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Objective To assess the positive predictive value (PPV) of noninvasive prenatal testing (NIPT) as a screening test for sex chromosome aneuploidy (SCA) with different maternal characteristics and prenatal decisions in positive cases. Materials and methods We retrospectively analysed 45,773 singleton pregnancies with different characteristics that were subjected to NIPT in the Maternity and Child Health Hospital of Anhui Province. The results were validated by karyotyping. Clinical data, diagnostic results, and data on pregnancy outcomes were collected. Results In total, 314 cases were SCA positive by NIPT; among those, 143 underwent invasive prenatal diagnostic testing, and 58 were true-positive. Overall, the PPVs for 45,X, 47,XXX, 47,XXY and 47,XYY were 12.5%, 51.72%, 66.67% and 83.33%, respectively. Interestingly, when only pregnant women of advanced maternal age (AMA) were screened, the PPVs for 45,X, 47,XXX, 47,XXY and 47,XYY were 23.81%, 53.33%, 78.95%, and 66.67%, respectively. The frequency of SCA was significantly higher in the AMA group than in the non-AMA group. The frequencies of 47,XXX and 47,XXY were significantly correlated with maternal age. Conclusion NIPT performed better in predicting sex chromosome trisomies than monosomy X, and patients with 45,X positive foetuses were more eager to terminate pregnancy than those with 47,XXX and 47,XYY. AMA may be a risk factor of having a foetus with SCA. Our findings may assist in genetic counselling of AMA pregnant women. Our pre- and posttest counselling are essential for familiarizing pregnant women with the benefits and limitations of NIPT, which may ease their anxiety and enable them to make informed choices for further diagnosis and pregnancy decisions.

Context Boys with XXY have greater adiposity and a higher risk of cardiovascular disease. Infants with XXY have lower testosterone concentrations than typical boys, but no studies have evaluated adiposity in infants with XXY or the physiologic effects of giving testosterone replacement. Objective To determine the effect of testosterone on body composition in infants with XXY. Design Prospective, randomized trial. Setting Tertiary care pediatric referral center. Participants 20 infants 6 to 15 weeks of age with 47,XXY. Intervention Testosterone cypionate 25 mg intramuscularly monthly for three doses vs no treatment. Main Outcome Measures Difference in change in adiposity (percent fat mass z scores); other body composition measures, penile length, and safety outcomes between treated and untreated infants; and comparison with typical infants. Results The increase in percent fat mass (%FM) z scores was greater in the untreated group than in the treated group (+0.92 ± 0.62 vs −0.12 ± 0.65, P = 0.004). Increases in secondary outcomes were greater in the testosterone-treated group for total mass, fat-free mass, length z score, stretched penile length, and growth velocity (P < 0.002 for all). At 5 months of age, adiposity in untreated infants with XXY was 26.7% compared with 23.2% in healthy male infants of the same age (P = 0.0037); there was no difference in %FM between the treated XXY boys and controls. Reported side effects were minimal and self-limited; no serious adverse events occurred. Conclusions Adiposity of untreated infants was 15% greater than that of male controls by 5 months of age. Testosterone treatment for infants with XXY resulted in positive changes in body composition.

Klinefelter syndrome (KS, 47,XXY) is a common sex chromosome aneuploidy in males that is associated with a wide range of cognitive, social and emotional characteristics. The neural bases of these symptoms, however, are unclear. Brain structure in 19 pre- or early-pubertal boys with KS (11.5 ± 1.8 years) and 22 typically developing (control) boys (8.1 ± 2.3 years) was examined using surface-based analyses of cortical gray matter volume, thickness and surface area. Boys in the KS group were treatment-naive with respect to testosterone replacement therapy. Reduced volume in the insula and dorsomedial prefrontal cortex was observed in the KS relative to the TD group, as well as increased volume in the parietal, occipital and motor regions. Further inspection of surface-based metrics indicated that whereas KS-associated increases in volume were driven by differences in thickness, KS-associated reductions in volume were associated with decreases in surface area. Exploratory analyses additionally indicated several correlations between brain structure and behavior, providing initial support for a neural basis of cognitive and emotional symptoms of this condition. Taken together, these data add support for a neuroanatomical phenotype of KS and extend previous studies through clarifying the precise neuroanatomical structural characteristics of that give rise to volumetric alterations.

IntroductionNon-invasive prenatal testing (NIPT) using cell-free foetal DNA has been widely accepted in recent years for detecting common foetal chromosome aneuploidies, such as trisomies 13, 18 and 21, and sex chromosome aneuploidies. In this study, the practical clinical performance of our foetal DNA testing was evaluated for analysing all chromosome aberrations among 7113 pregnancies in Italy.MethodsThis study was a retrospective analysis of collected NIPT data from the Ion S5 next-generation sequencing platform obtained from Altamedica Medical Centre in Rome, Italy.ResultsIn this study, NIPT showed 100% sensitivity and 99.9% specificity for trisomies 13, 18 and 21. Out of the 7113 samples analysed, 74 cases (1%) were positive by NIPT testing; foetal karyotyping and follow-up results validated 2 trisomy 13 cases, 5 trisomy 18 cases, 58 trisomy 21 cases and 10 sex chromosome aneuploidy cases. There were no false-negative results.ConclusionIn our hands, NIPT had high sensitivity and specificity for common chromosomal aneuploidies such as trisomies 13, 18 and 21.

After multiple divisions, the oosperm forms a morula composed of about 32 cells, then the cells begin to differentiate and form blastocyst...

