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In many species, sexual differentiation is a vital prelude to reproduction, and disruption of this process can have severe fitness effects, including sterility. It is thus interesting that genetic systems governing sexual differentiation vary among—and even within—species. To understand these systems more, we investigated a rare example of a frog with three sex chromosomes: the Western clawed frog, Xenopus tropicalis . We demonstrate that natural populations from the western and eastern edges of Ghana have a young Y chromosome, and that a male-determining factor on this Y chromosome is in a very similar genomic location as a previously known female-determining factor on the W chromosome. Nucleotide polymorphism of expressed transcripts suggests genetic degeneration on the W chromosome, emergence of a new Y chromosome from an ancestral Z chromosome, and natural co-mingling of the W, Z, and Y chromosomes in the same population. Compared to the rest of the genome, a small sex-associated portion of the sex chromosomes has a 50-fold enrichment of transcripts with male-biased expression during early gonadal differentiation. Additionally, X. tropicalis has sex-differences in the rates and genomic locations of recombination events during gametogenesis that are similar to at least two other Xenopus species, which suggests that sex differences in recombination are genus-wide. These findings are consistent with theoretical expectations associated with recombination suppression on sex chromosomes, demonstrate that several characteristics of old and established sex chromosomes (e.g., nucleotide divergence, sex biased expression) can arise well before sex chromosomes become cytogenetically distinguished, and show how these characteristics can have lingering consequences that are carried forward through sex chromosome turnovers.

Background The diagnosis of supernumerary X & Y chromosome variations has increased following the implementation of genetic testing in pediatric practice. Empirical evidence suggests that the delivery of the diagnosis has a lasting impact on how affected individuals and their parents perceive and adapt to the diagnosis. The purpose of this review is to synthesize the literature to obtain useful recommendations for delivering a pediatric diagnosis of a sex chromosome multisomy (SCM) based upon a growing body of quantitative and qualitative literature on patient experiences. Methods We conducted an integrative literature review using PubMed, Web of Science and CINAHL employing keywords “genetic diagnosis delivery,” “genetic diagnosis disclosure,” “sex chromosome aneuploidy,” “Klinefelter syndrome” or “”47, XXY,” “Jacob syndrome” or “47, XYY,” “Trisomy X,” “Triple X” or “47, XXX,” and “48 XXYY from January 1, 2000, to October 31, 2023. Results Literature supports that patients and parents value the provision of up-to-date information and connection with supportive resources. Discussion of next steps of care, including relevant referrals, prevents perceptions of provider abandonment and commitment to ongoing support. Proactively addressing special concerns such as disclosing the diagnosis to their child, family, and community is also beneficial. Tables are provided for useful information resources, medical specialties that may be required to support patients, and common misconceptions that interfere with accurate information about the diagnosis. Conclusion Patient experiences suggest there should be heightened attention to diagnosis delivery, in reference to the broader ethical and social impacts of a SCM diagnosis. We present recommendations for optimal disclosure of a SCM diagnosis in early and late childhood, adolescence, and young adulthood.

Men have a higher rate of completed suicide than women, which suggests that sex chromosome abnormalities may be related to the pathophysiology of suicide. Recent studies have found an aberrant loss of chromosome Y (LOY) in various diseases; however, no study has investigated whether there is an association between LOY and suicide. The purpose of this study was to determine whether LOY occurs in men who completed suicide. Our study consisted of 286 male Japanese subjects comprised of 140 suicide completers without severe physical illness (130 post-mortem samples of peripheral blood and 10 brains) and 146 age-matched control subjects (130 peripheral blood samples from healthy individuals and 16 post-mortem brains). LOY was measured as the chromosome Y/chromosome X ratio of the fluorescent signal of co-amplified short sequences from the Y-X homologous amelogenin genes (AMELY and AMELX). Regression analyses showed that LOY in the blood of suicide completers was significantly more frequent than that found in controls (odds ratio = 3.50, 95% confidence interval = 1.21-10.10), but not in the dorsolateral prefrontal cortex (DLPFC) region of brain. Normal age-dependent LOY in blood was found in healthy controls (r = -0.353, p < 0.001), which was not seen in suicide completers (r = -0.119, p = 0.177). DLPFC tissue had age-dependent LOY (B = -0.002, p = 0.015), which was independent of phenotype. To our knowledge, this is the first study demonstrating that LOY in blood is associated with suicide completion. In addition, our findings are the first to also indicate that age-dependent LOY may occur not only in blood, but also in specific brain regions.

