Association of Supernumerary Sex Chromosome Aneuploidies With Venous Thromboembolism.

Importance: An increased risk of venous thromboembolism (VTE) has been reported in men with an additional sex chromosome. The association between other sex chromosome aneuploidies and VTE is not well characterized. Objective: To determine if sex chromosome aneuploidy is associated with VTE. Design, Setting, and Participants: Retrospective cohort study of sex chromosome aneuploidy and VTE, performed by analyzing X- and Y-chromosome dosage and VTE incidence in 642 544 individuals from 2 population-scale biobanks: the US Geisinger MyCode Community Health Initiative (N = 154 519) and the UK Biobank (N = 488 025); analysis was limited to participants self-identified as White because of inadequate sample sizes for other race and ethnicity groups. A total of 108 461 unrelated MyCode participants with electronic health record follow-up ranging from September 1996 to December 2020 and 418 725 unrelated British and Irish UK Biobank participants who attended the baseline assessment between March 2006 and October 2010, with follow-up extending to November 2020, were included in analyses of VTE. Exposures: Sex chromosome aneuploidies. Main Outcomes and Measures: Individuals with 1 primary inpatient VTE diagnosis, 2 primary outpatient VTE diagnoses, or a self-reported VTE diagnosis were defined as VTE cases. P values were adjusted for multiple comparisons. Results: Identification of sex chromosome aneuploidy was undertaken among 642 544 individuals aged 18 to 90 years. Identification of a diagnosis of VTE was undertaken among 108 461 unrelated MyCode participants (65 565 [60.5%] female; mean age at last visit, 58.0 [SD, 17.6] years; median follow-up, 15.3 [IQR, 9.7] years) and among 418 725 unrelated UK Biobank participants (224 695 [53.7%] female; mean age at baseline interview, 56.9 [SD, 8.0] years; median follow-up, 12.0 [IQR, 1.6] years). Among MyCode participants, during 10 years of follow-up, 17 incident VTE events per 1353 person-years were detected among those with supernumerary sex chromosome aneuploidy (1.3% per person-year) compared with 2060 per 816 682 person-years among those with 46,XX or 46,XY (0.25% per person-year) (hazard ratio, 5.4 [95% CI, 3.4-8.7]; 10-year risk difference, 8.8% [95% CI, 4.2%-14.0%]; P < .001). Among UK Biobank participants, during 10 years of follow-up, 16 incident VTE events per 3803 person-years were detected among those with supernumerary sex chromosome aneuploidy (0.42% per person-year) compared with 4491 per 3 970 467 person-years among those with 46,XX or 46,XY (0.11% per person-year) (hazard ratio, 4.1 [95% CI, 2.5-6.7]; 10-year risk difference, 3.7% [95% CI, 1.4%-5.9%]; P < .001). Conclusions and Relevance: Adults with supernumerary sex chromosome aneuploidies compared with 2 sex chromosomes had a small but statistically significant increased risk of VTE. Further research is needed to understand the clinical implications of this association.

Clinical experience regarding the accuracy of NIPT in the detection of sex chromosome abnormality.

BACKGROUND: The present study aimed to determine the accuracy (Z-value) of non-invasive prenatal testing (NIPT) results for sex chromosome aneuploidy (SCA) in routine clinical practice. METHODS: Among a cohort of 12505 pregnant females, maternal plasma samples collected from our hospital were utilized for SCA analysis by NIPT detection. The positive samples were validated through an invasive procedure and karyotyping analysis. The predictive value from positive samples in sex chromosomes was compared to analyze the accuracy of the Z-value. RESULTS: There were 65 females with sex chromosome abnormalities within 12,505 pregnant females in the NIPT detection, which was validated by karyotype analysis of amniotic fluid puncture through sequencing, as well as bioinformatics analysis, with 18 true-positive samples. The true-positive results with 45,X, 47,XXY, 47,XXX and 47,XYY karyotypes predicted by NIPT were 14.29%, 50.00%, 66.67% and 71.43%, respectively. Among sex chromosome cases, the findings indicated that positive NIPT results with Z ≥ 9 show a higher accuracy. CONCLUSIONS: The findings of the present study demonstrate that the positive predictive value of NIPT for sex chromosome abnormalities is distinctive. The positive predictive value was highest for 47,XYY and lowest for 45,X. Additionally, the Z-value results are considered to be correlated with the accuracy of NIPT, although further studies need to be made.

