Sex Chromosome Abnormalities Research Articles

Assessing tall stature

Abstract Children and adults are considered ‘tall’ when their height is above 98th centile for age i.e. 2 standard deviations (SD) above the mean. Tall stature is familial in most cases. In assessing children with tall stature the mid-parental height centile should always be calculated and this article gives advice on how to proceed with investigation and management for children who are unexpectedly tall. Other common causes of tall stature are obesity or early normal puberty. Precocious puberty, hyperthyroidism and GH excess are less common but these will also cause rapid height velocity at any age and precocious puberty should be excluded in every child presenting with tall stature. Where height centile exceeds mid-parental centile prediction it is helpful to look for genetic syndromes, metabolic conditions and sex chromosome abnormalities. Constitutional tall stature i.e. physiologically normal advanced growth and development is a diagnosis of exclusion and treatment is rarely required. Treatment options include early and accelerated induction of pubertal development with a physiological sex hormone regimen, or epiphysiodesis, but need to be considered before puberty onset. High dose sex steroids are no longer indicated.

SUN-225 The 47,XYY Syndrome Is Associated with Increased Morbidity: A Nationwide Registry Study

Background: Although the 47,XYY syndrome is one of the most common sex chromosome abnormalities in males, as being diagnosed in 18 per 100,000 newborns, little is known about the long-term health outcomes of this condition. Objective: To describe morbidity in a national cohort of 47,XYY males as compared to the general male population using complete data on hospital admissions and prescribed medication. Design and setting: A nationwide registry study with complete follow-up in a uniform public health care system. Participants: A total of 251 males with 47,XYY (n=205), 46,XY/47,XYY (n=28) or compatible karyotypes (n=18) diagnosed during 1965-2014 and a randomly selected age-matched control cohort of 25,100 males from the general population. Results: The risk of being admitted to hospital owing to any diagnosis was significantly increased in 47,XYY compared to controls (HR=1.8, CI:1.6-2.4). Dividing diagnoses into 18 diagnostic groups showed an increased risk of admission in all but three groups. The highest HR was observed for congenital malformations (HR=6.1, CI: 4.8-7.6); psychiatric diseases (HR=5.7, CI: 4.5-7.1); endocrine and metabolic disorders (HR=3.2, CI: 2.4-4.4); neurologic diseases (HR=3.0, CI:2.2-4.0); and urogenital system disorders (HR=3.0, CI: 2.4-3.7). Overall, 47,XYY had an increased risk of receiving medicinal prescriptions compared to controls (HR=1.3, CI:1.1-1.5), and it was significantly increased in 11 out of 14 medicinal prescription groups. The highest HR was observed for medication related to the blood (HR=2.5, CI:1.8-3.5) and the nervous system (HR=2.2, CI:1.9-2.7) as well as for urogenital system disorders and sex hormones (HR=2.7, CI: 2.0-3.7). Conclusions: This study of an unselected nationwide cohort of males affected by the 47,XYY syndrome shows that an additional Y chromosome is associated with an increased morbidity as interpreted from data of hospital admissions and medicinal prescriptions. Approximately 80% of males affected by the 47,XYY syndrome suffer from non-diagnosis, and it remains unknown whether these data extend to those not yet diagnosed.

Current genetic counseling practice in the United States following positive non-invasive prenatal testing for sex chromosome abnormalities.