BackgroundCell-free fetal DNA (cffDNA) has opened up new approaches for non-invasive prenatal testing (NIPT), and it is often used as the second-tier test for high-risk pregnant women in detecting trisomy (T) 21, T18, and T13 after serum biochemistry screening. This study aims to discuss the clinical performance of NIPT as an alternative first-tier screening test for pregnant women in detecting T21, T18, T13, and sex chromosome aneuploidies (SCAs) in China.MethodsA total of 42,924 samples were recruited. The cell-free plasma DNA was directly sequenced. Each of the chromosome aneuploidies of PPV was analyzed. A total of 22 placental samples were acquired, including 14 FP and 8 TP samples. The placental verification of FP NIPT results was performed.ResultsAmong 42,924 samples, 281 (0.65%) positive cases, including 87 of T21, 31 of T18, 22 of T13, and 141 of SCAs were detected. For the detection of T21, the positive predictive value (PPV) was 78.46%, for trisomy 18, 62.96%, for trisomy 13, 10.00%, for SCAs, 47.22% in the total samples. For trisomy 21, the PPV was 86.67%, for trisomy 18, 80.00%, for trisomy 13, 20.00%, for SCAs, 56.52% in advanced maternal age (AMA) women. The PPV of T21 increased with age. For T18, the PPV showed an overall upward trend. For T13 and SCAs, PPV was raised first and then lowered. Placental verification of false positive (FP) NIPT results confirmed confined placental mosaicism(CPM) was the reason for false positives.ConclusionsThis study represents the first time that NIPT has been used as a first-tier screening test for fetal aneuploidies in a pilot city with large clinical samples in China. We propose that NIPT could replace serum biochemistry screening as a first-tier test.

One of the two X chromosomes in females is epigenetically inactivated, thereby compensating for the dosage difference in X‐linked genes between XX females and XY males. Not all X‐linked genes are completely inactivated, however, with 12% of genes escaping X chromosome inactivation and another 15% of genes varying in their X chromosome inactivation status across individuals, tissues or cells. Expression of these genes from the second and otherwise inactive X chromosome may underlie sex differences between males and females, and feature in many of the symptoms of XXY Klinefelter males, who have both an inactive X and a Y chromosome. We review the approaches used to identify genes that escape from X‐chromosome inactivation and discuss the nature of their sex‐biased expression. These genes are enriched on the short arm of the X chromosome, and, in addition to genes in the pseudoautosomal regions, include genes with and without Y‐chromosomal counterparts. We highlight candidate escape genes for some of the features of Klinefelter syndrome and discuss our current understanding of the mechanisms underlying silencing and escape on the X chromosome as well as additional differences between the X in males and females that may contribute to Klinefelter syndrome.

Increased prenatal diagnoses of sex chromosome aneuploidies (SCAs) amid limited knowledge of their prognoses heighten the need to understand how families contend with the implications of an SCA. To explore the experiences of parents and individuals who received a genetic diagnosis of an SCA (excluding Turner syndrome), we conducted semistructured qualitative telephone interviews with 43 participants affected by these conditions. Parents (n = 35) and individuals (n = 8) expressed almost unanimous interest in more optimistic portrayals of their condition from their providers, even when the prognosis is uncertain. While some participants reported success in receiving accurate information from their provider and identifying supportive resources, numerous families received outdated or misleading information about their condition and lacked direction in accessing follow-up care and support. Parents desire greater coordination of their child’s medical care and access to care that approaches an SCA holistically. Opportunities remain to improve the diagnosis and care of individuals with SCAs.

Case report The case concerns a 16-year-old boy with a history of high myopia and unilateral congenital cataract, tall stature for age, facial dysmorphism, hypermobile metacarpal-phalangeal joints, as well as behavioral problems. The mother had a history of recurrent pregnancy loss. Chromosomal analysis of the peripheral blood lymphocytes reported 47,XYY. Discussion Patients with sex chromosome aneuploidy 47,XYY have higher risk of congenital malformations, although ophthalmological anomalies are unusual. Evaluation of patients with tall stature and behavioral problems should include a chromosomal analysis in order to determine the etiology.

Objectives: To assess the accuracy of non-invasive prenatal testing (NIPT) for sex chromosome aneuploidy (SCA) in routine clinical practice and to review counselling and sonographic issues arising in SCA cases. Methods: Three specialist Australian obstetric ultrasound and prenatal diagnosis practices offering NIPT after 10 weeks' gestation participated in this study. NIPT was reported for chromosomes 21, 18, 13, X, and Y. Results: NIPT screening was performed in 5,267 singleton pregnancies. The odds of being affected given a positive screening result (OAPR) was lowest for SCAs, most notably for monosomy X (20%). Fewer women underwent invasive prenatal testing when counselled regarding a high risk for SCA (65.5%) compared with those who had a high risk for another aneuploidy (85%). The positive screening rate of NIPT including SCA was 2.3%, but 1.2% if only the autosomal trisomies were included in the panel. Conclusion: The addition of SCA testing to NIPT doubles the positive screening rate. The OAPR for SCAs (most notably for monosomy X) is reduced compared with the autosomal trisomies. Clinicians need a more extensive discussion with women prior to the inclusion of the X and Y chromosomes in the NIPT panel, given the complexity in counselling regarding further management and the additional anxiety that these abnormal results may cause. A benefit of sex chromosome analysis is an improvement in antenatal diagnosis of some disorders of sexual development.

