Sex Chromosome Trisomies Research Articles

An assessment of the analytical performance of non-invasive prenatal testing (NIPT) in detecting sex chromosome aneuploidies: 34,717-patient sample in a single prenatal diagnosis Centre in China.

The present study aimed to evaluate the efficacy of a non-invasive prenatal test (NIPT) in the detection of the sex chromosome aneuploidies (SCAs) at our prenatal diagnosis centre. Among a cohort of 34,717 pregnancies, maternal plasma samples from our prenatal diagnosis centre were subject to analysis of SCAs using NIPT detection. Pregnant women with NIPT positive results of SCAs were recommended to undergo an invasive prenatal diagnosis (i.e. karyotyping and fluorescence in situ hybridization) to validate the prediction value of NIPT. From 34,717 clinical pregnancies, 229 (0.66%) pregnancies were identified with SCAs. Of these, 78 (34.1%) cases were positive for 45,X and 151 (65.9%) cases comprised a sex chromosome trisomy. Of the 229 positive NIPT results, 193 (84.3%) cases had accepted an invasive diagnosis involving karyotyping analysis of the amniotic fluid, which confirmed 67 cases (34.7%) as true positive, as well as 126 cases (65.3%) as false positive. The positive predictive values were 23.07%, 50%, 36% and 27.27% respectively. The remaining 36 (15.7%) cases declined a prenatal diagnosis. The termination rates of 45,X, 47,XXY, 47,XXX and 47,XYY were 20.5%,46%,12.9% and 11.5% respectively. NIPT demonstrated a lower accuracy in predicting monosomy X than sex chromosome trisomies. After invasive testing, the fetal chromosome with 45,X and 47,XXY were terminated more often than those with 47,XXX, 47,XYY. Because NIPT is a screening test, false positive/negative cases exist, and pre- and post-test counselling is essential for informing patients about the benefits and limitations of the test. Confirmatory testing of abnormal results is recommended prenatally or after birth, and the importance of confirmatory testing and benefits of early diagnosis should be addressed.

The Impact of Sex Chromosome Trisomies (XXX, XXY, XYY) on Early Social Cognition: Social Orienting, Joint Attention, and Theory of Mind.

ObjectiveAbout 1:650–1,000 children are born with an extra X or Y chromosome (XXX; XXY; XYY), which results in a sex chromosome trisomy (SCT). This study aims to cross-sectionally investigate the impact of SCT on early social cognitive skills. Basic orienting toward social cues, joint attention, and theory of mind (ToM) in young children with SCT were evaluated.MethodAbout 105 children with SCT (range: 1–7 years old) were included in this study, as well as 96 age-matched nonclinical controls. Eyetracking paradigms were used to investigate the eye gaze patterns indicative of joint attention skills and orienting to social interactions. The ToM abilities were measured using the subtest ToM of the Developmental NEuroPSYchological Assessment, second edition, neuropsychological test battery. Recruitment and assessment took place in the Netherlands and in the United States.ResultsEyetracking results revealed difficulties in children with SCT in social orienting. These difficulties were more pronounced in children aged 3 years and older, and in boys with 47,XYY. Difficulties in joint attention were found over all age groups and karyotypes. Children with SCT showed impairments in ToM (26.3% in the [well] below expected level), increasing with age. These impairments did not differ between karyotypes.ConclusionsAn impact of SCT on social cognitive abilities was found already at an early age, indicating the need for early monitoring and support of early social cognition. Future research should explore the longitudinal trajectories of social development in order to evaluate the predictive relationships between social cognition and outcome later in life in terms of social functioning and the risk for psychopathology.

Stage 2 Registered Report: Variation in neurodevelopmental outcomes in children with sex chromosome trisomies: testing the double hit hypothesis.