The purpose of this study was to describe current genetic counseling practice in the United States following a non-invasive prenatal testing (NIPT) result positive for a sex chromosome abnormality (SCA). Screening for SCAs can be confounded by confined placental mosaicism, natural loss of the X chromosome from maternal cells during aging, and undiagnosed maternal SCA or copy number variant (CNV). Furthermore, with the exception of 45,X, individuals with SCAs usually have no ultrasound or postnatal findings. This makes follow-up for unresolved positive NIPT necessary; however, there are currently no clinical guidelines. This study used a cross-sectional design with an anonymous questionnaire to survey 176 genetic counselors. The majority of prenatal respondents always offered diagnostic testing (>88%) and anatomy ultrasound (~90%), but the percent consistently offering maternal karyotype (22%-52%) and postnatal evaluation (28%-87%) varied. Maternal karyotype was offered more often when NIPT was positive for 45,X or 47,XXX and patients had normal prenatal diagnostic testing (p<0.02) or declined testing (p<0.02). Offer of postnatal evaluation was more likely when diagnostic testing was declined (p<0.001). The majority of pediatric providers always offered a postnatal karyotype for the newborn (>72%) but the percent offering maternal karyotype (6%-46%) varied widely. With the current inconsistencies, many newborns with undiagnosed SCAs who could benefit from growth hormone therapy, early intervention, and/or targeted surveillance may be missed. Therefore, there is a need for professional guidelines to help improve the consistency of clinical care for patients with NIPT results positive for SCAs.

Epicardial fat: the role of testosterone and lipid metabolism in a cohort of patients with Klinefelter syndrome

ContextKlinefelter syndrome (KS), in which subjects have additional copies of X chromosomes, is the most common male sex chromosome abnormality, with a prevalence of 1 in 660 and an incidence of about 1 in 500–700 newborns. Its sign and symptoms include infertility, generally low testosterone levels, and an increased prevalence of obesity and metabolic syndrome. Epicardial fat thickness (EFT) reflects visceral adiposity rather than general obesity. ObjectiveThe aim of this study was to analyze echocardiographic EFT in a cohort of patients with KS in comparison with non-obese and obese euploid controls, and to evaluate its correlation with biochemical parameters. Design, setting and participantsTwo hundred and twenty-one KS patients referred to our Rare Endocrine Diseases clinic and 77 age-matched controls underwent Doppler echocardiography and a full investigation of anthropometric and body composition, Serum levels of total testosterone (T), estradiol (E2), sex hormone binding globulin (SHBG), fasting plasma glucose, insulin, cholesterol and triglycerides were obtained. All participants underwent dual energy X-ray absorptiometry (DEXA) scan to assess truncal body fat (TrBF). Main outcome measureEFT, body composition and metabolic parameters in KS patients and how they are affected by genotype. ResultsEFT was greater in KS patients than in healthy non-obese (NOb) controls, but lower than in obese (OB) controls. When KS patients were divided into groups (hypogonadal; eugonadal; receiving testosterone replacement therapy [TRT]), EFT was greater in hypogonadal patients than in NOb controls and eugonadal patients, but showed no difference from the OB controls or TRT patients. Hypogonadal patients showed increased TrBF in comparison with NOb controls and eugonadal and TRT patients, and similar TrBF to OB controls. As expected, there was a strong correlation between BMI and EFT in both KS patients and controls (P < 0.0001). In contrast, there was a strong inverse correlation between testosterone and EFT in the control group, but not in KS patients. EFT was significantly correlated with TrBF in both populations (P < 0.0001). Multivariate analyses showed that the major determinants of both EFT and TrBF were BMI and the presence of KS itself. Testosterone and triglycerides were not included as variables in the models. ConclusionEFT in hypogonadal KS subjects was similar to that of the obese eugonadal controls. Even though there was a direct correlation between BMI and EFT in both populations, the influence of TrBF on EFT was stronger. The presence of the supernumerary X chromosome appeared to be one of the strongest determinants of EFT and TrBF, independent of testosterone levels.

