research studies in Spain. A non-interventional, observational study with 160 PD patients was conducted. Patients included from four healthcare centers in Spain and completed the PDQ in two study visits separated for a period of 4-7 days from March 2018 to June 2019. Patients received no type of treatment or intervention. Different statistical tests were applied to the data in order to validate the structural and construct of the PDQ, as well as its internal reliability, temporal stability reliability, reliability between observers, and test-retest reliability. Cronbach's alpha over 0.9 showed good internal consistency. We found an ICC agreement of 0.82 (test-retest) for the three scales of the Spanish version of the PDQ, which demonstrates good reliability. When comparing Visit 1 and Visit 2 questionnaires mean scores, the PDQ showed non-significant differences, as expected because no intervention or treatment was administered to the patients between visits. Translation and validation of the PDQ for the Spanish population makes available a valid, useful, and reliable tool to properly evaluate quality of life of men suffering PD.

Penile low intensity shock wave treatment for PDE5I refractory erectile dysfunction: a randomized double-blind sham-controlled clinical trial.

PURPOSE: Over the last decade, penile low-intensity extracorporeal shockwave therapy (LI-ESWT) has emerged as a promising alternative for the treatment of erectile dysfunction (ED). The aim of this trial is to assess the effect of electromagnetic LI-ESWT on the erectile function of vascular phosphodiesterase type 5 inhibitor (PDE5I) refractory ED patients. METHODS: Randomized, double-blind, sham-controlled study. 76 patients with vascular PDE5I-refractory ED completed the study. 40 men were treated with LI-ESWT (1 session/week for 4 weeks, 5000 shocks/session, 0.09 mJ/mm2 energy density) and 36 were treated with a sham probe. Baseline and post-treatment (1, 3 and 6 months) evaluations were performed using validated erectile function questionnaires (IIEF-EF, EHS, SEP2, SEP3 and GAQ1). The groups were compared using Mann-Whitney-Wilcoxon and chi-squared tests, with results considered statistically significant at p < 0.05. RESULTS: At the 3-month follow-up, median change in IIEF-EF score for active and sham groups was 3.5 (IQR 0-10) and - 0.5 (IQR - 11 to 1), respectively (p < 0.05). Six months after treatment, 52.5% of patients (21/40) in the active group and 27.8% of patients (10/36) in the sham group presented an EHS > 2 (p < 0.05). At the same evaluation, 40.0% (16/40) and 13.9% (5/36) of patients had positive answers to GAQ-1, in the treated and sham groups, respectively (p < 0.05). No adverse events were observed during the study. CONCLUSION: This study showed that penile electromagnetic shockwave therapy may improve erectile function, to a modest extent, on certain patients that do not respond to PDE5I; making it an alternative for vascular ED patients that reject more invasive therapies.

Genetic dissection of spermatogenic arrest through exome analysis: clinical implications for the management of azoospermic men.

PURPOSE: Azoospermia affects 1% of men and it can be the consequence of spermatogenic maturation arrest (MA). Although the etiology of MA is likely to be of genetic origin, only 13 genes have been reported as recurrent potential causes of MA. METHODS: Exome sequencing in 147 selected MA patients (discovery cohort and two validation cohorts). RESULTS: We found strong evidence for five novel genes likely responsible for MA (ADAD2, TERB1, SHOC1, MSH4, and RAD21L1), for which mouse knockout (KO) models are concordant with the human phenotype. Four of them were validated in the two independent MA cohorts. In addition, nine patients carried pathogenic variants in seven previously reported genes-TEX14, DMRT1, TEX11, SYCE1, MEIOB, MEI1, and STAG3-allowing to upgrade the clinical significance of these genes for diagnostic purposes. Our meiotic studies provide novel insight into the functional consequences of the variants, supporting their pathogenic role. CONCLUSION: Our findings contribute substantially to the development of a pre-testicular sperm extraction (TESE) prognostic gene panel. If properly validated, the genetic diagnosis of complete MA prior to surgical interventions is clinically relevant. Wider implications include the understanding of potential genetic links between nonobstructive azoospermia (NOA) and cancer predisposition, and between NOA and premature ovarian failure.

Correction: gr/gr deletion predisposes to testicular germ cell tumour independently from altered spermatogenesis: results from the largest European study.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Treatment of Penile Prosthesis Implant's Infection.