Background: The presence of an extra sex chromosome is associated with an increased rate of neurodevelopmental difficulties involving language. The 'double hit' hypothesis proposes that the adverse impact of the extra sex chromosome is amplified when genes that are expressed from the sex chromosomes interact with autosomal variants that usually have only mild effects. We predicted that the impact of an additional sex chromosome on neurodevelopment would depend on common autosomal variants involved in synaptic functions. Methods: We analysed data from 130 children with sex chromosome trisomies (SCTs: 42 girls with trisomy X, 43 boys with Klinefelter syndrome, and 45 boys with XYY). Two comparison groups were formed from 370 children from a twin study. Three indicators of phenotype were: (i) Standard score on a test of nonword repetition; (ii). A language factor score derived from a test battery; (iii) A general scale of neurodevelopmental challenges based on all available information. Preselected regions of two genes, CNTNAP2 and NRXN1, were tested for association with neurodevelopmental outcomes using Generalised Structural Component Analysis. Results: There was wide phenotypic variation in the SCT group, as well as overall impairment on all three phenotypic measures. There was no association of phenotype with CNTNAP2 or NRXN1 variants in either the SCT group or the comparison groups. Supplementary analyses found no indication of any impact of trisomy type on the results, and exploratory analyses of individual SNPs confirmed the lack of association. Conclusions: We cannot rule out that a double hit may be implicated in the phenotypic variability in children with SCTs, but our analysis does not find any support for the idea that common variants in CNTNAP2 or NRXN1 are associated with the severity of language and neurodevelopmental impairments that often accompany an extra X or Y chromosome. Stage 1 report: http://dx.doi.org/10.12688/wellcomeopenres.13828.2.

Noninvasive prenatal detection of fetal sex chromosome abnormalities using the semiconductor sequencing platform (SSP) in Southern China

BackgroundNoninvasive prenatal testing (NIPT) has been widely used to screen for fetal aneuploidies, including fetal sex chromosome aneuploidies (SCAs). However, there is less information on the performance of NIPT in detecting SCAs.MethodsA cohort of 47,800 pregnancies was recruited to review the high-risk NIPT results for SCAs. Cell-free fetal DNA (cffDNA) was extracted and sequenced. All NIPT high-risk cases were recommended to undergo invasive prenatal diagnosis for karyotyping analysis and chromosome microarray analysis (CMA).ResultsA total of 238 high-risk cases were detected by NIPT, including 137 cases of 45,X, 27 cases of 47,XXX, and 74 cases of 47,XYY/47,XXY. Prenatal diagnosis, including karyotyping analysis and CMA, was available in 170 cases. The positive predictive value (PPV) was 30.00% for 45,X, 70.58% for 47,XXX, and 81.13% for 47,XYY/47,XXY. In addition, 13 cases of sex chromosome mosaicism and 9 cases of sex chromosome CNVs were incidentally found in this study.ConclusionOur study showed that NIPT was reliable for screening SCAs based on a large sample, and it performed better in predicting sex chromosome trisomies than monosomy X. Our study will provide an important reference for clinical genetic counseling and further processing of the results.

356 Is placental mosaicism identified by CVS associated with higher rates of adverse obstetric outcomes?

Placental mosaicism is identified in approximately 1-2% of women who undergo CVS. While high rates of adverse obstetric outcomes have been described, data is inconsistent. Our objective was to compare outcomes in pregnancies with and without mosaicism identified at CVS. All women who underwent CVS followed by amniocentesis from 2010-2020 were identified. Those who underwent amniocentesis due to mosaicism on CVS were compared to those who underwent amniocentesis after CVS for other reasons. Pregnancies terminated for genetic abnormalities were excluded. Obstetric outcomes were compared between the two groups. Student t test and Fisher’s exact test were used for statistical comparison. During the study period 2539 women underwent CVS, and 66 (2.6%) subsequently underwent amniocentesis: 29 (44%) due to mosaicism, 22 (33%) due to sampling/laboratory issues, and 15 (23%) for additional diagnostic testing. The most common forms of mosaicism were for sex chromosome abnormalities (n=4), tetraploidy (n=4), and Trisomy 9 (n=4). Mean maternal age was 36.7 ± 3.5-yrs, and 41% of women were nulliparous. Age and parity were similar between groups. There were no pregnancy losses or stillbirths. Obstetric outcomes are in Table 1. Those who had placental mosaicism did not have higher rates of adverse outcomes compared to those who underwent amniocentesis following CVS due to other reasons. Placental pathology was performed in 41% of cases, and placental mosaicism was not associated with higher rates of lesions of malperfusion (45.5% vs. 37.5%, p=0.71). We did not observe an association between placental mosaicism and adverse obstetric outcomes. As our study cohort consisted of small numbers of different forms of mosaicism, it is unclear if specific mosaic karyotypes have higher rates of adverse outcomes.