Cell-free DNA screening for sex chromosomal aneuploidies in 9985 pregnancies: Italian single experience.

OBJECTIVE: Non invasive prenatal testing (NIPT) using cell-free fetal DNA (cffDNA) has been widely accepted in recent years to detect common fetal autosomal chromosome aneuploidies and sex chromosome aneuploidies (SCAs). In this study, the clinical performance of our fetal DNA testing was investigated by analyzing the sex chromosome aneuploidy aberrations among 9985 pregnancies. The study was a retrospective analysis of collected NIPT data from the Ion S5 next-generation sequencing (NGS) platform obtained from Altamedica Medical Centre of Rome. RESULTS: NIPT analysis of 9985 pregnancies revealed 31 cases with abnormal SCA results (0.31%). Among the 31 positive NIPT cases, 22 women agreed to undergo fetal karyotyping, whereas 9 refused further analyses. Of the 22 women verified by karyotyping analysis, 77.3% (17/22) were confirmed to be true positive SCAs, whereas 22.7% (5/22) were false positive. Among the true positive cases, 53.0% (9/17) were positive for monosomy X, 17.6% (3/17) were positive for 47, XXX aneuploidy, 23.5% (4/17) were positive for 47, XXY aneuploidy, and 5.9% (1/17) were positive for 47, XYY aneuploidy. In conclusion, the present results confirm that NIPT is a potential method for SCA screening, although this technology needs to be further investigated to improve the test performance.

Chromosomal aberrations in women with primary and secondary amenorrhea: A cross-sectional study.

AIM: Among women of childbearing age, about 2-5% are affected by amenorrhea that is either primary or secondary. However, there are no data regarding the frequency and type of chromosomal abnormalities associated with amenorrhea in Saudi women. The present study aims to establish the frequency and pattern of chromosomal abnormalities in primary amenorrhea (PA) and secondary amenorrhea (SA) cases in a tertiary care center, Riyadh, Saudi Arabia. METHODS: This cross-sectional study was conducted between 2013 and 2016 on women referred to the Reproductive Endocrine and Infertility Medicine Department at a tertiary care center in Riyadh. Women were divided into two groups: PA and SA. After the initial diagnosis of amenorrhea based on medical history, physical examination, hormonal profile and ultrasonography, chromosome karyotype analysis was conducted on metaphase preparations following routine cytogenetics culture and harvest methods. RESULTS: Chromosomal tests were performed for 53 patients (42 with PA and 11 with SA) out of 79 referred patients with amenorrhea. About 19% of the 42 patients with PA and 1 patient (9.1%) diagnosed as SA showed an abnormal karyotype. The most common abnormal karyotypes observed were 46, XY and 45, X. CONCLUSION: The present study indicates that the chromosomal analysis after the exclusion of nongenetic causes should be essentially considered for the precise diagnosis and the development of more successful management for females with amenorrhea. This study also revealed that the prevalence of chromosomal abnormalities in women with PA and SA is similar to that reported in the literature.

[Association of maternal age with fetal sex chromosome aneuploidies].