INTRODUCTION: Penile prosthesis implant is a safe and effective option in erectile dysfunction patients, being implant procedures safe with a low risk of infection. However, when infection occurs, it represents a concrete problem for both surgeon and patient. METHODS: This is a comprehensive review of all issues relating to prosthesis infection, including causes and risk factors, methods of prevention, and management. We analyzed all preoperative and perioperative factors, which can play a role in infection of the device. RESULTS: Infection of penile prosthesis implant is hard to manage and correct. While the incidence of infection following first implant is up to 3%, in cases of re-implant surgery, the rate can reach as high as 18%. Many articles were found addressing prevention and treatment of penile prosthesis infection, and many analyzed all relevant pre- and perioperative factors associated with penile prosthesis implant. Although such factors have been well studied, there is no clear consensus worldwide on certain topics. CONCLUSIONS: Penile prosthesis implant is a safe and effective option. Despite infection is a rare event, surgeons should follow strictly pre-, intra- and postoperative recommendations in order to reduce the risk of device's infection. An appropriate antibiotic therapy should be tailored on patient's characteristics and pathogens isolated.

Rates of hypogonadism forms in Klinefelter patients undergoing testicular sperm extraction: A multicenter cross-sectional study.

INTRODUCTION AND OBJECTIVES: Adult patients with Klinefelter syndrome (KS) may present with testicular volume loss and a decrease in circulating testosterone (T) levels. However, the actual rate of hypogonadism in adult KS men is unknown. We aimed to (a) assess the prevalence of different forms of hypogonadism in a cohort of KS patients with non-obstructive azoospermia (NOA); and (b) investigate potential preoperative predictor of positive sperm retrieval (SR) at surgery in the same cohort of men. METHODS: Complete data from 103 KS men with NOA who underwent testicular sperm extraction (TESE) between 2008 and 2019 at five centers were analyzed. Comorbidities were scored with the Charlson Comorbidity Index (CCI). Patients were categorized into four groups of hypogonadism as follows: eugonadism [normal total T (tT) (≥3.03 ng/mL) and normal luteinizing hormone (LH) (≤9.4 mUI/mL)], secondary hypogonadism [low tT (≤3.03 ng/mL) and low/normal LH (≤9.4 mUI/mL)], primary hypogonadism [low tT (≤3.03 ng/mL) and elevated LH (≥9.4 mUI/mL)], and compensated hypogonadism [normal tT (≥3.03 ng/mL) and elevated LH (≥9.4 mUI/mL)]. Descriptive statistics tested the association between clinical characteristics and laboratory values among the four groups. RESULTS: Median (IQR) patients age was 32 (24, 37) years. Baseline follicle-stimulating hormone and tT levels were 29.5 (19.9, 40.9) mUI/mL and 3.8 (2.5, 11.0) ng/mL, respectively. Eugonadism, primary hypogonadism, and compensated hypogonadism were found in 16 (15.6%), 34 (33.0%), and 53 (51.4%) men, respectively. No patients had secondary hypogonadism. Positive SR rate at TESE was 21.4% (22 patients); of 22, 15 (68.2%) patients underwent assisted reproductive technology and five (22.7%) ended in live birth children. Patients' age, BMI, CCI, FSH levels, and positive SR rates were comparable among hypogonadism groups. No preoperative parameters were associated with positive SR at logistic regressions analysis. CONCLUSIONS: Findings from this cross-sectional study showed that 15.6% of adult KS men have normal tT values at presentation in the real-life setting. Most KS patients presented with either compensated or primary hypogonadism. Sperm retrieval rates were not associated with different forms of hypogonadism.

Sperm retrieval rates in non-mosaic Klinefelter patients undergoing testicular sperm extraction: What expectations do we have in the real-life setting?