Noninvasive prenatal testing for assessing foetal sex chromosome aneuploidy: a retrospective study of 45,773 cases

ObjectiveTo 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 methodsWe 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.ResultsIn 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.ConclusionNIPT 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.

Failure to recombine is a common feature of human oogenesis

Failure of homologous chromosomes to recombine is arguably the most important cause of human meiotic nondisjunction, having been linked to numerous autosomal and sex chromosome trisomies of maternal origin. However, almost all information on these "exchangeless" homologs has come from genetic mapping studies of trisomic conceptuses, so the incidence of this defect and its impact on gametogenesis are not clear. If oocytes containing exchangeless homologs are selected against during meiosis, the incidence may be much higher in developing germ cells than in zygotes. To address this, we initiated studies of exchangeless chromosomes in fetal ovarian samples from elective terminations of pregnancy. In total, we examined more than 7,000 oocytes from 160 tissue samples, scoring for the number of foci per cell of the crossover-associated protein MLH1. We identified a surprisingly high level of recombination failure, with more than 7% of oocytes containing at least one chromosome pair that lacked an MLH1 focus. Detailed analyses indicate striking chromosome-specific differences, with a preponderance of MLH1-less homologs involving chromosomes 21 or 22. Further, the effect was linked to the overall level of recombination in the cell, with the presence of one or two exchangeless chromosomes in a cell associated with a 10%-20% reduction in the total number of crossovers. This suggests individuals with lower rates of meiotic recombination are at an increased risk of producing aneuploid offspring.

Preverbal skills in 8-month-old children with sex chromosome trisomies

Individuals with sex chromosome trisomies (SCTs) have an increased risk of language delays and impairments. However, there are only a few data relative to their language development in early childhood. The present study aimed to investigate the preverbal skills shown by a group of 8-month-old children with SCTs to assess the presence of a possible early communicative delay. Moreover, the predictive role of early preverbal productions on later lexical development at 24 months was analysed. Twenty-six children with SCTs and 24 typically developing (TD) children participated in the study. Their use of vocal productions and gazes addressed to the communicative partner was assessed during a parent–child observation session held when the children were 8 months old. In addition, the children’s word comprehension at 8 months and their word production at 24 months were indirectly assessed by a parental report. Children’s word comprehension was similar in the two groups of children, whereas a significantly lower frequency per minute of gazes was found in children with SCTs than in TD children. A significantly lower proportion of children with SCTs showed the ability to produce babbling during the observation session, and significant differences were also found in the frequency of babbling utterances. No significant differences emerged among the subgroups of children with different types of SCTs. The predictive role of babbling on later lexical size was found in TD children but not in children with SCTs. This result could be probably explained by the small number of children in this group who could produce babbling utterances. The study leads to identify early signals of delay in the preverbal skills of children with SCTs. Early monitoring of their communicative development could help the clinicians in intervening with well-timed and targeted programmes.

Stage 2 Registered Report: Variation in neurodevelopmental outcomes in children with sex chromosome trisomies: testing the double hit hypothesis.