ObjectiveNeurodevelopmental concerns in males with sex chromosome aneuploidy (SCA) (XXY/Klinefelter syndrome, XYY, XXYY) include symptoms seen in autism spectrum disorder (ASD), such as language impairments and social difficulties. We aimed to: (1) evaluate ASD characteristics in research cohorts of SCA males under DSM-IV compared to DSM-5 criteria, and (2) analyze factors associated with ASD diagnoses in SCA.MethodsEvaluation of participants with XXY/KS (n=20), XYY (n=57) and XXYY (n=21) included medical history, cognitive/adaptive testing, Social Communication Questionnaire, Social Responsiveness Scale, Autism Diagnostic Observation Schedule, Autism Diagnostic Interview-Revised, and DSM ASD criteria. Clinical impressions of ASD diagnostic category using the ADOS and DSM-IV criteria were compared to ADOS-2 and DSM-5 criteria. T-tests compared cognitive, adaptive, SES and prenatal vs. postnatal diagnoses between ASD and no ASD groups.ResultsASD rates in these research cohorts were 10% in XXY/KS, 38% in XYY, and 52% in XXYY using ADOS-2/DSM-5, and were not statistically different compared to DSM-IV criteria. In XYY and XXYY, the ASD group had lower verbal IQ and adaptive functioning compared to those without ASD. Many children without ASD still showed some social difficulties.ConclusionASD rates in males with SCA are higher than reported for the general population. Males with Y chromosome aneuploidy (XYY and XXYY) were 4.8 times more likely to have a diagnosis of ASD than the XXY/KS group, and 20 times more likely than males in the general population (1 in 42 males, CDC 2010). ASD should be considered when evaluating social difficulties in SCA. Studies of SCA and Y-chromosome genes may provide insight into male predominance in idiopathic ASD.

Objective To estimate the positive predictive value (PPV) of fetal sex chromosome aneuploidy (SCA) screened in non-selective population and explore the rate of pregnancy termination and ultrasound findings for fetal SCA and the factors influencing parents’ decisions in South China.Methods This is a large-scale retrospective cohort of positive SCA screened from unselected singleton pregnancies by non-invasive prenatal testing (NIPT) from a single prenatal center of a tertiary hospital, from January 2016 to November 2019. Clinical information, indications, diagnostic results, ultrasound findings, pregnancy determinations, and follow-up were reviewed and analyzed.Results 248 cases of SCA positive were screened out of 52453, giving a positive detection rate of 0.47%. The majority of indications (42.7%) were low-risk pregnancies. After genetic counseling, 43 pregnancies (17.3%) declined to prenatal diagnosis, the rest of 205 cases (82.7%) conducted with amniocentesis to detect fetal chromosome, of which 95 were confirmed as true positive of SCA with PPV of 46.3% (95/205). The SCA consisted of 68 sex chromosomal trisomies (26 cases of 47,XXY, 20 cases of 47,XXX and 22 cases of 47,XYY), 17 cases of monosomy X (45,X), three cases of 48,XXYY, three cases of mosaicisms (45,X/46,XX), four cases with sex chromosomal deletions, included two cases of 46,X,del(Y)(q11.21), one case of 46,X,del(X)(p11) and one case of 46,X,i(X)(q10). Of the 95 cases confirmed as true positive SCA, 50 cases (52.6%)chose to terminate the pregnancy (82.6%, 64.3%, 17.6% and 33.3% for 45,X, 47,XXY, 47,XXX and 47,XYY, respectively), 45 cases (47.4%) elected to continue the pregnancy. Ninety-three pregnant were also continued pregnancy after the exclusion of SCA.Conclusions NIPT, as a first-tier routine method for screening autosomal aneuploidies, also could play an important role in screening SCA. Low-risk pregnant women are the main indication for the detection of SCA as NIPT test provides to non-selective population. The trend of overall termination rates of SCA-affected pregnancies is decreased. For 47,XXX and 47,XYY with mild phenotype, couples would like to continue the pregnancy. But for 45,X and 47,XXY, parents apt to terminate pregnancy no matter ultrasound abnormalities were found or not. pregnancy determinations are affected by types of SCA, sonographic findings, maternal age, and presence of infertility.

Klinefelter syndrome (KS; 47, XXY) and Turner syndrome (TS; 45, XO) are caused by two relatively common sex chromosome aneuploidies. These conditions are associated with an increased odds of neuropsychiatric disorders, including attention deficit/hyperactivity disorder (ADHD), as well as impairments in cognition that include learning delays, attentional dysfunction and impulsivity. We studied cognitive functions in the XY* mouse model, which allows comparison of XXY to XY males (KS model), and XO to XX females (TS model). We evaluated adult mice with and without gonads, using a version of an operant reversal-learning task (RLT) that can be used to measure various facets of learning, impulsivity and attention. In the KS model, only one measure related to impulsivity – perseverative responding under reversal conditions – reliably discriminated gonadally intact XXY and XY mice. In contrast, a fundamental learning impairment (more trials to criterion in acquisition phase) in XXY mice, as compared to XY, was observed in gonadectomized subjects. No other task measures showed differences consistent with KS. In the TS mouse model, XO mice did not show a pattern of results consistent with TS, similar to past observations. Thus, the application of this RLT to these XY* models reveals only limited behavioral impairments relevant to KS.