BACKGROUND: A recent meta-analysis (Human Reproduction Update 23, 2017 and 265) reported positive sperm retrieval rates (SRR) in 50% of patients with Klinefelter syndrome (KS) undergoing testicular sperm extraction (TESE). However, these results do not reflect the rates of SR that we observe in clinical practice. We assessed the rate and potential predictors of SR in Klinefelter patients in the real-life setting. MATERIALS AND METHODS: We reviewed clinical data of 103 KS men who underwent TESE between 08/2008 and 03/2019 at five tertiary referral Andrology centers. Patients underwent testis ultrasound, hormonal evaluation, and genetic testing. All patients were azoospermic based on the 2010 WHO reference criteria. Conventional TESE (cTESE) or microsurgical TESE (mTESE) was performed based on the surgeon's preference. We used descriptive statistics and logistic regression models to describe the whole cohort. RESULTS: Median (IQR) patient's age was 32 (24-37) years. Baseline serum FSH and total testosterone levels were 29.5 (19.9-40.9) mUI/mL and 3.8 (2.5-11.0) ng/mL, respectively. Conventional TESE and mTESE were performed in 38 (36.5%) and 65 (63.5%) men, respectively. The sperm retrieval rate was 21.4% (22/103 men). Fifteen patients used spermatozoa for ICSI and five ended in live birth children. Patients with positive SR were similar to those with a negative TESE in terms of clinical, hormonal, and procedural parameters (all P > .05). Logistic regression analyses confirmed the lack of association between clinical, hormonal, and procedural parameters with SR outcome. DISCUSSION: Given the conflicting results in the literature regarding SRR in KS, patients should be carefully counseled regarding TESE outcomes based on data from published literature and local results. CONCLUSIONS: In the real-life setting, we observed a lower SRR (21.4%) than that reported in meta-analyses in our cohort of KS patients. No associations between clinical, hormonal, and procedural variables with TESE success were found.

Clinical factors affecting semen improvement after microsurgical subinguinal varicocelectomy: which subfertile patients benefit from surgery?

BACKGROUND: The exact mechanism of varicocele-related infertility is still elusive, therefore, the current challenges for its management lie in determining which patients stand to benefit most from surgical correction. The authors aimed to assess the clinical factors affecting semen improvement after left microsurgical subinguinal varicocelectomy (MSV) in relation to patient age, ultrasound varicocele grading (USVG), and presence of a right subclinical varicocele (RSV). METHODS: From 2010 to 2017 a total of 228 infertile patients underwent left MSV for clinical varicocele. Descriptive statistics were used to describe the cohort and verify the surgical benefit in terms of semen improvement, in addition, subsets of patients were selected according to clinical covariates. Logistic regression modeling was applied to evaluate the presence of RSV, operative time, age, and USVG as explanatory variables. RESULTS: Sperm concentration (SC), progressive sperm motility (PSM), and normal sperm morphology (NSM) increased significantly after surgery (p = 0.002; p = 0.011; p = 0.024; respectively). Mean SC improved after MSV in ⩾35 year-old patients and the grade 3 USVG group (p = 0.01; p = 0.02; respectively). Logistic regression modeling showed a that the probability of SC improvement was 76% lower in subjects presenting RSV (p = 0.011). In addition, patients with a grade 3 USVG presented a three-times greater probability of SC improvement compared with patients with a lower USVG (p = 0.035). In addition, older patients showed a greater probability of SC improvement after MSV (p = 0.041). CONCLUSIONS: MSV is an effective varicocele-related infertility treatment that should also be offered to older patients. In addition, patients with a higher USVG benefit from surgery. In infertile men with an RSV in association with a left clinical disease, a bilateral varicocele repair should be considered.

gr/gr deletion predisposes to testicular germ cell tumour independently from altered spermatogenesis: results from the largest European study.

The association between impaired spermatogenesis and TGCT has stimulated research on shared genetic factors. Y chromosome-linked partial AZFc deletions predispose to oligozoospermia and were also studied in TGCT patients with controversial results. In the largest study reporting the association between gr/gr deletion and TGCT, sperm parameters were unknown. Hence, it remains to be established whether this genetic defect truly represents a common genetic link between TGCT and impaired sperm production. Our aim was to explore the role of the following Y chromosome-linked factors in the predisposition to TGCT: (i) gr/gr deletion in subjects with known sperm parameters; (ii) other partial AZFc deletions and, for the first time, the role of partial AZFc duplications; (iii) DAZ gene dosage variation. 497 TGCT patients and 2030 controls from two Mediterranean populations with full semen/andrological characterization were analyzed through a series of molecular genetic techniques. Our most interesting finding concerns the gr/gr deletion and DAZ gene dosage variation (i.e., DAZ copy number is different from the reference sequence), both conferring TGCT susceptibility. In particular, the highest risk was observed when normozoospermic TGCT and normozoospermic controls were compared (OR = 3.7; 95% CI = 1.5-9.1; p = 0.006 for gr/gr deletion and OR = 1.8; 95% CI = 1.1-3.0; p = 0.013 for DAZ gene dosage alteration). We report in the largest European study population the predisposing effect of gr/gr deletion to TGCT as an independent risk factor from impaired spermatogenesis. Our finding implies regular tumour screening/follow-up in male family members of TGCT patients with gr/gr deletion and in infertile gr/gr deletion carriers.