OBJECTIVE: To analyze the impact of maternal age on sex chromosome aneuploidies (SCA). METHODS: Pregnant women who had karyotype analysis of amniotic fluid in Women's Hospital, Zhejiang University School of Medicine from January 2014 to July 2018 were recruited. The association of the maternal age with fetal SCAs was analyzed. RESULTS: The incidence of 45, X in age group >34-<38 was lower than that of ≤ 28 age group (P<0.05). For the incidences of total sex chromosome trisomy and 47, XXY in age groups 34-<38 and ≥38 were higher than age groups ≤28 and >28-34 (P<0.05 or P<0.01). The incidence of 47, XXX in age group ≥ 38 was higher than that in age group>28-34 (P<0.05). However, the incidence of 47, XYY had no differences among the four groups (P>0.05). After excluding the high risk of sex chromosome abnormalities by non-invasive prenatal testing (NIPT), we found that for 45, X, the incidences of two groups with advanced age were lower than that of ≤ 28 year-old group of age group (P<0.05 or P<0.01), and incidence in age group >34-<38 was also lower than that in age group >28-34 (P<0.05). The other results were consistent with those without excluding the high risk of sex chromosome abnormalities by NIPT. CONCLUSIONS: Advanced age decreases the incidence of 45, X, but increases the risk of sex chromosome trisomy, especially 47, XXX and 47, XXY.

Population-based trends in the prenatal diagnosis of sex chromosome aneuploidy before and after non-invasive prenatal testing.

OBJECTIVE: To assess the impact of non-invasive prenatal testing (NIPT) on trends in the prenatal diagnosis of sex chromosome aneuploidy (SCA) in a population with >73,000 annual births. METHOD: Retrospective population-based cohort study from 1986-2016 of all women undergoing prenatal diagnosis before 25 weeks gestation in the Australian state of Victoria. Statistical significance was tested using the chi-square test for trend or proportions. RESULTS: There were 2,043,345 births and 842 SCA diagnoses from 1986-2016. The percentage of prenatal diagnostic tests leading to a SCA diagnosis increased significantly from 0.95% in 2010 to 2.93% in 2016 (p < 0.001) but due to a concurrent decline in testing, the annual prenatal diagnosis rate of SCA remained stable at 4.4/10,000 births. Among confirmed fetal SCAs the most common indication for testing in 1986 was advanced maternal age (63%); in 2016 it was high risk NIPT (49%). CONCLUSION: SCAs now make up an increasing proportion of prenatal diagnostic results but due to the overall decline in diagnostic testing, the prenatal prevalence as a percentage of births remained steady. The ascertainment of fetal SCA has evolved from an incidental finding after testing for increased risk of trisomy 21, to a diagnosis obtained after suspected SCA on NIPT.

Outdoor air pollution and mosaic loss of chromosome Y in older men from the Cardiovascular Health Study.

BACKGROUND: Mosaic loss of chromosome Y (mLOY) can occur in a fraction of cells as men age, which is potentially linked to increased mortality risk. Smoking is related to mLOY; however, the contribution of air pollution is unclear. OBJECTIVE: We investigated whether exposure to outdoor air pollution, age, and smoking were associated with mLOY. METHODS: We analyzed baseline (1989-1993) blood samples from 933 men ≥65 years of age from the prospective Cardiovascular Health Study. Particulate matter ≤10 µm (PM10), carbon monoxide, nitrogen dioxide, sulfur dioxide, and ozone data were obtained from the U.S. EPA Aerometric Information Retrieval System for the year prior to baseline. Inverse-distance weighted air monitor data were used to estimate each participants' monthly residential exposure. mLOY was detected with standard methods using signal intensity (median log-R ratio (mLRR)) of the male-specific chromosome Y regions from Illumina array data. Linear regression models were used to evaluate relations between mean exposure in the prior year, age, smoking and continuous mLRR. RESULTS: Increased PM10 was associated with mLOY, namely decreased mLRR (p-trend = 0.03). Compared with the lowest tertile (≤28.5 µg/m3), the middle (28.5-31.0 µg/m3; ß = -0.0044, p = 0.09) and highest (≥31 µg/m3; ß = -0.0054, p = 0.04) tertiles had decreased mLRR, adjusted for age, clinic, race/cohort, smoking status and pack-years. Additionally, increasing age (ß = -0.00035, p = 0.06) and smoking pack-years (ß = -0.00011, p = 1.4E-3) were associated with decreased mLRR, adjusted for each other and race/cohort. No significant associations were found for other pollutants. CONCLUSIONS: PM10 may increase leukocyte mLOY, a marker of genomic instability. The sample size was modest and replication is warranted.

