Explore the vast range of titles available.

To evaluate the clinical performance of noninvasive prenatal screening (NIPS) for fetal sex chromosome aneuploidies (SCAs), pregnant women were recruited in this retrospective observational study. The NIPS test was undertaken using high-throughput gene sequencing. In total,50,301 pregnant women were analysed for demographic characteristics and medical history. Of them, 308 women (0.61%) had high risk for fetal SCAs, including 138 for 45,X, 111 for 47,XXY, 42 for 47,XXX, and 17 for 47,XYY. After the pre-test counselling, 182 participants chose to undergo invasive prenatal diagnosis, confirming 59 positive cases. The combined positive predictive value of NIPS was 32.42% (59/182), 18.39% (16/87), 44.4% (12/27), 39.29% (22/56), and 75% (9/12) for detecting SCAs, 45,X, 47,XXX, 47,XXY, and 47,XYY, respectively. NIPS can be a useful method to detect the fetal SCAs using high-throughput gene sequencing, though accuracy can still be improved, especially for 45,X. Although the value of NIPS compare favorably with those seen in traditional screening approaches for SCAs, it is important to highlight the limitations of NIPS while educating clinicians and patients.

The developmental and clinical aspects in the literature on triple X syndrome are reviewed. Prenatal diagnosis depends on karyotyping. The incidence is 1 of 1000 females. At birth, 47,XXX girls have a lower mean birth weight and a smaller head circumference. Triple X diagnosis was not suspected at birth. The maternal age seems to be increased. Toddlers with triple X syndrome show delayed language development. The youngest girls show accelerated growth until puberty. EEG abnormalities seem to be rather common. Many girls show motor-coordination problems and auditory-processing disorders are not rare. Scoliosis is probably more common in adolescent cases. The IQ levels are 20 points below that of controls, and verbal IQ is lowest. The girls struggle with low self-esteem and they need psychological, behavioural and educational support. They perform best in stable families. After leaving school they seem to feel better. In adults, premature ovarian failure seems to be more prevalent than in controls. MRIs of the brain seem to show decreased brain volumes. The 47,XXX women most often find jobs that reflect their performance abilities. Psychotic illness seems to be more prevalent in triple X adult women than in controls. Psychotic disorders respond well to psychotropic drugs. Triple X adults suffer more frequently from cyclothymic and labile personality traits. Research on triple X syndrome may yield more insight into brain and behaviour relations, developmental psychopathology, auditory-processing disorders, EEG disorders, personality and psychotic disorders, etc.

The study of sexual dimorphism in psychiatric and neurodevelopmental disorders is challenging due to the complex interplay of diverse biological, psychological, and social factors. Males are more susceptible to neurodevelopmental disorders including intellectual disability, autism spectrum disorder, and attention-deficit activity disorder. Conversely, after puberty, females are more prone to major depressive disorder and anxiety disorders compared to males. One major biological factor contributing to sex differences is the sex chromosomes. First, the X and Y chromosomes have unique and specific genetic effects as well as downstream gonadal effects. Second, males have one X chromosome and one Y chromosome, while females have two X chromosomes. Thus, sex chromosome constitution also differs between the sexes. Due to this complexity, determining genetic and downstream biological influences on sexual dimorphism in humans is challenging. Sex chromosome aneuploidies, such as Turner syndrome (X0) and Klinefelter syndrome (XXY), are common genetic conditions in humans. The study of individuals with sex chromosome aneuploidies provides a promising framework for studying sexual dimorphism in neurodevelopmental and psychiatric disorders. Here we will review and contrast four syndromes caused by variation in the number of sex chromosomes: Turner syndrome, Klinefelter syndrome, XYY syndrome, and XXX syndrome. Overall we describe an increased rate of attention-deficit hyperactivity disorder and autism spectrum disorder, along with the increased rates of major depressive disorder and anxiety disorders in one or more of these conditions. In addition to contributing unique insights about sexual dimorphism in neuropsychiatric disorders, awareness of the increased risk of neurodevelopmental and psychiatric disorders in sex chromosome aneuploidies can inform appropriate management of these common genetic disorders.

To assess the clinical performance of an expanded noninvasive prenatal screening (NIPS) test (“NIPS-Plus”) for detection of both aneuploidy and genome-wide microdeletion/microduplication syndromes (MMS). A total of 94,085 women with a singleton pregnancy were prospectively enrolled in the study. The cell-free plasma DNA was directly sequenced without intermediate amplification and fetal abnormalities identified using an improved copy-number variation (CNV) calling algorithm. A total of 1128 pregnancies (1.2%) were scored positive for clinically significant fetal chromosome abnormalities. This comprised 965 aneuploidies (1.026%) and 163 (0.174%) MMS. From follow-up tests, the positive predictive values (PPVs) for T21, T18, T13, rare trisomies, and sex chromosome aneuploidies were calculated as 95%, 82%, 46%, 29%, and 47%, respectively. For known MMS (n=32), PPVs were 93% (DiGeorge), 68% (22q11.22 microduplication), 75% (Prader–Willi/Angleman), and 50% (Cri du Chat). For the remaining genome-wide MMS (n=88), combined PPVs were 32% (CNVs ≥10Mb) and 19% (CNVs <10Mb). NIPS-Plus yielded high PPVs for common aneuploidies and DiGeorge syndrome, and moderate PPVs for other MMS. Our results present compelling evidence that NIPS-Plus can be used as a first-tier pregnancy screening method to improve detection rates of clinically significant fetal chromosome abnormalities.