Background The most common sex chromosomal aneuploidy in males is Klinefelter syndrome, which is characterized by at least one supernumerary X chromosome. While these men have long been considered infertile, focal spermatogenesis can be observed in some patients, and sperm can be surgically retrieved and used for artificial reproductive techniques. Although these gametes can be used for fertility treatments, little is known about the molecular biology of the germline in Klinefelter men. Specifically, it is unclear if germ cells in Klinefelter syndrome correctly establish the androgenetic DNA methylation profile and transcriptome. This is due to the low number of germ cells in the Klinefelter testes available for analysis. Results Here, we overcame these difficulties and successfully investigated the epigenetic and transcriptional profiles of germ cells in Klinefelter patients employing deep bisulfite sequencing and single-cell RNA sequencing. On the transcriptional level, the germ cells from Klinefelter men clustered together with the differentiation stages of normal spermatogenesis. Klinefelter germ cells showed a normal DNA methylation profile of selected germ cell-specific markers compared with spermatogonia and sperm from men with normal spermatogenesis. However, germ cells from Klinefelter patients showed variations in the DNA methylation of imprinted regions. Conclusions These data indicate that Klinefelter germ cells have a normal transcriptome but might present aberrant imprinting, showing impairment in germ cell development that goes beyond mere germ cell loss. Electronic supplementary material The online version of this article (10.1186/s13148-019-0720-3) contains supplementary material, which is available to authorized users.

48,XXYY is a sex chromosome aneuploidy affecting one in 18,000–50,000 male births (Visootsak et al. 2013). The presence of one additional X chromosome in males leads to testicular dysgenesis and hy...

Background\ud \ud The phenotype of children with XXYY has predominantly been defined by comparison to other sex chromosome aneuploidies trisomies affecting male children; however, the intellectual ability of children with XXYY is lower than children with other sex chromosome aneuploidies trisomies. It is not known to what extent the phenotype identified to date is specific to XXYY, rather than a reflection of lower IQ. This study evaluates the mental health and behaviour of children with XXYY, in comparison to children with intellectual disabilities of heterogeneous genetic origin.\ud \ud \ud Methods\ud \ud Fifteen children with XXYY and 30 controls matched for age (4–14 years), sex and intellectual ability were ascertained from the IMAGINE ID study. IMAGINE ID participants have intellectual disabilities due to genetic anomalies confirmed by National Health Service Regional Genetic Centre laboratories. The mental health and behaviour of participants was examined with the Development and Well‐being Assessment and the Strengths and Difficulties Questionnaire.\ud \ud \ud Results\ud \ud Children with XXYY experienced significantly more frequent and intense temper outbursts than the control group.\ud \ud \ud Conclusion\ud \ud Our results suggest that temper outbursts may be specifically associated with the XXYY phenotype. These problems have a significant impact on the daily lives of boys with XXYY and their families. It is crucial to ensure that families are well supported to manage these difficulties.

Background Noninvasive prenatal testing (NIPT) for fetal aneuploidies by scanning cell-free fetal DNA in maternal plasma is rapidly becoming a first-tier aneuploidy screening test in clinical practices. With the development of whole-genome sequencing technology, small subchromosomal deletions and duplications that could not be detected by conventional karyotyping are now able to be detected with NIPT technology. Methods In the present study, we examined 8141 single pregnancies with NIPT to calculate the positive predictive values of each of the chromosome aneuploidies and the subchromosomal microdeletions and microduplications. Results We confirmed that the positive predictive values (PPV) for trisomy 13, trisomy 18, trisomy 21, and sex chromosome aneuploidy were 14.28%, 60%, 80%, and 45.83%, respectively. At the same time, we also found 51 (0.63%) positive cases for chromosomal microdeletions or microduplications but only 13 (36.11%) true-positive cases. These results indicate that NIPT for trisomy 21 detection had the highest accuracy, while accuracy was low for chromosomal microdeletion and microduplications. Conclusions Therefore, it is very important to improve the specificity, accuracy, and sensitivity of NIPT technology for the detection of subchromosomal microdeletions and microduplications.

Introduction Pentasomy 49,XXXXY is a sex chromosome anomaly difficult to be diagnosed prenatally. We describe a patient of pentasomy 49,XXXXY with false low-risk results using a noninvasive prenatal screening (NIPS). A 30-year-old G1P0 woman presented at 336/7 weeks, secondary to sonographic fetal anomalies. She had low-risk NIPS at 136/7 weeks. Anatomy survey showed bilateral clubfeet, clinodactyly of the left fifth digit, micropenis, and echogenic bowel. Cytogenetics analysis revealed pentasomy 49,XXXXY syndrome. We report third-trimester sonographic features of a fetus with pentasomy 49,XXXXY and the importance of thorough pre- and posttest counseling for NIPS.

This chapter will focus on two genetic syndromes affecting gonadotropin function that typically present in childhood, Klinefelter syndrome, and testotoxicosis.

Studies on gene–environment interactions suggest that some individuals may be more susceptible to life adversities than others due to their genetic profile. This study assesses whether or not children with an extra X chromosome are more vulnerable to the negative impact of early life stress on cognitive functioning than typically-developing children.A total of 50 children with an extra X chromosome and 103 non-clinical controls aged 9 to 18 years participated in the study. Cognitive functioning in domains of language, social cognition and executive functioning were assessed. Early life stress was measured with the Questionnaire of Life Events. High levels of early life stress were found to be associated with compromised executive functioning in the areas of mental flexibility and inhibitory control, irrespective of group membership. In contrast, the children with an extra X chromosome were found to be disproportionally vulnerable to deficits in social cognition on top of executive dysfunction, as compared to typically-developing children. Within the extra X group the number of negative life events is significantly correlated with more problems in inhibition, mental flexibility and social cognition. It is concluded that children with an extra X chromosome are vulnerable to adverse life events, with social cognition being particularly impacted in addition to the negative effects on executive functioning. The findings that developmental outcome is codependent on early environmental factors in genetically vulnerable children also underscores opportunities for training and support to positively influence the course of development.