Rare X Chromosome Abnormalities in Systemic Lupus Erythematosus and Sjögren's Syndrome.

OBJECTIVE: Sjögren's syndrome (SS) and systemic lupus erythematosus (SLE) are related by clinical and serologic manifestations as well as genetic risks. Both diseases are more commonly found in women than in men, at a ratio of ~10 to 1. Common X chromosome aneuploidies, 47,XXY and 47,XXX, are enriched among men and women, respectively, in either disease, suggesting a dose effect on the X chromosome. METHODS: We examined cohorts of SS and SLE patients by constructing intensity plots of X chromosome single-nucleotide polymorphism alleles, along with determining the karyotype of selected patients. RESULTS: Among ~2,500 women with SLE, we found 3 patients with a triple mosaic, consisting of 45,X/46,XX/47,XXX. Among ~2,100 women with SS, 1 patient had 45,X/46,XX/47,XXX, with a triplication of the distal p arm of the X chromosome in the 47,XXX cells. Neither the triple mosaic nor the partial triplication was found among the controls. In another SS cohort, we found a mother/daughter pair with partial triplication of this same region of the X chromosome. The triple mosaic occurs in ~1 in 25,000-50,000 live female births, while partial triplications are even rarer. CONCLUSION: Very rare X chromosome abnormalities are present among patients with either SS or SLE and may inform the location of a gene(s) that mediates an X dose effect, as well as critical cell types in which such an effect is operative.

Incidence of X and Y Chromosomal Aneuploidy in a Large Child Bearing Population.

BACKGROUND: X&Y chromosomal aneuploidies are among the most common human whole-chromosomal copy number changes, but the population-based incidence and prevalence in the child-bearing population is unclear. METHODS: This retrospective analysis of prospectively collected data leveraged a routine non-invasive prenatal test (NIPT) using parental genotyping to estimate the population-based incidence of X&Y chromosome variations in this population referred for NIPT (generally due to advanced maternal age). RESULTS: From 141,916 women and 29,336 men, 119 X&Y chromosomal abnormalities (prevalence: 1 in 1,439) were identified. Maternal findings include: 43 cases of 45,X (40 mosaic); 30 cases of 47,XXX (12 mosaic); 3 cases of 46,XX uniparental disomy; 2 cases of 46,XY/46,XX; 23 cases of mosaicism of unknown type; 2 cases of 47,XX,i(X)(q10). Paternal findings include: 2 cases of 47,XXY (1 mosaic); 10 cases of 47,XYY (1 mosaic); 4 partial Y deletions. CONCLUSIONS: Single chromosome aneuploidy was present in one of every 1,439 individuals considered in this study, showing 47,XXX; 47,XX,i(X)(q10); 47,XYY; 47,XXY, partial Y deletions, and a high level of mosaicism for 45,X. This expands significantly our understanding of X&Y chromosomal variations and fertility issues, and is critical for families and adults affected by these disorders. This current and extensive information on fertility will be beneficial for genetic counseling on prenatal diagnoses as well as for newly diagnosed postnatal cases.

The outcome of prenatal identification of sex chromosome abnormalities.

OBJECTIVE: The outcome of a pregnancy following identification of a sex chromosome abnormality (SCA) is unclear. The aims of this study were to ascertain the prevalence of SCA detected prenatally in Scotland and to determine the outcomes for these cases. DESIGN: Following retrospective identification of all prenatal karyotypes performed in Scotland between 2000 and 2012, data linkage was performed to obtain information regarding maternal characteristics and pregnancy outcomes. Detailed outcome data were also collected for all affected offspring in the West of Scotland and Grampian regions within Scotland. RESULTS: Of the 28 145 pregnancies that had a karyotype over the study period, records were available for 27 152 (96%). Karyotype abnormalities were identified in 2139 (8%), with SCA being identified in 321(1%) tests. 45,X was identified as the commonest SCA in 135 pregnancies. Of 121 pregnancies with SCA in the West of Scotland and Grampian, 64 (53%), 52 (43%) and 5 (4%) led to a live birth, termination and intrauterine death, respectively. Of the 64 live births, 21 (33%) had a postnatal karyotype and 35 (54%) received specialist follow-up for the SCA that was identified prenatally. CONCLUSIONS: Abnormalities of sex chromosomes are identified in approximately 1% of all pregnancies that undergo a prenatal karyotype. There is a need to review the prenatal as well as postnatal care of the affected mother and offspring.