From exome analysis in idiopathic azoospermia to the identification of a high-risk subgroup for occult Fanconi anemia.

PURPOSE: In about 10% of patients affected by Fanconi anemia (FA) the diagnosis is delayed until adulthood, and the presenting symptom in these "occult" FA cases is often a solid cancer and cancer treatment-related toxicity. Highly predictive clinical parameter(s) for diagnosing such an adult-onset cases are missing. METHODS: (1) Exome sequencing (ES), (2) Sanger sequencing of FANCA, (3) diepoxybutane (DEB)-induced chromosome breakage test. RESULTS: ES identified a pathogenic homozygous FANCA variant in a patient affected by Sertoli cell-only syndrome (SCOS) and in his azoospermic brother. Although they had no overt anemia, chromosomal breakage test revealed a reverse somatic mosaicism in the former and a typical FA picture in the latter. In 27 selected SCOS cases, 1 additional patient showing compound heterozygous pathogenic FANCA variants was identified with positive chromosomal breakage test. CONCLUSION: We report an extraordinarily high frequency of FA in a specific subgroup of azoospermic patients (7.1%). The screening for FANCA pathogenic variants in such patients has the potential to identify undiagnosed FA before the appearance of other severe clinical manifestations of the disease. The definition of this high-risk group for "occult" FA, based on specific testis phenotype with mild/borderline hematological alterations, is of unforeseen clinical relevance.

Priapism secondary to tamsulosin: a case report / Priapismo secundario a tratamiento con tamsulosina: caso clínico

Priapism is defined as a continuous erection of the penis without any sexual desire and with a duration of more than 4 h; this phenomenon represents a medical emergency requiring urgent treatment and can be followed by fibrosis of the corpora cavernosa and permanent impotence. Priapism can be divided into three subtypes depending on the cause and can be induced by certain agents. We present a case report of priapism induced by tamsulosin treatment in a patient with obstructive lower urinary tract symptoms (LUTS) and also review the relevant literature. Priapism secondary to tamsulosin treatment is a rare event that has seldom been reported in the literature. In cases of priapism secondary to medical treatment, interruption of treatment should avoid further events (AU)

El priapismo se define como una erección continua del pene sin ningún deseo sexual y con una duración de más de 4 horas. Este fenómeno representa una emergencia médica que requiere tratamiento urgente y puede ser seguido por la fibrosis de los cuerpos cavernosos y la impotencia permanente. El priapismo puede dividirse en tres subtipos dependiendo de la causa y puede ser inducido por ciertos agentes. Presentamos un caso de priapismo inducido por tratamiento con tamsulosina en un paciente con síntomas del tracto urinario inferior obstructivos (STUI) y también revisamos la bibliografía pertinente. El priapismo secundario a tratamiento con tamsulosina es un evento raro que raramente se ha reportado en la literatura. En los casos de priapismo secundario a tratamiento médico, la interrupción del tratamiento debe evitar nuevos eventos (AU)

X chromosome-linked CNVs in male infertility: discovery of overall duplication load and recurrent, patient-specific gains with potential clinical relevance.

INTRODUCTION: Spermatogenesis is a highly complex process involving several thousand genes, only a minority of which have been studied in infertile men. In a previous study, we identified a number of Copy Number Variants (CNVs) by high-resolution array-Comparative Genomic Hybridization (a-CGH) analysis of the X chromosome, including 16 patient-specific X chromosome-linked gains. Of these, five gains (DUP1A, DUP5, DUP20, DUP26 and DUP40) were selected for further analysis to evaluate their clinical significance. MATERIALS AND METHODS: The copy number state of the five selected loci was analyzed by quantitative-PCR on a total of 276 idiopathic infertile patients and 327 controls in a conventional case-control setting (199 subjects belonged to the previous a-CGH study). For one interesting locus (intersecting DUP1A) additional 338 subjects were analyzed. RESULTS AND DISCUSSION: All gains were confirmed as patient-specific and the difference in duplication load between patients and controls is significant (p = 1.65 × 10(-4)). Two of the CNVs are private variants, whereas 3 are found recurrently in patients and none of the controls. These CNVs include, or are in close proximity to, genes with testis-specific expression. DUP1A, mapping to the PAR1, is found at the highest frequency (1.4%) that was significantly different from controls (0%) (p = 0.047 after Bonferroni correction). Two mechanisms are proposed by which DUP1A may cause spermatogenic failure: i) by affecting the correct regulation of a gene with potential role in spermatogenesis; ii) by disturbing recombination between PAR1 regions during meiosis. This study allowed the identification of novel spermatogenesis candidate genes linked to the 5 CNVs and the discovery of the first recurrent, X-linked gain with potential clinical relevance.