Purpose: To report the clinical experience and performance of plasma cell-free DNA sequencing-based noninvasive ­prenatal testing (NIPT) as a screening method in detecting trisomy 21, 18, 13 (T21/T18/T13) as well as sex chromosome aneuploidy (SCA) in a mixed-risk population in Iran. Methods: In a 2-year period between January 1, 2015, and December 31, 2016, over 150 medical centers in Iran offered NIPT as clinical screening tests for fetal T21, T18, T13 and SCA. All NIPT positive cases were recommended to undergo invasive prenatal diagnosis. Results: 11,414 maternal blood samples were received for NIPT, for which 11,223 samples obtained NIPT results. Among 11,213 cases with confirmatory results, 94 T21, 39 T18, 8 T13, 15 XO, 6 XXX, 3 XYY, 5 XXY and 11,042 euploid cases were detected. The overall sensitivity of NIPT was 98.90, 100.00, 100.00, 90.91, 100.00, 100.00 and 100.00%, and specificities were 99.96, 99.97, 99.99, 99.96, 99.98, 100.00 and 99.99% for detecting T21, T18, T13, XO, XXX, XYY and XXY, respectively. Conclusion: With a stringent protocol, our prospective large-scale multicentric nationwide study demonstrated that NIPT showed excellent performance as screening test for the detection of fetal T21, T18, T13 and SCA in mixed-risk pregnancies in Iran.

Background Cell-free fetal DNA in maternal plasma represents a source of fetal genetic material that can be sampled noninvasively. There are ample studies confirming the accuracy of NIPT in singleton pregnancies, but there is still relatively little studies demonstrate the feasibility and clinical application of a NIPT for fetal aneuploidy screening in twin pregnancies. Results In this study, we have finished 432 twin pregnancies screening by NIPT. There were 4 double chorionic dichorionic diamniotic (DCDA) cases of true positive NIPT results, including 1of T18 and 3 of T21, and 1 monochorionic diamniotic (MCDA) cases of true positive NIPT results, including 1of T21. The combined false-positive frequency for trisomies 21, 18 was 0%. Furthermore, there were 2 cases of false positive NIPT results, including 1 of T7 and 1 of sex chromosome aneuploidy. There was no false negative case, which gave a combined sensitivity and specificity of 100 and 99.53% respectively. Conclusion Our study demonstrated NIPT performed well in the detection of trisomy 21 in twin pregnancy. It is feasible and clinical applicable of NIPT for fetal aneuploidy screening in twin pregnancies. But, it needs a large number of clinical samples to demonstrate the applicability of other chromosomal abnormalities besides trisomies 21 and 18 in both singleton pregnancies and twin pregnancies.

BACKGROUND: The intent of noninvasive prenatal testing is to screen for fetal aneuploidies. The assumption is that overrepresented and underrepresented chromosomes are of fetal origin. However, this is not always the case. CASES: We report three cases in which maternal sex chromosome aneuploidy (confirmed by karyotype), two cases of which were previously unknown, resulted in false-positive results. In each, results were positive for fetal aneuploidy, but neonatal karyotypes confirmed normal karyotype. CONCLUSION: Noninvasive prenatal testing assesses the proportion of chromosomes 21, 18, 13, and sex chromosomes in maternal circulation. Intrinsic to the analysis is that the underrepresentations and overrepresentations are of fetal origin. We present three cases in which this assumption is not valid. We suggest that maternal sex chromosome aneuploidy be considered when results suggest fetal sex chromosome aneuploidies.

Background: In cultured, dividing transformed T lymphocytes and in dividing bone marrow cells from normal men and those with a haematological malignancy, sex chromosome aneuploidy has been found to increase in prevalence and degree with age. This has rarely been investigated in non-dividing uncultured blood samples. The loss and gain of the X chromosome in dividing transformed lymphocytes in women with age is much more frequent than that of the Y chromosome in males. However, paradoxically X chromosome aneuploidy is rarely seen in the dividing cells of bone marrow of females. Methods: In blood samples from 565 men with breast cancer and 54 control men from the England and Wales general population, 80 cell nuclei per sample were scored for presence of X and Y chromosomes using fluorescent centromeric probes. Results: Sex chromosome aneuploidy, largely Y chromosome loss, was present in 63% of cases and 57% of controls, with the prevalence and degree of aneuploidy increasingly sharply and highly significantly with age. At ages 65–80 years, 71% of cases and 85% of controls showed aneuploidy and 15% and 25%, respectively, had ⩾10% of cells aneuploid. Allowing for age, aneuploidy was less prevalent (P=0.03) in cases than controls. Conclusion: Sex chromosome aneuploidy in non-dividing nuclei of peripheral blood cells is frequent in adult men, the prevalence and degree increasing sharply with age. The possible relation of sex chromosome aneuploidy to breast cancer risk in men, and to cancer risk generally, needs further investigation, ideally in cohort studies.

As a group, people with the sex chromosome aneuploidy 49,XXXXY have characteristic physical and cognitive/behavioral tendencies, although there is high individual variation. In this study we use magnetic resonance imaging (MRI) to examine brain morphometry in 14 youth with 49,XXXXY compared to 42 age-matched healthy controls. Total brain size was significantly smaller (t = 9.0, p, Highlights ► Total brain size was significantly smaller. ► Rates of brain abnormalities were significantly increased. ► Smaller cross sectional area of the corpus callosum.