Dialkyl phosphate urinary metabolites and chromosomal abnormalities in human sperm.

BACKGROUND: The past decade has seen numerous human health studies seeking to characterize the impacts of environmental exposures, such as organophosphate (OP) insecticides, on male reproduction. Despite an extensive literature on OP toxicology, many hormone-mediated effects on the testes are not well understood. OBJECTIVES: This study investigated environmental exposures to OPs and their association with the frequency of sperm chromosomal abnormalities (i.e., disomy) among adult men. METHODS: Men (n=159) from a study assessing the impact of environmental exposures on male reproductive health were included in this investigation. Multi-probe fluorescence in situ hybridization (FISH) for chromosomes X, Y, and 18 was used to determine XX18, YY18, XY18 and total disomy in sperm nuclei. Urine was analyzed using gas chromatography coupled with mass spectrometry for concentrations of dialkyl phosphate (DAP) metabolites of OPs [dimethylphosphate (DMP); dimethylthiophosphate (DMTP); dimethyldithiophosphate (DMDTP); diethylphosphate (DEP); diethylthiophosphate (DETP); and diethyldithiophosphate (DEDTP)]. Poisson regression was used to model the association between OP exposures and disomy measures. Incidence rate ratios (IRRs) were calculated for each disomy type by exposure quartiles for most metabolites, controlling for age, race, BMI, smoking, specific gravity, total sperm concentration, motility, and morphology. RESULTS: A significant positive trend was seen for increasing IRRs by exposure quartiles of DMTP, DMDTP, DEP and DETP in XX18, YY18, XY18 and total disomy. A significant inverse association was observed between DMP and total disomy. Findings for total sum of DAP metabolites concealed individual associations as those results differed from the patterns observed for each individual metabolite. Dose-response relationships appeared nonmonotonic, with most of the increase in disomy rates occurring between the second and third exposure quartiles and without additional increases between the third and fourth exposure quartiles. CONCLUSIONS: This is the first epidemiologic study of this size to examine the relationship between environmental OP exposures and human sperm disomy outcomes. Our findings suggest that increased disomy rates were associated with specific DAP metabolites, suggesting that the impacts of OPs on testis function need further characterization in epidemiologic studies.

Use of suboptimal sperm increases the risk of aneuploidy of the sex chromosomes in preimplantation blastocyst embryos.

OBJECTIVE: To compare autosomal and sex chromosome aneuploidy rates of embryos derived from sperm with abnormal and normal parameters. DESIGN: Retrospective cohort study. SETTING: Assisted reproduction center. PATIENT(S): Three thousand eight hundred thirty-five embryos generated from 629 couples undergoing IVF. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Incidence of aneuploidy in the trophectoderm of blastocyst embryos derived from standard IVF embryos and intracytoplasmic (ICSI) males with normal and oligozoospermic semen samples, in couples with donor eggs (mean maternal age, 25.0 years) and their own eggs (mean maternal age, 35.4 years). RESULT(S): The rate of sex chromosome aneuploidy was significantly (around threefold) higher in the oligozoospermic group compared with in both control groups (standard vs. ICSI insemination). This applied whether donor (young) or own (older) eggs were used. Significant differences were seen in the oligozoospermic samples for autosomes 1, 2, 11 (own eggs), and 18 (donor eggs) compared with both control groups; however, no significant difference was seen between each of the treatment groups for the overall rate of autosomal aneuploidy. No significant differences were seen between the two control groups (normozoospermic males, standard vs. ICSI insemination) in either of the egg group types for any chromosome pairs. CONCLUSION(S): Severe male factor infertility is associated with a significant increase in the occurrence of sex chromosome abnormalities in blastocyst embryos compared with in embryos derived from normal semen samples. Aneuploidy rates in embryos derived from sperm with normal parameters were not significantly different whether ICSI or standard insemination was used to achieve fertilization. These results highlight severe male factor infertility as a possible referral category for preimplantation comprehensive chromosomal screening.