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

Background To evaluate the accuracy and feasibility of noninvasive prenatal testing (NIPT) according to the results of NIPT and pregnancy outcomes with different indications. Methods Between October 2014 and December 2020, 20,626 pregnant women who received NIPT were included in this study. The positive predictive value (PPV) of trisomy 21, 18, and 13 (T21, T18, T13), sex chromosome abnormalities (SCAs), other chromosomal aneuploidies, and chromosomal microdeletion/microduplication were calculated. The positive results of NIPT were confirmed by amniocentesis, Karyotype analysis, and chromosome microarray analysis (CMA). Results In total, 263 positive cases (263/20,626, 1.28%) were detected by NIPT, of which T21, T18, and T13 were 69, 26, and 9 cases, respectively. Sex chromosome abnormalities (SCAs), other chromosomal aneuploidies, and copy number variants (CNVs) were 69, 12, and 38 cases, respectively. There were true positive in 49 of T21, 13 of T18, 1 of T13, 32 of SCAs, 1 of other chromosomal aneuploidies, and 15 of CNVs. The NIPT sensitivity of T21, T18, T13, SCAs, other chromosomal aneuploidies, and CNVs was all 100%, the specialty was 99.90%, 99.94%, 99.96%, 99.82%, 99.95%, 99.89%, and the PPV was 71.01%, 50.00%, 11.11%, 46.38%, 8.33%, 39.47%, respectively. The PPV was high in T21, moderate in T18 and SCAs, and low in T13 and other chromosomal abnormalities. Conclusion NIPT has high accuracy, specificity and and can effectively avoid the occurrence of birth defects, but it cannot replace prenatal diagnosis. The accuracy, specificity, and sensitivity of NIPT in detecting sex chromosomes, chromosome microdeletion/microduplication, and other chromosomal abnormalities should be improved. Noninvasive detection process to detect fetal free DNA in maternal plasma samples.

This study aimed to investigate the serum biochemical markers’ propensity associated with sex chromosome abnormalities (SCAs) and assess the clinical efficacy of SCAs in serum biochemical screening during the second trimester. A retrospective case-control analysis was conducted on pregnant women who underwent serum biochemical screening during the second trimester. The study compared groups of women with SCAs to those with normal chromosome karyotypes to assess changes in biochemical markers. We analysed and compared the performance of serum biochemical screening in each SCA group. The results showed that the alterations in serum biochemical markers varied among the different SCA groups. Typically, the serum biochemical markers of fetal SCAs were either above the 95th percentile or below the 5th percentile. The proportions of high- and intermediate-risk findings for 45,X, 47,XXX, 47,XXY, 47,XYY, and mosaic sex chromosomal abnormalities were 43.48%, 78.95%, 63.89%, 70.59%, and 78.13%, respectively. Besides detecting fetal trisomy 21 and trisomy 18, the current contingent screening procedures may also accidentally identify various fetal SCAs at a rate of 69.18%.

Primary ovarian insufficiency is one of the main causes of female infertility owing to an abnormal ovarian reserve. Its relevance has increased in more recent years due to the fact that age of motherhood is being delayed in developed countries, with the risk of having either primary ovarian insufficiency or less chances of pregnancy when women consider the option of having their first baby. Several exogenous factors can lead to this event, such us viral infections, metabolomic dysfunction, autoimmune diseases, and environmental or iatrogenic factors, although in most cases the mechanism that leads to the disorder is unknown. Genetic factors represent the most commonly identified cause and the impact of sex chromosome abnormalities (e.g., Turner syndrome or X structural abnormalities), autosomal and X-linked mutations on the genesis of primary ovarian insufficiency has also been well described. Yet in most cases, the genetic origin remains unknown and there are multiple candidate genes. This review aims to collect all the genetic abnormalities and genes associated with syndromic and non syndromic primary ovarian insufficiency that have been published in the literature to date using the candidate-gene approach and a genome-wide analysis.

