Search

Turner syndrome, a congenital condition that affects ∼1/2,500 births, results from absence or structural alteration of the second sex chromosome. There has been substantial effort by numerous clinical and genetic research groups to delineate the clinical, pathophysiological, cytogenetic, and molecular features of this multisystem condition. Questions about the molecular-genetic and biological basis of many of the clinical features remain unanswered, and health care providers and families seek improved care for affected individuals. The inaugural "Turner Resource Network (TRN) Symposium" brought together individuals with Turner syndrome and their families, advocacy group leaders, clinicians, basic scientists, physician-scientists, trainees and other stakeholders with interest in the well-being of individuals and families living with the condition. The goal of this symposium was to establish a structure for a TRN that will be a patient-powered organization involving those living with Turner syndrome, their families, clinicians, and scientists. The TRN will identify basic and clinical questions that might be answered with registries, clinical trials, or through bench research to promote and advocate for best practices and improved care for individuals with Turner syndrome. The symposium concluded with the consensus that two rationales justify the creation of a TRN: inadequate attention has been paid to the health and psychosocial issues facing girls and women who live with Turner syndrome; investigations into the susceptibility to common disorders such as cardiovascular or autoimmune diseases caused by sex chromosome deficiencies will increase understanding of disease susceptibilities in the general population.

Abstract Background A number of neurodevelopmental syndromes are caused by mutations in genes encoding proteins that normally function in epigenetic regulation. Identification of epigenetic alterations occurring in these disorders could shed light on molecular pathways relevant to neurodevelopment. Results Using a genome-wide approach, we identified genes with significant loss of DNA methylation in blood of males with intellectual disability and mutations in the X-linked KDM5C gene, encoding a histone H3 lysine 4 demethylase, in comparison to age/sex matched controls. Loss of DNA methylation in such individuals is consistent with known interactions between DNA methylation and H3 lysine 4 methylation. Further, loss of DNA methylation at the promoters of the three top candidate genes FBXL5, SCMH1, CACYBP was not observed in more than 900 population controls. We also found that DNA methylation at these three genes in blood correlated with dosage of KDM5C and its Y-linked homologue KDM5D. In addition, parallel sex-specific DNA methylation profiles in brain samples from control males and females were observed at FBXL5 and CACYBP. Conclusions We have, for the first time, identified epigenetic alterations in patient samples carrying a mutation in a gene involved in the regulation of histone modifications. These data support the concept that DNA methylation and H3 lysine 4 methylation are functionally interdependent. The data provide new insights into the molecular pathogenesis of intellectual disability. Further, our data suggest that some DNA methylation marks identified in blood can serve as biomarkers of epigenetic status in the brain.

Introduction Aortic abnormalities contribute to increased morbidity and mortality of women with Turner syndrome ( TS). Impaired aortic stiffness may prove to have clinical prognostic value in TS as is the case in other diseases such as Marfan syndrome, diabetes and hypertension. Additionally, the parental origin of the X chromosome in TS may influence aortic stiffness. Objective To assess the relation between X chromosome parental origin and aortic stiffness in TS patients. Methods Twenty-four subjects with TS participated in this cross-sectional study at a tertiary care centre. The parental origin of the X chromosome was determined. Cardiac-gated multidetector computerized tomography ( MDCT) was performed and distensibility of the ascending aorta ( AA), a measure of aortic stiffness, was calculated. Results Fourteen women were Xm (maternal origin) and 10 were Xp (paternal origin) for their inheritance of the single X chromosome. Age, body size, blood pressure and AA areas were similar in the two groups. However, the calculated AA distensibility was significantly lower in the Xm group (2·8 ± 1·1 mm/Hg) than in the Xp group (4·1 ± 1·5 mm/Hg); P < 0·05. Conclusion This study demonstrates that TS subjects that inherit their single X chromosome from their mother (Xm) have a significantly stiffer aorta compared with the TS with a paternally originating X chromosome (Xp), consistent with a potentially greater risk for cardiovascular complications. These findings suggest that parental chromosomal analysis and aortic stiffness measurements would be useful for the risk assessment and clinical management of TS patients. [ABSTRACT FROM AUTHOR]

Background Congenital heart disease (CHD) is a cardinal feature of X chromosome monosomy, or Turner syndrome (TS). Haploinsufficiency for gene(s) located on Xp have been implicated in the short stature characteristic of the syndrome, but the chromosomal region related to the CHD phenotype has not been established. Design We used cardiac MRI to diagnose cardiovascular abnormalities in four non-mosaic karyotype groups based on 50-metaphase analyses: 45,X (n=152); 46,X,del(Xp) (n=15); 46,X,del(Xq) (n=4); and 46,X,i(Xq) (n=14) from peripheral blood cells. Results Bicuspid aortic valves (BAV) were found in 52/152 (34%) 45,X study subjects and aortic coarctation (COA) in 19/152 (12.5%). Isolated anomalous pulmonary veins (APV) were detected in 15/152 (10%) for the 45,X study group, and this defect was not correlated with the presence of BAV or COA. BAVs were present in 28.6% of subjects with Xp deletions and COA in 6.7%. APV were not found in subjects with Xp deletions. The most distal break associated with the BAV/COA trait was at cytologic band Xp11.4 and ChrX:41,500 000. One of 14 subjects (7%) with the 46,X,i(Xq) karyotype had a BAV and no cases of COA or APV were found in this group. No cardiovascular defects were found among four patients with Xq deletions. Conclusions The high prevalence of BAV and COA in subjects missing only the X chromosome short arm indicates that haploinsufficiency for Xp genes contributes to abnormal aortic valve and aortic arch development in TS. [ABSTRACT FROM AUTHOR]

Abstract: The selective silencing of certain alleles depending on the parent of origin is known as genomic imprinting. Specific cognitive skills, statural growth and visceral adiposity have all been linked to the parental origin of the single normal X-chromosome in girls and women with Turner syndrome (TS). The putatively imprinted traits in TS reflect typical differences between eukaryotic males and females. This chapter reviews the evidence for parental X-chromosome imprinting in the TS phenotype. [Copyright &y& Elsevier]

Premature ovarian failure (POF) is a condition characterized by cessation of ovarian function before the age of 40. The recent meeting at the National Institute of Child Health and Human Development brought together experts from diverse disciplines to share current perspectives on the genetic and physiologic origins of POF, with the idea that insights gained from these studies may provide important clues about the regulation of normal ovarian aging and perhaps aging processes in general It was suggested that several murine genes, me chiding Zfx, c = kit, and the . kit ligand, should be fertile candidates for investigation of the etiology of POE in human families The specific roles of the human DIA and FMR1 gene products in germ cell development need clarification in murine models, and there are more as yet unidentified genes residing on the long arm of the X chromosome that are also implicated in the regulation of human ovarian function Genes acting at later stages of oocyte or ovarian follicle function, such as gonadotropin hormones and receptors, are responsible for POF in some women. POF has been found to be a heterogeneous disorder, the dissection of which offers promising insights into mechanism governing, germ cell origination, migration, and proliferation, meiotic mechanisms, and factors governing oocyte maturation and survival. [ABSTRACT FROM AUTHOR]

An abstract of the article " Shunt and right ventricular structural findings in isolated anomalous pulmonary venous return in Turner syndrome," by Laura Olivieri, Anjali Chelliah, Li-Yueh Hsu, Richard B. Thompson, Vladimir Bakalov, Douglas Rosing, Carolyn Bondy, and Andrew E. Arai is presented.