Prenatal diagnosis of monochorionic-diamniotic twins discordant for 45,X/46,XX mosaicism

To explore the prenatal screening and diagnosis for a pair of monochorionic-diamniotic (MCDA) twins discordant for 45,X/46,XX mosaicism. Amniotic fluid samples were taken from both twins for whom non-invasive prenatal testing has signaled a high risk for sex chromosomal abnormality. Uncultured amniotic fluid was analyzed by fluorescence in situ hybridization (FISH) and single nucleotide polymorphism array (SNP-array). Conventional G-banded karyotyping analysis was performed on the cultured amniotic fluid. Metaphase chromosome analysis showed that one of the twins had a mos 45,X[11]/46,XX[26] karyotype, while the other had a normal karyotype. FISH and SNP-array applied on uncultured amniotic fluid revealed about 30% mosaicism in one of the twins. The twins were confirmed to be monozygotic by SNP-array analysis. To avoid confusion arising from discordant karyotypes in MCDA twins with abnormal non-invasive prenatal testing (NIPT) results, dual amniocentesis should be carried out to obtain amniotic fluid samples for chromosomal as well as molecular analysis. To determine the ratio of 45,X and 46,XX cells in Turner syndrome can provide valuable information for prenatal genetic counseling.

Time to consider ovarian tissue cryopreservation for girls with Turner's syndrome: an opinion paper.

Turner’s syndrome (TS) is the most common sex chromosome abnormality in women. In addition to short stature and gonadal dysgenesis, it is associated with cardiac and renal anomalies. Due to rapid follicular atresia, the majority of women with TS suffer from primary ovarian insufficiency around puberty. Thus far, donor oocyte conception has been the key fertility option for these women. With advancing technology, ovarian tissue cryopreservation (OTCP) has emerged as a clinically justifiable option especially for pre-pubertal girls with cancer. Recently published results following the use of cryopreserved ovarian tissue are reassuring. It would be prudent to consider the extension of these technological and scientific advances to other conditions, such as TS, where accelerated follicular atresia is suspected. It is possible to obtain competent oocytes from cryopreserved ovaries of girls with TS provided the ovaries were preserved before ovarian failure. However, it is a complex decision whether and when to offer OTCP as a fertility preservation (FP) option for girls with TS. The rate of decline in fertility is variable in girls with TS and can be more complex in cases with mosaicism. On the other hand, OTCP has shown some promising results in patients with cancer, which can potentially be replicated in TS and other benign indications of patients at risk of premature ovarian failure. There are proven psychological and clinical benefits of FP. Thus, an argument could be made for offering OTCP to these patients to endow these girls with the option of having biological fertility using this innovative technology. Ethical, clinical and psychological dilemmas should be considered, discussed and addressed before considering such a novel approach. We believe that the time has come to start this discussion and open this avenue of FP for girls with TS.

Surgical management of hypospadias in cases with concomitant disorders of sex development.

To review the surgical treatment of hypospadias (HP) associated with disorders of sex development (DSD). HP cases were assessed for DSD by gross examination for atypical external genitalia, and assessment of hormone levels and karyotype. There were 58 HP cases with concomitant DSD treated between 1999 and 2017. DSD classification, type of HP, sex assignment, hormonal abnormality, surgical strategy, and post-urethroplasty complications (post-UPC) were reviewed. DSD were sex chromosome abnormalities (n = 4), 46,XY (n = 51), 46,XX (n = 1), and 47,XY + 21 (n = 2). HP was perineal: (n = 26), scrotal: (n = 16), penoscrotal: (n = 15), and midshaft: (n = 1); repair was primary (n = 6) or staged (n = 52). Mean age at final urethroplasty (UP) was 4.12 ± 0.21 years; all cases had soft tissue interposition at UP. At mean follow-up 5.16 ± 0.56years after final UP, observed post-UPC (n = 8; 13.8%) were urethral stenosis (n = 3), urethral diverticulum (n = 2), urethrocutaneous fistula (n = 2), and curvature (n = 1). Mean onset of post-UPC was 1.24 ± 0.77years (range 0.1-6.3). The second half of our cases (n = 29; treated 2015 ~) had significantly less post-UPC (0/29; 0%) than the first half (8/29; 27.6%) (p = 0.0075). Although UP for HP + DSD was formidably challenging, we achieved a significant decrease in post-UPC through a combination of surgical techniques and experience.

Endocrine aspects of Klinefelter syndrome.