Background: The presence of an extra sex chromosome is associated with an increased rate of neurodevelopmental difficulties involving language. The 'double hit' hypothesis proposes that the adverse impact of the extra sex chromosome is amplified when genes that are expressed from the sex chromosomes interact with autosomal variants that usually have only mild effects. We predicted that the impact of an additional sex chromosome on neurodevelopment would depend on common autosomal variants involved in synaptic functions. Methods: We analysed data from 130 children with sex chromosome trisomies (SCTs: 42 girls with trisomy X, 43 boys with Klinefelter syndrome, and 45 boys with XYY). Two comparison groups were formed from 370 children from a twin study. Three indicators of phenotype were: (i) Standard score on a test of nonword repetition; (ii). A language factor score derived from a test battery; (iii) A general scale of neurodevelopmental challenges based on all available information. Preselected regions of two genes, CNTNAP2 and NRXN1, were tested for association with neurodevelopmental outcomes using Generalised Structural Component Analysis. Results: There was wide phenotypic variation in the SCT group, as well as overall impairment on all three phenotypic measures. There was no association of phenotype with CNTNAP2 or NRXN1 variants in either the SCT group or the comparison groups. Supplementary analyses found no indication of any impact of trisomy type on the results, and exploratory analyses of individual SNPs confirmed the lack of association. Conclusions: We cannot rule out that a double hit may be implicated in the phenotypic variability in children with SCTs, but our analysis does not find any support for the idea that common variants in CNTNAP2 or NRXN1 are associated with the severity of language and neurodevelopmental impairments that often accompany an extra X or Y chromosome. Stage 1 report: http://dx.doi.org/10.12688/wellcomeopenres.13828.2.

Maternal input to children with sex chromosome trisomies.

Although language difficulties are one of the most distinctive characteristics of the neuropsychological profile of children with sex chromosome trisomies (SCT), the analysis of the maternal input addressed to them is a neglected topic. The present study aims to analyse the lexical, morphosyntactic, and functional features of the input addressed to children with SCT comparing them with those of the input directed to typically developing children (TD). Participants were 38 mothers and their 8-month-old children, 19 with SCT and 19 TD children. Maternal utterances, collected during video-recorded play sessions, have been transcribed and coded. No significant differences between groups have been found in the lexical and syntactic characteristics of maternal input. However, considering the input functional features, the proportion of directives and questions was significantly higher in the maternal input addressed to children with SCT than in the input addressed to TD children whereas the opposite pattern was found in the proportion of affect-salient speech. The awareness of a possible delay in their children's language development could influence the way the mothers speak to them. In particular, the functional features of maternal input could be affected. Support groups for parents of children with SCT at the preverbal stage could be useful to reassure the mothers about their role in their children's language development. What this paper adds What is already known on the subject Studies in the literature identified a high percentage of language delays or impairments in children with SCT. To date, according to our knowledge, there are no studies that analyse the linguistic input addressed to these children. What this study adds The lexical and syntactic features of maternal input addressed to 8-month-old children with SCT are adequate to the children's communicative skills. However, the mothers of children with SCT seem to provide additional scaffolding in their verbal input, using a lower proportion of affect-salient speech and a higher proportion of questions. In addition, a higher proportion of directives suggests the use of a more demanding style. Clinical implications of this study The awareness of possible language delays could influence the functional features of input leading mothers to use a more supportive and demanding input. Support groups for parents of children with SCT at the preverbal stage could be useful to reassure the mothers about their role in their children's language development.

Early neurodevelopmental and medical profile in children with sex chromosome trisomies: Background for the prospective eXtraordinarY babies study to identify early risk factors and targets for intervention.

Sex chromosome trisomies (SCT), including Klinefelter syndrome/XXY, Trisomy X, and XYY syndrome, occur in 1 of every 500 births. The past decades of research have resulted in a broadening of known associated medical comorbidities as well as advances in psychological research. This review summarizes what is known about early neurodevelopmental, behavioral, and medical manifestations in young children with SCT. We focus on recent research and unanswered questions related to the risk for neurodevelopmental disorders that commonly present in the first years of life and discuss the medical and endocrine manifestations of SCT at this young age. The increasing rate of prenatal SCT diagnoses provides the opportunity to address gaps in the existing literature in a new birth cohort, leading to development of the eXtraordinarY Babies Study. This study aims to better describe and compare the natural history of SCT conditions, identify predictors of positive and negative outcomes in SCT, evaluate developmental and autism screening measures commonly used in primary care practices for the SCT population, and build a rich data set linked to a bank of biological samples for future study. Results from this study and ongoing international research efforts will inform evidence-based care and improve health and neurodevelopmental outcomes.