Klinefelter syndrome (XXY) is a common yet significantly underdiagnosed condition with considerable medical, psychological and social implications. Many health care providers lack familiarity with XXY, resulting in medical management challenges and a limited understanding of the personal impact of the condition. Genetic counselors benefit from understanding the challenges adolescents and men with XXY face to effectively address their medical and psychosocial needs. The purpose of this study was to understand the impact of living with XXY as an adolescent or an adult. Individuals aged 14 to 75 years with self-reported XXY were recruited from online support networks to complete a web-based survey that included open-ended questions. Open-ended responses were coded and analyzed thematically (n = 169 to 210 for each open-ended question). Over half of respondents to the open-ended questions reported challenges in finding health care providers who are knowledgeable about XXY, with many describing an extensive diagnostic odyssey and relief when receiving a diagnosis. Individuals sought support coping with the challenges they face and acknowledgement of the positive aspects of XXY. Recommendations are made for how genetic counseling can enhance quality of life for individuals living with XXY.

Turner Syndrome (TS) is a sex chromosome aneuploidy (45,X) associated with social skill difficulties. Recent clinical care guidelines recommend that the Program for the Education and Enrichment of Relational Skills (PEERS) social skills intervention programme be trialled in this population. PEERS has been successfully used in adolescents with autism spectrum conditions without intellectual disabilities. The PEERS program will be piloted with adolescents and young women with TS aged 16-20 using an uncontrolled study trial with a multiple-case series design. The program will be delivered face to face and online. The assessment battery is designed to measure social skills comprehensively from diverse informants (parent, teacher young person). It includes measures of social performance, social knowledge and social cognition. Parents and young people taking part in the intervention will also feedback on the acceptability and feasibility of the pilot. The outcomes of this small scale pilot (n=6-10) will be used to adapt the programme based on feedback and estimate the sample for a future randomised controlled trial.

A further study of the electrocardiogram in patients with sex chromosome abnormalities who have no evidence of heart disease is described. It is confirmed that in 47, XYY males the atrioventricular conduction is delayed and that in 45, X females it is accelerated. In 47, XYY males there is also a higher than normal frequency of minor defects of intraventricular conduction. No significant deviation from normal was found in the electrocardiogram of men with a 47, XXY karyotype or in 47, XXX women. The significance of the finding is discussed.

49,XXXXY syndrome is a rare sex chromosome aneuploidy syndrome characterized by mental retardation, severe speech impairment, craniofacial abnormalities, multiple skeletal defects, and genital abnormalities. We describe a 13-year-old boy with 49,XXXXY syndrome, language impairment, seizures, and left-hemisphere magnetic resonance imaging abnormalities and review the distinctive neurologic, cognitive, and behavioral phenotypes associa t e d w i t h t h i s d i s o r d e r. F i n a l l y, w e d i s c u s s testosterone supplementation in the treatment of this syndrome. ( J Child Neurol 2003;18:501—504).

48,XXYY is a rare sex chromosome aneuploidy affecting 1 in 18,000 to 50,000 male births. They present with developmental delay, hypogonadism, gynecomastia, intention tremors, and a spectrum of neurodevelopmental and psychiatric disorders. At one time this condition was considered a variant of Klinefelter syndrome. In clinically suspected cases, 48,XXYY syndrome can be diagnosed by chromosome culture and karyotyping. This patient presented with hypergonadotrophic hypogonadism, attention deficit hyperactive disorder, and renal malformatons. Klinefelter syndrome was clinically suspected. The karyotype confirmed the diagnosis of 48,XXYY syndrome. This is the first reported case of 48,XXYY syndrome from Sri Lanka.

We describe four examples of the XO condition in wild mammals. One XO house mouse (Mus musculus domesticus) was caught in nature and subsequently gave birth to three litters in captivity, confirming for wild mice the fertility observed for XO laboratory mice. Two other XO house mice were produced from laboratory crosses of wild-caught mice. An immature XO common shrew (Sorex araneus) was caught in nature; this appears to be the first XO recorded in the order Insectivora. We collected data from researchers studying chromosome variation in house mice and common shrews and found an overall incidence of 0.22% sex chromosome aneuploidy in 4608 mice and 0.05% in 6625 shrews. The discrepancy related to a much higher frequency of XO’s in mice than shrews. Single XXY and XYY shrews and an XXX mouse have been recorded in nature.

Trisomy X, the presence of an extra X chromosome in females (47,XXX), is a relatively common but under-recognized chromosomal disorder associated with characteristic cognitive and behavioral features of varying severity. The objective of this study was to determine whether there were neuroanatomical differences in girls with Trisomy X that could relate to cognitive and behavioral differences characteristic of the disorder during childhood and adolescence. MRI scans were obtained on 35 girls with Trisomy X (mean age 11.4, SD 5.5) and 70 age- and sex-matched healthy controls. Cognitive and behavioral testing was also performed. Trisomy X girls underwent a semi-structured psychiatric interview. Regional brain volumes and cortical thickness were compared between the two groups. Total brain volume was significantly decreased in subjects with Trisomy X, as were all regional volumes with the exception of parietal gray matter. Differences in cortical thickness had a mixed pattern. The subjects with Trisomy X had thicker cortex in bilateral medial prefrontal cortex and right medial temporal lobe, but decreased cortical thickness in both lateral temporal lobes. The most common psychiatric disorders present in this sample of Trisomy X girls included anxiety disorders (40%), attention-deficit disorder (17%) and depressive disorders (11%). The most strongly affected brain regions are consistent with phenotypic characteristics such as language delay, poor executive function and heightened anxiety previously described in population-based studies of Trisomy X and also found in our sample.