Klinefelter syndrome is the most common sex chromosome abnormality in men. Hypogonadism and testicular degeneration are almost universal. Truncal adiposity, metabolic syndrome and low bone mass occur frequently. This review summarizes the most recent advances in the pathogenesis and management of the endocrine abnormalities in Klinefelter syndrome. It is expected that optimal endocrine management will improve outcomes and quality of life in Klinefelter syndrome. In Klinefelter syndrome, testosterone replacement is routinely prescribed despite lack of evidence on the optimal dose and time for initiation of therapy. Cross-sectional studies have linked hypogonadism to the development of metabolic abnormalities and low bone mass. Testosterone therapy, however, is not consistently associated with improved metabolic and bone outcomes. Increased truncal adiposity and high rates of metabolic syndrome are present in prepubertal children. A randomized trial of oxandrolone in prepubertal boys showed improvement in visual-motor function, socialization and cardiometabolic health. Testicular sperm extraction (TESE) has success rates similar to other causes of nonobstructive azoospermia when performed between 16 and 35 years of age. Endocrine care in Klinefelter syndrome should start in childhood and include evaluation of metabolic risk factors and bone health. Further research to guide evidence-based endocrine care is very much needed.

Changes in the cohort composition of turner syndrome and severe non-diagnosis of Klinefelter, 47,XXX and 47,XYY syndrome: a nationwide cohort study

BackgroundKnowledge on the prevalence of sex chromosome abnormalities (SCAs) is limited, and delayed diagnosis or non-diagnosis of SCAs are a continuous concern. We aimed to investigate change over time in incidence, prevalence and age at diagnosis among Turner syndrome (TS), Klinefelter syndrome (KS), Triple X syndrome (Triple X) and Double Y syndrome (Double Y).MethodsThis study is a nationwide cohort study in a public health care system. The Danish Cytogenetic Central Registry (DCCR) holds information on all karyotypes performed in Denmark since 1961. We identified all individuals in the DCCR with a relevant SCA during 1961–2014; TS: n = 1156; KS: n = 1235; Triple X: n = 197; and Double Y: n = 287. From Statistics Denmark, which holds an extensive collection of data on the Danish population, complete data concerning dates of death and migrations in and out of Denmark were retrieved for all individuals.ResultsThe prevalence among newborns was as follows: TS: 59 per 100,000 females; KS: 57 per 100,000 males; Triple X: 11 per 100,000 females; and Double Y: 18 per 100,000 males. Compared with the expected number among newborns, all TS, 38% of KS, 13% of Triple X, and 18% of Double Y did eventually receive a diagnosis. The incidence of TS with other karyotypes than 45,X (P < 0.0001), KS (P = 0.02), and Double Y (P = 0.03) increased during the study period whereas the incidence of 45,X TS decreased (P = 0.0006). The incidence of Triple X was stable (P = 0.22).ConclusionsThe prevalence of TS is higher than previously identified, and the karyotypic composition of the TS population is changing. Non-diagnosis is extensive among KS, Triple X and Double Y, whereas all TS seem to become diagnosed. The diagnostic activity has increased among TS with other karyotypes than 45,X as well as among KS and Double Y.

Discrepancy of QF-PCR, CMA and karyotyping on a de novo case of mosaic isodicentric Y chromosomes