Copy number variation burden does not predict severity of neurodevelopmental phenotype in children with a sex chromosome trisomy.

Sex chromosome trisomies (SCTs) (XXX, XXY, and XYY karyotypes) are associated with an elevated risk of neurodevelopmental disorders. The range of severity of the phenotype is substantial. We considered whether this variable outcome was related to the presence of copy number variants (CNVs)-stretches of duplicated or deleted DNA. A sample of 125 children with an SCT were compared with 181 children of normal karyotype who had been given the same assessments. First, we compared the groups on measures of overall CNV burden: number of CNVs, total span of CNVs, and likely functional impact (probability of loss-of-function intolerance, pLI, summed over CNVs). Differences between groups were small relative to within-group variance and not statistically significant on overall test. Next, we considered whether a measure of general neurodevelopmental impairment was predicted by pLI summed score, SCT versus comparison group, or the interaction between them. There was a substantial effect of SCT/comparison status but the pLI score was not predictive of outcomes in either group. We conclude that variable presence of CNVs is not a likely explanation for the wide phenotypic variation in children with SCTs. We discuss methodological challenges of testing whether CNVs are implicated in causing neurodevelopmental problems.

The behavioral profile of children aged 1-5 years with sex chromosome trisomy (47,XXX, 47,XXY, 47,XYY).

Children with SCT have an increased risk of suboptimal neurodevelopment. Previous studies have shown an elevated risk for neurobehavioral problems in individuals with SCT. However, not much is known about neurobehavioral problems in very young children; knowledge that could help with early identification of children at risk for suboptimal development, and that could help establish targets for early intervention. This study addressed the question of what the behavioral profile of children with SCT aged 1–5 years looks like. In total, 182 children aged 1–5 years participated in this study (NSCT=87, Nnonclinical controls = 95). Recruitment and assessment took place in the Netherlands and the United States. The SCT group was recruited through prospective follow‐up (50%), information seeking parents (31%), and clinical referral (18%). Behavioral profiles were assessed with the child behavior checklist and the ages‐and‐stages social–emotional questionnaire.Levels of parent‐rated problem behavior were higher in children with SCT. Difficulties with overall social–emotional functioning were already present in 1‐year‐olds, and elevated scores were persistent across the full age range. Affective and pervasive developmental behaviors were seen in late toddlerhood and prominent at preschool age. Anxiety, attention deficit, and oppositional defiant behaviors were seen in preschool‐aged children. Within this cross‐sectional study, the developmental trajectory of affective, pervasive developmental, and oppositional defiant behaviors seemed to be different for SCT children than nonclinical controls.Collectively, these results demonstrate the importance of behavioral screening for behavioral problems in routine clinical care for children with SCT from a young age. Social–emotional problems may require special attention, as these problems seem most prominent, showing increased risk across the full age range, and with these problems occurring regardless of the timing of diagnosis, and across all three SCT karyotypes.

Chapter 6 - Gender differences in language are small but matter for disorders

Gender differences in language can be signs of cognitive differences, but can also by themselves be the cause for such differences. Females have a slight linguistic advantage over males, but effect sizes are small, and gender explains very little of the variance seen in the normal population (1%-2%). However, males outnumber females in the lowest 10th percentile in language tests (2:1), causing males to more often be diagnosed with developmental disorders, which rely on tests of language development. Thus, gender differences in language are negligible, if you focus on the whole population, but if you focus on language deficits, gender differences are outspoken. Differences in voice and word use can be observed among the genders, making it possible to predict gender from these measures with a high degree of certainty. A subtle finding is that women use more first person pronouns. This is also observed in depression, which is more prevalent in females, opening up a potential link. Sex chromosome trisomies are often accompanied by language deficits, but the causes for this are not known. No gender differences are observed in the linguistic symptoms of neurodegenerative disorders. Poststroke aphasia is more prevalent among women than among men, but this seems to be an age-effect. A link between the brain and gender differences in language is thus missing.