Occupational risk factors and frequency of sex chromosome disomy.

Possible reproductive toxicants such as occupational factors may affect the normal disjunction of chromosomes during meiosis, thereby altering the number of chromosomes in sperm nuclei. The purpose of the present analysis was to determine whether exposure to occupational factors existing in a contemporary work setting affected sperm aneuploidy. The study population consisted of 212 men who attended the infertility clinic for diagnostic purposes. The men either had a normal semen concentration of 20-300 million/ml or slight oligozoospermia (semen concentration of 15-20 million/ml) ( WHO 1999 ). All participants were interviewed and provided a semen sample. Sperm aneuploidy was assessed using multicolor FISH. After adjustment for potential confounders, positive associations were found between disomy XY18, 18, and sex chromosome disomy and exposure to mechanical vibrations (p = 0.03, p = 0.04, p = 0.03, respectively). In addition, sitting for more than 6 h at work increased X and Y disomy (p = 0.03, p = 0.04, respectively). To the best of our knowledge, this is the first study to show a significant effect of occupational factors on sperm aneuploidy. As such, the results need to be confirmed in larger studies.

High frequency of X chromosome abnormalities in women with short stature and elevated liver enzymes.

CONTEXT: Paucisymptomatic forms of Turner's syndrome (TS), in which short stature is the predominant clinical abnormality, remain underdiagnosed. Abnormal liver tests are extremely frequent in adult TS patients reflecting various types of hepatic lesions. OBJECTIVE: The objective of the study was to investigate whether unexplained elevated liver enzymes in women with short stature could reveal X chromosome abnormalities of undiagnosed TS. DESIGN AND PARTICIPANTS: Thirty-one consecutive short stature women displaying elevated liver enzymes and no previous diagnosis of TS were compared with 31 age-matched controls in a prospective study. Liver biopsy was performed in 26 patients. MAIN OUTCOME MEASURES: Systematic karyotype analysis and fluorescence in situ hybridization. RESULTS: X chromosome abnormalities were found in 27 patients and one control (87.0% vs 3.2%, P < .0001), including a 45,X/46,XX mosaicism in 24 patients and isochromosome of the long arm in three. Liver histological analysis showed architectural changes in 17 patients with nodular regenerative hyperplasia in 12. Biliary lesions were present in 13 patients and liver steatosis in 20. CONCLUSIONS: X chromosome abnormalities indicative of cryptic TS are extremely frequent in short-stature women with unexplained elevated liver enzymes. In short-stature women, abnormal liver tests should lead to systematic karyotype analysis.

Prenatal diagnosis of sex chromosome aneuploidies: experience at a mainland Chinese hospital.

The aim of this study is to assess the initial indications, frequency and termination rates of pregnancies with sex chromosome aneuploidies (SCAs), at a mainland Chinese hospital. A total of 56 cases (0.9%) with SCAs were identified in 6,515 pregnancies referred for fetal karyotyping. Turner syndrome was the most commonly diagnosed SCA in prenatal diagnosis (48.2%). The most common referral reason for pregnancies with Turner syndrome was cystic hygroma on ultrasonography. The main reasons for fetal karyotyping in other types of SCAs were a positive prenatal screening test and advanced maternal age. A total of 47 (84%) of the pregnancies with SCAs were terminated and nine (16%) continued. This study first reported the rate of SCAs detected at prenatal diagnosis and the outcomes of these pregnancies in mainland China, and showed a very high termination rate for pregnancies with SCAs.