Recent published studies have demonstrated the incremental value of the use of cell-free DNA for noninvasive prenatal testing with 100% sensitivity for trisomies 21 and 18 and a specificity of ≥99.7% for both. Data presented by two independent groups suggesting positive results by noninvasive prenatal testing were not confirmed by cytogenetic studies. Concordance of results among cases with noninvasive prenatal testing referred for cytogenetic prenatal and/or postnatal studies by karyotyping, fluorescence in situ hybridization, and/or oligo–single-nucleotide polymorphism microarray was evaluated for 109 consecutive specimens. Cytogenetic results were positive for trisomy 21 in 38 of the 41 noninvasive prenatal testing–positive cases (true-positive rate: 93%) and for trisomy 18 in 16 of the 25 noninvasive prenatal testing–positive cases (true-positive rate: 64%). The true-positive rate was only 44% (7/16 cases) for trisomy 13 and 38% (6/16 cases) for sex chromosome aneuploidy. These findings raise concerns about the limitations of noninvasive prenatal testing and the need for analysis of a larger number of false-positive cases to provide true positive predictive values for noninvasive testing and to search for potential biological or technical causes. Our data suggest the need for a careful interpretation of noninvasive prenatal testing results and cautious transmission of the same to providers and patients. Genet Med 17 3, 234–236.

Objective: To compare the frequencies of aneuploidy for chromosomes X, Y and 18 in spermatozoa of infertile and fertile males, using 3-color fluorescence in situ hybridization. Methods: Twelve infertile patients who underwent intracytoplasmic sperm injection treatment at Queen's Medical Centre, Nottingham were studied. Three fertile men served as controls. Aneuploidy frequencies in both groups were compared using 2-sample t-tests. Results: A total of 26,615 ad 93,649 cells were scored in the control and infertile groups respectively. The frequencies of diploidy, sex chromosome disomy and chromosome 18 disomy in the fertile (0.11, 0.28 and 0.11%) compared to the infertile males (0.05, 0.18 and 0.06%) were not statistically significantly different. Conclusion: Our preliminary data do not indicate an increased risk from paternal origin sex chromosome aneuploidies in ICSI. However, we recommend further investigations of the cytogenetic constitution of spermatozoa from severe male factor patients.

48, XXYY syndrome is a form of sex chromosome aneuploidy that affects between 1 in 18emsp14;000 to 1 in 40emsp14;000 males. It is not inherited and is diagnosed by karyotyping. It has similarities to 47, XXY Klinefelter's syndrome, with tall stature, micro-orchidism, hypergonadotropic hypogonadism and infertility in males. However, patients with 48, XXYY syndrome also commonly have dental problems, tremor, attention deficit disorder, learning difficulties, allergies and asthma. The tremor is typically reported as an intention tremor (in 71% of patients XXYY aged20 years with 48), which becomes more common with age and worsens over time.

48, XXYY is a very rare sex chromosome aneuploidy, characterized by both an extra X and Y chromosome with a prevalence of 1:18,000-1:40,000. Most patients are diagnosed prenatally by cytogenetic examination of amniotic fluid, or during the first years of life because of severe developmental delay, cognitive impairment and behavioural disorders. This syndrome shares two findings with Klinefelter syndrome, namely tall stature and hypergonadotropic hypogonadism but at this time no genital anomalies have been reported in patients with this tetrasomy. We describe a 48, XXYY neonate and a clinical picture characterized by small penis, bifid scrotum, scrotal hypospadias and testes palpable in the labioscrotal folds.

Objective: The pathogenesis of Autism spectrum disorders (ASD) is complex and still not clear. Genetic factors contribute to the occurrence of ASD. However, the genetics of ASD is highly heterogeneous. Chromosomal aberrations have a key role to the genetic abnormalities of both syndromic and non-syndromic ASD. Methods: In our study, we conducted karyotyping analysis in a sample of 231 Egyptian children with ASD aged 3-13 years (132 males and 99 females) from five Governorates in Upper Egypt. Results: Eleven patients (4.7%) were found to have chromosomal abnormalities in this study. We found five patients having sex chromosome aneuploidy, including two patients with Turner syndrome, two with 47XYY and one with 47XXY. In addition, we detected three patients have Down syndrome, one patient has monosomy 1p36, one patient has Williams-Beuren syndrome and one patient has a deletion of the long arm of chromosome 13. Conclusions: The present study reinforces the findings of the association between some chromosomal aberrations and ASD. Further investigations into these regions may lead to discovery of new genes involved in ASD. The present study directs the attention of the clinicians about the importance of karyotyping in the evaluation of ASD patients.

Background Male sex chromosome aneuploidies are underdiagnosed despite concomitant physical and behavioral manifestations. Objective To develop a non-invasive, rapid and high-throughput molecular diagnostic assay for detection of male sex chromosome aneuploidies, including 47,XXY (Klinefelter), 47,XYY, 48,XXYY and 48,XXXY syndromes. Methods The assay utilizes three XYM and four XA markers to interrogate Y:X and X:autosome ratios, respectively. The seven markers were PCR amplified using genomic DNA isolated from a cohort of 323 males with aneuploid (n = 117) and 46,XY (n = 206) karyotypes. The resulting PCR products were subjected to Pyrosequencing, a quantitative DNA sequencing method. Results Receiver operator characteristic (ROC) curves were used to establish thresholds for the discrimination of aneuploid from normal samples. The XYM markers permitted the identification of 47,XXY, 48,XXXY and 47,XYY syndromes with 100% sensitivity and specificity in both purified DNA and buccal swab samples. The 48,XXYY karyotype was delineated by XA marker data from 46,XY; an X allele threshold of 43% also permitted detection of 48,XXYY with 100% sensitivity and specificity. Analysis of X chromosome-specific biallelic SNPs demonstrated that 43 of 45 individuals (96%) with 48,XXYY karyotype had two distinct X chromosomes, while 2 (4%) had a duplicate X, providing evidence that 48,XXYY may result from nondisjunction during early mitotic divisions of a 46,XY embryo. Conclusions Quantitative Pyrosequencing, with high-throughput potential, can detect male sex chromosome aneuploidies with 100% sensitivity.