BackgroundIsodicentric chromosomes are the most frequent structural aberrations of human Y chromosome, and usually present in mosaicism with a 45, X cell line. Several cytogenetic techniques have been used for diagnosing of uncommon abnormal sex chromosome abnormalities in prenatal cases.Case presentationA 26-year-old healthy woman was referred to our centre at 24 weeks of gestation age. Ultrasound examination indicated she was pregnant with imbalanced development of twins. Amniocentesis was referred to the patient for further genetic analyses. Quantitative Fluorescent Polymerase Chain Reaction (QF-PCR) indicated the existence of an extra Y chromosome or a structurally abnormal Y chromosome in primary amniotic cells. Chromosome microarray (CMA) analysis based on Comparative Genomic Hybridization (aCGH) platform was performed and identified a 10.1 Mb deletion on Y chromosome in 8-days cultured amniotic cells. Combined with the data of QF-PCR and aCGH, karyotyping and fluorescence in situ hybridization (FISH) revealed a mosaic cell line of 45,X[27]/46,X, idic(Y)(q11.22) [14] in fetus.The karyotyping analysis of cord blood sample was consistent with amniotic cells. The parental karyotypes were normal, which indicated this mosaic case of isodicentric Y (idicY) chromosomes of the fetus was a de novo case.ConclusionSeveral approaches have been used for the detection of numerical and structural chromosomal alterations of on prenatal cases. Our report supported the essential role of incorporating multiple genetic techniques in prenatal diagnosing and genetic counseling of potential complex sex chromosomal rearrangements.

Chorionicity definition by ultrasound

Ultrasound is the main prenatal tool to diagnose chorionicity and amnionicity in multiple pregnancies. The importance of this differentiation lies on the fact that monochorionic (MC) pregnancies present with higher morbidity and mortality than dichorionic ones (DC), what can be explained by a sum of factors. Firstly, the placental vascular communications that are present in all MC pregnancies, which unbalance between fetal sides promote complications exclusive for this type of twins, such as twin-twin transfusion syndrome (TTTS), twin anemia–polycythemia sequence (TAPS) and twin reversed arterial perfusion sequence (TRAP). Secondly, monoamniotic (MA) pregnancies are also associated with other exclusive complications, such as intertwin cord entanglement and conjoined twins. Finally, adverse outcomes common to all multiple gestations are more prevalent in MC ones, probably because of unequal placental sharing, such as selective fetal growth restriction (SFGR), single fetal demise and congenital anomalies. Chorionicity and amnionicity should be ideally determined in the first trimester of pregnancy, when sensitivity approaches 100% by the identification of one or more of the following ultrasonographic criteria: two separate placentas (DC), absence of intertwin membrane (MC/MA), lambda (DC) or T sign (MC/DA) at intertwin membrane placental insertion. Other interamniotic membrane characteristics such thickness greater than 1.5 to 2 mm (DC) or counting the number of layers can be used, since DC membranes have 4 layers and MC only 2. After the first trimester, chorionicity and amnionicity determination becomes less sensible (approaching 90%), because identification of the previous features are impacted by fetal crowding, progressive thinning of membranes and lower prevalence of lambda sign with advancing gestational age. However, identification of discordant fetal sexes after the second trimester arises as a reliable marker of DC. Although these reported findings can be taken as general rules for the determination of chorioamnionicity, it's important to emphasize that in rare situations there are some pitfalls that can lead to incorrect diagnosis, such as oligohydramnios in one cavity misleading to a false MA diagnosis, discordant fetal sex in MC pregnancies due to genital malformation or sex chromosome abnormalities, bipartite MC placenta, false positive or negative lambda sign for various reasons. Concluding, providers must be aware of the importance of early chorioamnionicity determination and how to perform it reliably, since this diagnosis is the key to appropriate management of multiple pregnancies.

Late Presentation of Turner Syndrome and Its Complications

Turner syndrome is one of the most common sex chromosome abnormalities with an estimated true prevalence of 1 in 2,000 in newborns. This case report is of a girl who presented to the adult endocrinologist at 16 years of age and subsequently diagnosed with Turner syndrome. Despite frequenting clinics for unrelated ailments, her short stature was overlooked hence not investigated for a causative pathology. The aim of this report is to explore the diagnostics of Turner syndrome, hormone treatments available and the importance of starting treatment early.&#x0D; KEYWORDS: Turner syndrome, short stature, primary amenorrhoea, osteoporosis

Prenatal diagnosis of sex chromosome mosaicism with two marker chromosomes in three cell lines and a review of the literature.