Chromosomal abnormalities in patients with oligozoospermia and non-obstructive azoospermia.

PURPOSE: To assess the frequency and types of chromosomal abnormalities in 204 Ukrainian patients with non-obstructive azoospermia and oligozoospermia and 87 men with normozoospermia. METHODS: Cytogenetic studies were performed on peripheral blood lymphocyte samples of 164 men with oligozoospermia, 40 men with non-obstructive azoospermia and 87 men with normozoospermia attending infertility clinic. RESULTS: Chromosomal abnormalities were detected in 17% of patients with sperm disorders: in 35% of men with azoospermia and in 12.7% of men with oligozoospermia. The frequency of chromosomal abnormalities in patients with sperm disorders was significantly higher, than in patients with normozoospermia (P = 0.0001). An increase in the incidence of chromosomal abnormalities with the decrease of sperm count was observed. Chromosomal abnormalities were detected in 1.1% of patients with normozoospermia, 6.5% of patients with mild oligozoospermia (sperm count 5-15 × 10(6)/ml), 18.4% of patients with severe oligozoospermia (sperm count <5 × 10(6)/ml) and 35% of patients with azoospermia. A significant increase in the frequency of chromosomal abnormalities in patients with severe oligozoospermia was observed when compared to mild oligozoospermia (P = 0.01). A statistically significant association (P = 0.02) of chromosomal abnormalities and sex chromosome abnormalities (P = 0.0001) with azoospermia when compared to oligozoospermia was observed. CONCLUSIONS: Our results highlight the importance of cytogenetic studies in patients with oligozoospermia (both mild and severe) and non-obstructive azoospermia. The presence of chromosomal abnormalities influences significantly the fertility treatment protocols, as well as provides a definite diagnosis to couples suffering from infertility.

The rate of sex chromosome aneuploidies in prenatal diagnosis and subsequent decisions in Western Turkey.

AIMS: Sex chromosome abnormalities (SCAs) are the most common genetic disorder with a frequency of 1/400 or 1/500 live births. In this study we aimed to evaluate the initial indications, frequencies, and pregnancy termination rates of pregnancies with SCAs referred to Ege University Medical Faculty, Department of Medical Genetics. Prenatal diagnosis was performed in 7505 cases in the period of January 1998 through December 2009. RESULTS: In this study, their initial indications and fetal karyotype results were evaluated retrospectively. A total of 60 pregnancies (0.80%) with SCA were evaluated. Turner syndrome was the most commonly diagnosed SCA in prenatal diagnosis (60%). The most common referral reason for pregnancies with Turner syndrome was cystic hygroma on ultrasonography. Of 14 pregnancies having a prenatal diagnosis with SCA (Turner syndrome: 7, Klinefelter syndrome: 5, Mosaic Turner syndrome: 2), 12 with SCA (85.7%) were terminated. The ratio of SCA in the prenatally diagnosed cases was similar to those reported in the literature. Although the ratio of terminated pregnancies with Turner syndrome was similar to those reported from European countries, all the pregnancies with Klinefelter syndrome have chosen termination, which showed a regional difference in Turkey. CONCLUSION: It is important to consider the decisions of the families during the genetic counseling sessions of the couples having SCAs.

Sex chromosome trisomies in Europe: prevalence, prenatal detection and outcome of pregnancy.