We compare social skills in three groups of males with sex chromosome aneuploidies (SCAs) using the Social Responsiveness Scale (SRS). Participants included males with XXY (N=102, M=10.08 years), XYY (N=40, M=9.93 years), and XXYY (N=32, M=11.57 years). XXY had lower (better) SRS scores compared to XYY and XXYY. Scores were not significantly different between XYY and XXYY. In all groups, there were significantly more with SRS scores in the severe range compared to the SRS normative sample. All groups scored lowest (better) on Social Motivation. Relationships between SRS scores and demographic and clinical variables were examined. Results describe the social skills in males with SCA, and suggest that an additional Y chromosome may contribute to increased risk of autistic behaviors.

This chapter reviews some recent advances in our understanding of human sex development, and discusses a newly suggested nomenclature and classification system for disorders of sex development (DSD). It provides a brief overview of some known genetic causes of DSD, and outlines some challenges for research and clinical practice in this field related to the theme of reproductive genetics. Sex chromosome DSD includes all cases of sex chromosome aneuploidy. Complete gonadal dysgenesis results in a complete lack of androgenisation and a female phenotype. The most common cause of androgen excess is congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency. Increasing number of cases of DSD are being diagnosed earlier owing to discordance between a karyotype performed in the first trimester and genital appearance on prenatal ultrasound or at birth. The early postnatal management of a child born with ambiguous genitalia or karyotype/phenotype discordance is very important.

Advances in understanding the human genome and clinical application have led to identification of genetically based disorders that have distinctive behavioral phenotypes and risk for serious psychiatric disorders. Some patients have unrecognized genetic disorders presenting as psychiatric symptoms. Practitioners must be knowledgeable about the association between symptoms and underlying genetic bases. Treatment of neurogenetic disorders includes providing information about causes and prognoses. Patients are served best if they remain long term with a multidisciplinary team of providers who recognize the realities of a lifetime course, the high risk for symptom recurrence, and the need for providing information and support to families and coordinating medical and psychiatric care.

Presences of normal genes on the Y chromosome are essential for normal sex determination and sex differentiation of male genitalia. Several genes on the X chromosome and other autosomes have been shown to be anti-testes and have a detrimental effect on the development process of normal male genital system. The addition of X chromosomes to the 46, XY karyotype results in seminiferous tubules dysgenesis, hypogonadism, and malformed genitalia. We report an infant male with 49, XXXXY syndrome presenting with ambiguous genitalia and multiple extra-gonadal anomalies.

Objective To evaluate placental growth factor (P1GF) in abnormal early pregnancies. Methods Placental growth factor (P1GF) was retrospectively quantified (DELFIA DXpress; Perkin Elmer) in women with known pregnancy outcomes. Study group consisted of: (i) normal (n = 300); (ii) abnormal: trisomy 21 (n = 56), trisomy 18 (n = 23), trisomy 13 (n = 6), triploid (n = 15), monosomy X (n = 7). P1GF MoM values were calculated by LifeCycle v4 (Perkin Elmer), using lot specific derived polynomial regression curve. Results Median P1GF MoM values were depressed in pregnancies carrying a fetus affected with: trisomy 21 = 0.81 (95%CI 0.72-0.90), trisomy 13=0.87 (95%CI 0.79-0.95), trisomy 18 = 0.89 (95%CI 0.78-1.00) and triploidy = 0.68 (95%CI 0.59-0.77). However, in viable sex chromosome aneuploidy, such as monosomy X, P1GF proved less discriminatory with median MoM = 0.91 (95%CI 0.76-1.06). Conclusions The above findings support the inclusion of P1GF in the marker panel for first trimester screening for fetal aneuploidy. In addition to improving detection of fetal aneuploidy, P1GF has a role in first trimester detection of early onset pre-ecalmpsia1.

We report on a case of a female fetus found to be mosaic for Turner syndrome (45,X) and trisomy X (47,XXX). Chromosomal microarray analysis (CMA) failed to detect the aneuploidy because of a normal average dosage of the X chromosome. This case represents an unusual instance in which CMA may not detect chromosomal aberrations. Such a possibility should be taken into consideration in similar cases where CMA is used in a clinical setting.

Pentasomy 49,XXXXY is a rare sex chromosome disorder usually presenting with ambigous genitalia, facial dysmorphism, mental retardation and a combination of cardiac, skeletal and other malformations. The incidence of the condition is estimated to be 1 in 85,000 male births. Previously, this condition was identified as a Klinefelter variant. The condition is suspected in a patient, by a combination of characteristic clinical findings, and the diagnosis is confirmed by chromosome culture and karyotyping. In the case we report here, the main presentation of ambiguous genitalia led to a suspicion of a sex chromosome aneuploidy which was subsequently confirmed by chromosomal analysis.