The present study described the diagnosis of a fetus with sex chromosome mosaicism in three cell lines and two marker chromosomes. A 24‑year‑old woman underwent amniocentesis at 21weeks and 4days of gestation due to noninvasive prenatal testing identifying that the fetus had sex chromosome abnormalities. Amniotic cell culture revealed a karyotype of 45,X[13]/46,X,+mar1[6]/46,X,+mar2[9], and prenatal ultrasound was unremarkable. The woman underwent repeat amniocentesis at 23weeks and 4days of gestation for molecular detection. Single nucleotide polymorphism (SNP) microarray analysis on uncultured amniocytes revealed that the fetus had two Y chromosomes and 7.8‑Mb deletions in Yq11.222q12. The deletion regions included DAZ, RBMY and PRY genes, which could cause spermatogenesis obstacle and sterility. Interphase fluorescence insitu hybridization (FISH) using centromeric probes DXZ1/DYZ3/D18Z1 was performed on uncultured amniocytes to verify the two marker chromosomes to be Y chromosome derivatives. According to these examinations, the mar1 was identified as a derivative of the Y chromosome with a deletion in Yq11.222q12, and the mar2 was identified as a dicentric derivative of the Y chromosome. The molecular karyotype was therefore 45,X,ish(DXZ1+, DYZ3‑,D18Z1++)[5]/46,X,del(Y)(q11.222),ish(DXZ1+,DYZ3+,D18Z1++)[11]/46, X,idic(Y)(q11.222),ish(DXZ1+,DYZ3++,D18Z1++)[14]. The comprehensive use of cytogenetic, SNP array and FISH detections was advantageous for accurately identifying the karyotype, identifying the origin of the marker chromosome and preparing effective genetic counseling.

Baseline Characteristics of Infants With Atypical Genital Development: Phenotypes, Diagnoses, and Sex of Rearing.

PurposeLittle is known about the phenotypes, diagnoses, and sex of rearing of infants with atypical genital development in the United States. As part of a multicenter study of these infants, we have provided a baseline report from US difference/disorder of sex development clinics describing the diagnoses, anatomic features, and sex of rearing. We also determined whether consensus guidelines are followed for sex designation in the United States.MethodsEligible participants had moderate-to-severe genital atypia, were aged <3 years, and had not undergone previous genitoplasty. Karyotype, genetic diagnosis, difference/disorder of sex development etiology, family history, and sex of rearing were collected. Standardized examinations were performed.ResultsOf 92 subjects, the karyotypes were 46,XX for 57%, 46,XY for 34%, and sex chromosome abnormality for 9%. The median age at the baseline evaluation was 8.8 months. Most 46,XX subjects (91%) had congenital adrenal hyperplasia (CAH) and most 46,XY subjects (65%) did not have a known diagnosis. Two individuals with CAH underwent a change in sex of rearing from male to female within 2 weeks of birth. The presence of a uterus and shorter phallic length were associated with female sex of rearing. The most common karyotype and diagnosis was 46,XX with CAH, followed by 46,XY with an unknown diagnosis. Phenotypically, atypical genitalia have been most commonly characterized by abnormal labioscrotal tissue, phallic length, and urethral meatus location.ConclusionsAn increased phallic length was positively associated with rearing male. Among the US centers studied, sex designation followed the Consensus Statement recommendations. Further study is needed to determine whether this results in patient satisfaction.

A Search for Disorders of Sex Development among Infertile Men

A retrospective cross-sectional study was performed in a DSD clinic at a tertiary service (University Hospital) to estimate the frequency of disorders of sex development (DSD) among men who seek medical care because of infertility. The sample included 84 men >20 years of age referred from 2010-2017 due to oligozoospermia or nonobstructive azoospermia of unknown etiology. Twelve cases (14%) were diagnosed as DSD, including Klinefelter Syndrome, 46,XX testicular DSD, and mild androgen insensitivity syndrome. Y chromosome microdeletions were detected in 2 patients. Among the remaining 70 cases there were patients with chromosome abnormalities which are not included in the DSD classification as well as rare NR5A1 variants of uncertain significance and hypergonadotropic hypogonadism and microorchidism in 46,XY subjects. In conclusion, the frequency of DSD in this study was 14%, consisting mainly of sex chromosome abnormalities but also 46,XX and 46,XY DSD. However, this figure may increase as further investigations are conducted in idiopathic cases with signs of primary testicular failure, which may present partial gonadal dysgenesis.