Autism and social anxiety in children with sex chromosome trisomies: an observational study.

Background: Recent studies suggest that an extra sex chromosome increases the risk of both autism and social anxiety, but it unclear whether these risks are specific to particular karyotypes. Methods: We considered diagnostic data from an online psychiatric assessment (DAWBA - The Development and Well-Being Assessment) and questionnaire responses completed by parents of children with 47,XXX (N = 29), 47,XXY (N = 28) and 47,XYY (N = 32) karyotypes. Analysis focused mainly on 54 children who were diagnosed prenatally or on the basis of other medical concerns in childhood (Low Bias subgroup), to minimise ascertainment bias. Results: Children with symptoms of autism who fell short of meeting the Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV criteria were coded as cases of Pervasive Developmental Disorder Not Otherwise Specified (PDDNOS). The odds ratio of autism orPDDNOS in the Low Bias group was computed relative to gender-specific population norms. This gave log odds ratio (95% confidence interval) of 5.56 (4.25 - 6.88) for XXX girls; 4.00 (2.66 - 5.33) for XXY boys; and 4.60 (3.46 - 5.74) for XYY boys. Despite this elevated risk, most children had no autistic features. A diagnosis of DSM-IV Social Phobia was rare, though, in line with prediction, all three Low Bias cases with this diagnosis had 47,XXY karyotype. All three trisomy groups showed increased risk of milder symptoms of social anxiety. Conclusions: An increased risk of autism was found in girls with 47,XXX karyotype, as well as in boys with 47,XXY or 47,XYY. Symptoms of social anxiety were increased in all three karyotypes. There was wide variation in psychiatric status of children with the same karyotype, suggesting that an extra sex chromosome affects developmental stability in a non-specific way, with a diverse range of possible phenotypes.

Autism and social anxiety in children with sex chromosome trisomies: an observational study

Background: Recent studies suggest that an extra sex chromosome increases the risk of both autism and social anxiety, but it unclear whether these risks are specific to particular karyotypes. Methods: We considered diagnostic data from an online psychiatric assessment (DAWBA – The Development and Well-Being Assessment) and questionnaire responses completed by parents of children with 47,XXX (N = 29), 47,XXY (N = 28) and 47,XYY (N = 32) karyotypes. Analysis focused mainly on 54 children who were diagnosed prenatally or on the basis of other medical concerns in childhood (Low Bias subgroup), to minimise ascertainment bias. Results: Children with symptoms of autism who fell short of meeting the Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV criteria were coded as cases of Pervasive Developmental Disorder Not Otherwise Specified (PDDNOS). The odds ratio of autism or PDDNOS in the Low Bias group was computed relative to gender-specific population norms. This gave log odds ratio (95% confidence interval) of 5.56 (4.25 - 6.88) for XXX girls; 4.00 (2.66 - 5.33) for XXY boys; and 4.60 (3.46 - 5.74) for XYY boys. Despite this elevated risk, most children had no autistic features. A diagnosis of DSM-IV Social Phobia was rare, though, in line with prediction, all three Low Bias cases with this diagnosis had 47,XXY karyotype. All three trisomy groups showed increased risk of milder symptoms of social anxiety. Conclusions: An increased risk of autism was found in girls with 47,XXX karyotype, as well as in boys with 47,XXY or 47,XYY. Symptoms of social anxiety were increased in all three karyotypes. There was wide variation in psychiatric status of children with the same karyotype, suggesting that an extra sex chromosome affects developmental stability in a non-specific way, with a diverse range of possible phenotypes.

A review of neurocognitive functioning of children with sex chromosome trisomies: Identifying targets for early intervention.