Clinical relevance of Y-linked CNV screening in male infertility: new insights based on the 8-year experience of a diagnostic genetic laboratory.

AZF microdeletion screening is routinely performed in the diagnostic work-up for male infertility; however, some issues remain debated. In this study, we provide insights into the sperm concentration cutoff value for routine testing, the predictive value of AZFc deletion for testicular sperm retrieval and the Y-background contribution to the interpopulation variability of deletion frequencies. In the Spanish population, partial AZFc rearrangements have been poorly explored and no data exist on partial duplications. In our study, 27/806 (3.3%) patients carried complete AZF deletions. All were azoo/cryptozoospermic, except for one whose sperm concentration was 2 × 10(6)/ml. In AZFc-deleted men, we observed a lower sperm recovery rate upon conventional TESE (9.1%) compared with the literature (60-80% with microTESE). Haplogroup E was the most represented among non-Spanish and hgr P among Spanish AZF deletion carriers. The analysis of AZFc partial rearrangements included 330 idiopathic infertile patients and 385 controls of Spanish origin. Gr/gr deletion, but not AZFc partial duplications, was significantly associated with spermatogenic impairment. Our data integrated with the literature suggest that: (1) routine AZF microdeletion testing could eventually include only men with ≤2 × 10(6)/ml; (2) classical TESE is associated with low sperm recovery rate in azoospermic AZFc-deleted men, and therefore microTESE should be preferred; (3) Y background could partially explain the differences in deletion frequencies among populations. Finally, our data on gr/gr deletion further support the inclusion of this genetic test in the work-up of infertile men, whereas partial AZFc duplications do not represent a risk for spermatogenic failure in the Spanish population.

High resolution X chromosome-specific array-CGH detects new CNVs in infertile males.

CONTEXT: The role of CNVs in male infertility is poorly defined, and only those linked to the Y chromosome have been the object of extensive research. Although it has been predicted that the X chromosome is also enriched in spermatogenesis genes, no clinically relevant gene mutations have been identified so far. OBJECTIVES: In order to advance our understanding of the role of X-linked genetic factors in male infertility, we applied high resolution X chromosome specific array-CGH in 199 men with different sperm count followed by the analysis of selected, patient-specific deletions in large groups of cases and normozoospermic controls. RESULTS: We identified 73 CNVs, among which 55 are novel, providing the largest collection of X-linked CNVs in relation to spermatogenesis. We found 12 patient-specific deletions with potential clinical implication. Cancer Testis Antigen gene family members were the most frequently affected genes, and represent new genetic targets in relationship with altered spermatogenesis. One of the most relevant findings of our study is the significantly higher global burden of deletions in patients compared to controls due to an excessive rate of deletions/person (0.57 versus 0.21, respectively; p = 8.785×10(-6)) and to a higher mean sequence loss/person (11.79 Kb and 8.13 Kb, respectively; p = 3.435×10(-4)). CONCLUSIONS: By the analysis of the X chromosome at the highest resolution available to date, in a large group of subjects with known sperm count we observed a deletion burden in relation to spermatogenic impairment and the lack of highly recurrent deletions on the X chromosome. We identified a number of potentially important patient-specific CNVs and candidate spermatogenesis genes, which represent novel targets for future investigations.

ESR1 promoter polymorphism is not associated with nonsyndromic cryptorchidism.

The ESR1 promoter microsatellite (TA)n was reported as a potential functional polymorphism. In a case-control study, we were unable to demonstrate any association between (TA)n and nonsyndromic cryptorchidism in Italian and Spanish study populations.