SEst: Accurate Sex-Estimation and Abnormality Detection in Methylation Microarray Data.

DNA methylation influences predisposition, development and prognosis for many diseases, including cancer. However, it is not uncommon to encounter samples with incorrect sex labelling or atypical sex chromosome arrangement. Sex is one of the strongest influencers of the genomic distribution of DNA methylation and, therefore, correct assignment of sex and filtering of abnormal samples are essential for the quality control of study data. Differences in sex chromosome copy numbers between sexes and X-chromosome inactivation in females result in distinctive sex-specific patterns in the distribution of DNA methylation levels. In this study, we present a software tool, sEst, which incorporates clustering analysis to infer sex and to detect sex-chromosome abnormalities from DNA methylation microarray data. Testing with two publicly available datasets demonstrated that sEst not only correctly inferred the sex of the test samples, but also identified mislabelled samples and samples with potential sex-chromosome abnormalities, such as Klinefelter syndrome and Turner syndrome, the latter being a feature not offered by existing methods. Considering that sex and the sex-chromosome abnormalities can have large effects on many phenotypes, including diseases, our method can make a significant contribution to DNA methylation studies that are based on microarray platforms.

Human blastocysts of normal and abnormal karyotypes display distinct transcriptome profiles

Unveiling the transcriptome of human blastocysts can provide a wealth of important information regarding early embryonic ontology. Comparing the mRNA production of embryos with normal and abnormal karyotypes allows for a deeper understanding of the protein pathways leading to viability and aberrant fetal development. In addition, identifying transcripts specific for normal or abnormal chromosome copy number could aid in the search for secreted substances that could be used to non-invasively identify embryos best suited for IVF embryo transfer. Using RNA-seq, we characterized the transcriptome of 71 normally developing human blastocysts that were karyotypically normal vs. trisomic or monosomic. Every monosomy and trisomy of the autosomal and sex chromosomes were evaluated, mostly in duplicate. We first mapped the transcriptome of three normal embryos and found that a common core of more than 3,000 genes is expressed in all embryos. These genes represent pathways related to actively dividing cells, such as ribosome biogenesis and function, spliceosome, oxidative phosphorylation, cell cycle and metabolic pathways. We then compared transcriptome profiles of aneuploid embryos to those of normal embryos. We observed that non-viable embryos had a large number of dysregulated genes, some showing a hundred-fold difference in expression. On the contrary, sex chromosome abnormalities, XO and XXX displayed transcriptomes more closely mimicking those embryos with 23 normal chromosome pairs. Intriguingly, we identified a set of commonly deregulated genes in the majority of both trisomies and monosomies. This is the first paper demonstrating a comprehensive transcriptome delineation of karyotypic abnormalities found in the human pre-implantation embryo. We believe that this information will contribute to the development of new pre-implantation genetic screening methods as well as a better understanding of the underlying developmental abnormalities of abnormal embryos, fetuses and children.

GENETIC FACTORS OF MALE INFERTILITY, THEIR COMBINATIONS AND THE SPERMATOLOGICAL CHARACTERISTICS OF MEN WITH FERTILITY FAILURES