Background Data from high-income countries have shown that expanded non-invasive prenatal testing (NIPT) is highly reliable for detecting common autosomal trisomies (CATs), whereas its diagnostic accuracy for rare autosomal trisomies (RATs) remains relatively low. Information on the clinical performance of expanded NIPT in middle- and low-income countries is still limited. The objective of this study was to evaluate the clinical validity and utility of an expanded NIPT for CATs, sex chromosome aneuploidies (SCAs), and RATs following its nationwide clinical implementation. Methods The results of NIPT were retrospectively reviewed. Those with high-risk test results were followed up via phone and/or by reviewing medical records regarding the downstream prenatal diagnosis and the pregnancy outcomes. Results The NIPT results of 19,714 samples were analyzed. We found screening positive rate of 0.95%; sensitivity at 97.92%, 94.12%, 85.71%, and 90% for T21, T18, T13, and SCAs; and PPV at 87.04%, 69.57%, 50%, and 54.55% for T21, T18, T13, and SCAs respectively. As for RATs, clinical validity included sensitivity at 100% and PPV of 13.3%. Over 95% of the participants with high-risk NIPT results underwent prenatal diagnosis. The majority (86.52%) of those with a confirmed diagnosis chose termination of the pregnancy. Conclusions This large-scale study of mixed-risk pregnancies revealed that expanded NIPT had a good sensitivity for CATs (specifically for T21 and T18) and RATs; and fair sensitivity for T13 and SCAs. The PPV is acceptable for CATs and SCAs, but poor for RATs. These data indicated that expanded NIPT results strongly influenced pregnancy outcomes in a real-world experience.

ObjectiveNon-invasive prenatal screening (NIPS) utilizes circulating cell-free DNA (cfDNA) to screen for fetal genetic abnormalities. NIPS is the first widely-available prenatal screen to assess genotypic sex. Most pediatricians have limited familiarity with NIPS technology and potential etiologies of discordant results. Increased familiarity may provide diagnostic insight and improve clinical care.Study designWe reviewed all patients with discordant genotypic fetal sex assessed by cfDNA and neonatal phenotypic sex referred to our medical center.ResultFour infants with discordant cfDNA result and phenotypic sex were identified. Etiologies include vanishing twin syndrome, difference of sexual development, sex chromosome aneuploidy and maternal chimerism.ConclusionsWe present four cases illustrating potential etiologies of discordant cfDNA result and postnatal phenotypic sex. Unanticipated cfDNA results offer the perinatologist a unique opportunity for early diagnosis and targeted treatment of various conditions, many of which may not have otherwise been detected in the perinatal period.

The generic status of Lasiopodomys and its division into subgenera Lasiopodomys (L. mandarinus, L. brandtii) and Stenocranius (L. gregalis, L. raddei) are not generally accepted because of contradictions between the morphological and molecular data. To obtain cytogenetic evidence for the Lasiopodomys genus and its subgenera and to test the autosome to sex chromosome translocation hypothesis of sex chromosome complex origin in L. mandarinus proposed previously, we hybridized chromosome painting probes from the field vole (Microtus agrestis, MAG) and the Arctic lemming (Dicrostonyx torquatus, DTO) onto the metaphases of a female Mandarin vole (L. mandarinus, 2n = 47) and a male Brandt's vole (L. brandtii, 2n = 34). In addition, we hybridized Arctic lemming painting probes onto chromosomes of a female narrow-headed vole (L. gregalis, 2n = 36). Cross-species painting revealed three cytogenetic signatures (MAG12/18, 17a/19, and 22/24) that could validate the genus Lasiopodomys and indicate the evolutionary affinity of L. gregalis to the genus. Moreover, all three species retained the associations MAG1bc/17b and 2/8a detected previously in karyotypes of all arvicolins studied. The associations MAG2a/8a/19b, 8b/21, 9b/23, 11/13b, 12b/18, 17a/19a, and 5 fissions of ancestral segments appear to be characteristic for the subgenus Lasiopodomys. We also validated the autosome to sex chromosome translocation hypothesis on the origin of complex sex chromosomes in L. mandarinus. Two translocations of autosomes onto the ancestral X chromosome in L. mandarinus led to a complex of neo-X1, neo-X2, and neo-X3 elements. Our results demonstrate that genus Lasiopodomys represents a striking example of rapid chromosome evolution involving both autosomes and sex chromosomes. Multiple reshuffling events including Robertsonian fusions, chromosomal fissions, inversions and heterochromatin expansion have led to the formation of modern species karyotypes in a very short time, about 2.4 MY.