Sex chromosome trisomies (SCT) are among the most common chromosomal duplications in humans. Due to recent technological advances in non‐invasive screening, SCT can already be detected during pregnancy. This calls for more knowledge about the development of (young) children with SCT. This review focused on neurocognitive functioning of children with SCT between 0 and 18 years, on domains of global intellectual functioning, language, executive functioning, and social cognition, in order to identify targets that could benefit from early treatment.Online databases were used to identify peer‐reviewed scientific articles using specific search terms. In total 18 studies were included. When applicable, effect sizes were calculated to indicate clinical significance.Results of the reviewed studies show that although traditionally, the focus has been on language and intelligence (IQ) in this population, recent studies suggest that executive functioning and social cognition may also be significantly affected already in childhood.These findings suggest that neuropsychological screening of children diagnosed with SCT should be extended, to also include executive functioning and social cognition. Knowledge about these neurocognitive risks is important to improve clinical care and help identify targets for early support and intervention programs to accommodate for the needs of individuals with SCT.

Association of maternal age with fetal sex chromosome aneuploidies

To analyze the impact of maternal age on sex chromosome aneuploidies (SCA). 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. 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. Advanced age decreases the incidence of 45, X, but increases the risk of sex chromosome trisomy, especially 47, XXX and 47, XXY.

Screening, prenatal diagnosis, and prenatal decision for sex chromosome aneuploidy

ABSTRACTObjective: To assess the performance of non-invasive prenatal testing (NIPT) in screening sex chromosome aneuploidy (SCA), and explore prenatal decision-making in NIPT positive cases.Methods: The study retrospectively analyses singleton pregnancies who underwent NIPT screening. Clinical data, diagnostic results, and pregnancy outcomes were also collected.Results: There were 140 positive screens for SCA, including 62 cases of 45,X, 29 cases with 47,XXX, 28 cases of 47,XXY, 20 cases of 47,XYY, and one case of lower X chromosome. Karyotypic information was available in 103 cases. The positive predictive value was 26.09% for 45,X, 85.00% for 47,XXX, 85.00% for 47,XXY, and 68.75% for 47,XYY. The termination rates of 45,X, 47,XXX, 47,XXY, 47,XYY were 83.33%, 26.67%, 82.35%, and 54.54%, respectively (not including mosaic cases).Conclusion: Our findings demonstrated that the NIPT performed better in predicting sex chromosome trisomies than monosomy X even though false-positive cases do exist in NIPT. For prenatal decisions, pregnancies with diagnoses of fetal 45,X and 47,XXY were terminated more often than those with 47,XXX, 47,XYY. To better guide positive screening pregnancies, pre- and post-test counseling are essential in telling patients the benefits and limitations of the test, comforting their anxiety and giving them the choice for further diagnosis and pregnancy decision.

A review of neurocognitive functioning and risk for psychopathology in sex chromosome trisomy (47,XXY, 47,XXX, 47, XYY).

About one in 650-1000 children is born with an extra X or Y chromosome, referred to as sex chromosome trisomies (SCTs). Studying SCTs may uncover unique insights in neurodevelopmental pathways underlying the risk for neurobehavioral problems and psychopathology. There is also a clinical need for more knowledge about the phenotype of SCT with the recent introduction of noninvasive prenatal screening. The reviewed studies illustrate an increased vulnerability for psychopathology such as (symptoms of) autism spectrum disorder, attention-deficit/hyperactivity disorder, anxiety, depression and, to a lesser degree, psychotic disorders. Although traditionally the primary focus has been on language and learning problems, recent research suggests that impairments in executive functioning, social cognition and emotion regulation may also be key factors underlying the risk for neurobehavioral problems. The research field of SCT is in need of a more longitudinal perspective to identify early markers of 'at risk' development, and to assess the effectiveness of early interventions. Neurocognitive markers that signal compromised neurodevelopment may prove to be helpful in this. Variability in the SCT phenotype provides a unique opportunity to identify not only genetic but also environmental factors that shape neurodevelopmental outcome, calling for studies focused on understanding individual differences.