The objectiveis to study the occurrence of common genetic factors of male infertility in men with reproductive problems, their combinations and spermatological characteristics.Materials and methods. 393 men with infertility in marriage were examined. According to the results of the cytogenetic study, the sample is divided into 3 groups: 135 men with numerical sex chromosome abnormalities; 58 male patients with a balanced structural rearrangement; 200 men with normal karyotype. Y chromosome microdeletions, CFTR gene mutations and CAG-repeats polymorphism of AR gene were analyzed.Results. The Y-chromosome microdeletions partially AZFc deletions were detected in 13 % male patients with sex chromosome abnormalities. A combination of chromosomal abnormalities with AZF deletions and/or CFTR gene mutations and long CAG repeats of AR gene was found in 19 % infertile men with balanced chromosome rearrangements. Infertile men with normal male karyotype presented the frequency of common genetic factors of male infertility was almost 2 times higher than the combined frequency of these factors in groups of patients with chromosomes abnormalities. Azoospermia in men with normal karyotype and patients with chromosome abnormalities was diagnosed with the same frequency (58 %). In all men who have identified the presence of two or more genetic factors of male infertility, severe forms of pathozoospermia (azoospermia and severe oligozoospermia) were found.Conclusion. The combination of genetic factors of male infertility is accompanied by severe forms of pathozoospermia that indicates a possible additive effect of negative effect on spermatogenesis and male fertility.

Application of karyotype analysis combined with BACs-on-Beads for prenatal diagnosis.

This study explored the clinical application of karyotype analysis combined with BACs-on-Beads (BoBs) technology in prenatal diagnosis. A total of 558 pregnant women who were admitted to Xuzhou Maternity and Child Health Care Hospital from July 2015 to June 2017 were enrolled in this study. All the subjects underwent amniocentesis. BoBs assay was performed for subjects in the observation group, and karyotype analysis was performed for subjects in the control group. The main technical indicators of subjects in the two groups were summarized, and cases of chromosome abnormalities were further evaluated. Clinical follow-up of their pregnancy and neonatal birth was undertaken. Finally, the chromosomal manifestations of these patients were compared with those of normal male and normal female, as well as common chromosomal abnormalities. All 558 pregnant women underwent amniocentesis again. Karyotype analysis combined with BoBs assay of amniotic fluid was performed. Cases of chromosomal abnormalities detected were: 75 cases of trisomy 21, 20 cases of trisomy 18, 1 case of trisomy 13, 27 cases of sex chromosomal abnormalities, 12 cases of balanced chromosome translocation, and 2 cases of chromosome microdeletion. The results indicated that karyotype analysis combined with BoBs technology for prenatal diagnosis was easy to perform, and provided quick results with high accuracy. The two testing methods were complementary to each other, which significantly improved the diagnostic rate of chromosomal abnormalities thus reducing birth defects and guiding continued pregnancy of high-risk pregnant women.

Molecular Karyotyping in Children and Adolescents with Gender Dysphoria

Purpose: The presence of a disorder of sexual development (DSD) acts as a diagnostic specifier for gender dysphoria (GD) under DSM-5, while the International Classification of Diseases (ICD)-10 specifically states that its equivalent diagnosis, gender identity disorder (GID), must not be the result of a chromosomal abnormality. For these reasons, routine karyotyping has been previously advocated in the clinical work-up of children and adolescents with suspected GD or GID. However, the utility of such testing remains unclear.Methods: The results of routine molecular karyotyping were analyzed in 128 patients attending our Australian statewide pediatric gender service from 2013 to 2016. Karyotyping was performed using an Illumina BeadChip platform and provided information on both sex chromosome composition and copy number variation (CNV).Results: No sex chromosome abnormalities directly suggestive of a DSD were discovered. The rate of CNVs among our patient cohort was 8.6% (11/128), similar to that previously reported for the general population. Unexpectedly, three trans male patients shared the same CNV, involving an almost identical 400 kbp deletion on chromosome 15q11.2. The frequency of this deletion within birth-assigned females in our cohort (3/69; 4.3%) was significantly higher than that within local control populations (0.3%; Fisher's exact test p-value=0.002), suggesting a possible association between 15q11.2 deletions and trans male identity.Conclusion: Routine molecular karyotyping failed to detect any occult DSD and indicated that the rate of CNVs was similar to that of the general population. Given these findings, we suggest that molecular karyotyping has minimal clinical utility in the routine management of children and adolescents with GD.