Background Knowledge 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). Methods This 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. Results The 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). Conclusions The 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.

Rare genetic disorders (RGDs) often exhibit significant clinical variability among affected individuals, a disease characteristic termed variable expressivity. Recently, the aggregate effect of common variation, quantified as polygenic scores (PGSs), has emerged as an effective tool for predictions of disease risk and trait variation in the general population. Here, we measure the effect of PGSs on 11 RGDs including four sex-chromosome aneuploidies (47,XXX; 47,XXY; 47,XYY; 45,X) that affect height; two copy-number variant (CNV) disorders (16p11.2 deletions and duplications) and a Mendelian disease (melanocortin 4 receptor deficiency ( MC4R )) that affect BMI; and two Mendelian diseases affecting cholesterol: familial hypercholesterolemia (FH; LDLR and APOB ) and familial hypobetalipoproteinemia (FHBL; PCSK9 and APOB ). Our results demonstrate that common, polygenic factors of relevant complex traits frequently contribute to variable expressivity of RGDs and that PGSs may be a useful metric for predicting clinical severity in affected individuals and for risk stratification. Rare genetic disorders (RGDs) often exhibit significant clinical variability among affected individuals. Here, Oetjens et al. systematically study the contribution of common genetic variation to variable expressivity of RGDs and find it is frequently influenced by polygenic factors identified in genome-wide association studies of relevant traits.

Introduction In this register‐based study of pregnancies in Denmark, we assessed the associations between maternal age and the risk of fetal aneuploidies (trisomy 21, trisomy 18, trisomy 13, triploidy, monosomy X and other sex chromosome aberrations). Additionally, we aimed to disentangle the maternal age‐related effect on fetal aneuploidies by cases with translocation trisomies and mosaicisms. Material and methods We followed a nationwide cohort of 542 375 singleton‐pregnant women attending first trimester screening in Denmark between 2008 and 2017 until delivery, miscarriage or termination of pregnancy. We used six maternal age categories and retrieved information on genetically confirmed aneuploidies of the fetus and infant from the national cytogenetic register. Results We confirmed the known associations between advanced maternal age and higher risk of trisomy 21, 18, 13 and other sex chromosome aberrations, especially in women aged ≥35 years, whereas we found no age‐related associations with triploidy or monosomy X. Cases with translocation trisomies and mosaicisms did not influence the overall reported association between maternal age and aneuploidies. Conclusion This study provides insight into the accurate risk of fetal aneuploidies that pregnant women of advanced ages encounter. With this study, we found an association between advanced maternal age and the risk of trisomy 21, 18, 13 and other sex chromosome aberrations. In addition to this, we observed that cases with translocation trisomies and mosaicisms did not influence the overall reported association between maternal age and aneuploidies. In other words, we confirm the findings of previous studies, but we are one of the first to provide meaningful estimates on maternal age‐related risk of more specific types of aneuploidies due to our large dataset and high level of power.

The growth studies were carried out using the methods and equipment devised by Professor J M Tanner after I had undertaken training at the Institute of Child Health in London. 4 No invasive procedures were done, hormone assays being carried out on urine or saliva. 5 The parents of children with XXY and XXX karyotypes were given as much information as was then available about their conditions, with the explanation that the purpose of the study was to provide a clearer picture of the whole condition. [...]all three categories have an increased incidence of delayed speech development suggesting that sex chromatin screening of patients attending speech clinics would be beneficial.

Purpose Male infertility remains poorly understood at the molecular level. We aimed in this study to investigate the yield of a “genomics first” approach to male infertility. Methods Patients with severe oligospermia and nonobstructive azoospermia were investigated using exome sequencing (ES) in parallel with the standard practice of chromosomal analysis. Results In 285 patients, 10.5% ( n  = 30) had evidence of chromosomal aberrations while nearly a quarter ( n  = 69; 24.2%) had a potential monogenic form of male infertility. The latter ranged from variants in genes previously reported to cause male infertility with or without other phenotypes in humans (24 patients; 8.4%) to those in novel candidate genes reported in this study (37 patients; 12.9%). The 33 candidate genes have biological links to male germ cell development including compatible mouse knockouts, and a few ( TERB1 [ CCDC79 ], PIWIL2 , MAGEE2 , and ZSWIM7 ) were found to be independently mutated in unrelated patients in our cohort. We also found that male infertility can be the sole or major phenotypic expression of a number of genes that are known to cause multisystemic manifestations in humans ( n  = 9 patients; 3.1%). Conclusion The standard approach to male infertility overlooks the significant contribution of monogenic causes to this important clinical entity.