This study aims to assess prevalence and pregnancy outcome for sex chromosome trisomies (SCTs) diagnosed prenatally or in the first year of life. Data held by the European Surveillance of Congenital Anomalies (EUROCAT) database on SCT cases delivered 2000-2005 from 19 population-based registries in 11 European countries covering 2.5 million births were analysed. Cases included were livebirths diagnosed to 1 year of age, fetal deaths from 20 weeks gestation and terminations of pregnancy for fetal anomaly (TOPFA). In all, 465 cases of SCT were diagnosed between 2000 and 2005, a prevalence of 1.88 per 10,000 births (95% CI 1.71-2.06). Prevalence of XXX, XXY and XYY were 0.54 (95% CI 0.46-0.64), 1.04 (95% CI 0.92-1.17) and 0.30 (95% CI 0.24-0.38), respectively. In all, 415 (89%) were prenatally diagnosed and 151 (36%) of these resulted in TOPFA. There was wide country variation in prevalence (0.19-5.36 per 1000), proportion prenatally diagnosed (50-100%) and proportion of prenatally diagnosed resulting in TOPFA (13-67%). Prevalence of prenatally diagnosed cases was higher in countries with high prenatal detection rates of Down syndrome. The EUROCAT prevalence rate for SCTs diagnosed prenatally or up to 1 year of age represents 12% of the prevalence expected from cytogenetic studies of newborn babies, as the majority of cases are never diagnosed or are diagnosed later in life. There is a wide variation between European countries in prevalence, prenatal detection and TOPFA proportions, related to differences in screening policies as well as organizational and cultural factors.

Morphological nuclear integrity of sperm cells is associated with preimplantation genetic aneuploidy screening cycle outcomes.

OBJECTIVE: To examine the effect of sperm morphology on embryo development at the chromosomal level. DESIGN: Prospective study. SETTING: Assisted fertilization center. PATIENT(S): Couples who underwent IVF-PGS cycle, as a result of advanced maternal age, were randomly allocated into two groups: intracytoplasmic sperm injection (ICSI; n = 60) or intracytoplasmic morphologically selected sperm injection (IMSI; n = 60). INTERVENTION(S): IVF in conjunction with preimplantation genetic screening (PGS). MAIN OUTCOME MEASURE(S): Sperm nuclear morphology at high-magnification ICSI and incidence of aneuploidy in derived embryo. RESULT(S): There was a significantly increased incidence for sex chromosome aneuploidy in ICSI embryos when compared with IMSI embryos (23.5% vs. 15.0%, respectively). High-magnification sperm selection was associated with a significantly lower risk of sex chromosome abnormalities (odds ratio [OR], 0.57; confidence interval [CI], 0.37-0.90). The incidence of chaotic embryos was also significantly higher with the ICSI procedure (27.5% vs. 18.8%), while the IMSI procedure was associated with a significantly lower risk of chaotic embryos (OR, 0.64; CI, 0.43-0.96). Moreover, the cycle cancellation rate was significantly higher in ICSI cycles (11.8% vs. 2.5%). High-magnification sperm selection was a significant predictor of the likelihood of cycle cancellation (OR, 0.26; CI, 0.11-0.62). CONCLUSION(S): Spermatozoa free of nuclear morphological malformations were found to be significantly associated with the lower incidence of aneuploidy in derived embryos, resulting in lower rates of cycle cancellation.

Quality control and quality assurance in genotypic data for genome-wide association studies.

Genome-wide scans of nucleotide variation in human subjects are providing an increasing number of replicated associations with complex disease traits. Most of the variants detected have small effects and, collectively, they account for a small fraction of the total genetic variance. Very large sample sizes are required to identify and validate findings. In this situation, even small sources of systematic or random error can cause spurious results or obscure real effects. The need for careful attention to data quality has been appreciated for some time in this field, and a number of strategies for quality control and quality assurance (QC/QA) have been developed. Here we extend these methods and describe a system of QC/QA for genotypic data in genome-wide association studies (GWAS). This system includes some new approaches that (1) combine analysis of allelic probe intensities and called genotypes to distinguish gender misidentification from sex chromosome aberrations, (2) detect autosomal chromosome aberrations that may affect genotype calling accuracy, (3) infer DNA sample quality from relatedness and allelic intensities, (4) use duplicate concordance to infer SNP quality, (5) detect genotyping artifacts from dependence of Hardy-Weinberg equilibrium test P-values on allelic frequency, and (6) demonstrate sensitivity of principal components analysis to SNP selection. The methods are illustrated with examples from the "Gene Environment Association Studies" (GENEVA) program. The results suggest several recommendations for QC/QA in the design and execution of GWAS.