Congenital heart defects (CHD) occur in ∼1 in every 100 live births. In addition, an estimated 10% of fetal loss is due to severe forms of CHD. This makes heart defects the most frequently occurring ...birth defect and single cause of in utero fatality in humans. There is considerable evidence that CHD is heritable, indicating a strong contribution from genetic risk factors. There are also known external environmental exposures that are significantly associated with risk for CHD. Hence, the majority of CHD cases have long been considered to be multifactorial, or generally caused by the confluence of several risk factors potentially from genetic, epigenetic, and environmental sources. Consequently, a specific cause can be very difficult to ascertain, although patterns of associations are very important to prevention. While highly protective of the fetus, the
environment is not immune to insult. As the conduit between the mother and fetus, the placenta plays an essential role in maintaining fetal health. Since it is not a fully-formed organ at the onset of pregnancy, the development of the placenta must keep pace with the growth of the fetus in order to fulfill its critical role during pregnancy. In fact, the placenta and the fetal heart actually develop in parallel, a phenomenon known as the placenta-heart axis. This leaves the developing heart particularly vulnerable to early placental insufficiency. Both organs share several developmental pathways, so they also share a common vulnerability to genetic defects. In this article we explore the coordinated development of the placenta and fetal heart and the implications for placental involvement in the etiology and pathogenesis of CHD.
Turner syndrome is caused by complete or partial loss of the second sex chromosome, occurring in ~1 in 2,000 female births. There is a greatly increased incidence of aortopathy of unknown etiology, ...including bicuspid aortic valve (BAV), thoracic aortic aneurysms, aortic dissection and rupture. We performed whole exome sequencing on 188 Turner syndrome participants from the National Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Related Conditions (GenTAC). A gene-based burden test, the optimal sequence kernel association test (SKAT-O), was used to evaluate the data with BAV and aortic dimension z-scores as covariates. Genes on chromosome Xp were analyzed for the potential to contribute to aortopathy when hemizygous. Exome analysis revealed that TIMP3 was associated with indices of aortopathy at exome-wide significance (p = 2.27 x 10(-7)), which was replicated in a separate cohort. The analysis of Xp genes revealed that TIMP1, which is a functionally redundant paralogue of TIMP3, was hemizygous in >50% of our discovery cohort and that having only one copy of TIMP1 increased the odds of having aortopathy (OR = 9.76, 95% CI = 1.91-178.80, p = 0.029). The combinatorial effect of a single copy of TIMP1 and TIMP3 risk alleles further increased the risk for aortopathy (OR = 12.86, 95% CI = 2.57-99.39, p = 0.004). The products of genes encoding tissue inhibitors of matrix metalloproteinases (TIMPs) are involved in development of the aortic valve and protect tissue integrity of the aorta. We propose that the combination of X chromosome TIMP1 hemizygosity and variants of its autosomal paralogue TIMP3, significantly increases the risk of aortopathy in Turner syndrome.
This overview highlights the actionable near-term objectives for the TRN drawn from discussions in the breakout sessions. A major purpose of the symposium was to focus attention on establishing ...priorities, setting goals, and identifying the steps toward accomplishing those goals. Two major objectives were identified. One is to establish Turner syndrome as a priority area of research for the National Institutes of Health. Turner syndrome should not only be viewed as a rare disorder, but also as a model for common diseases that have a male sex bias in the general population attributable to the lack of a second X chromosome. Barriers to recognition of Turner syndrome as an important area of research were identified, and new approaches to enhancing visibility are discussed. The second major objective is to further development of the Turner Syndrome Research Registry (TSRR). This patient-powered research registry is a paradigm-shifting model for how human-based research can be improved through equal partnerships between researchers and study subjects. The TSRR is founded on an agreement that study participants are the ultimate owners of their personal data. The major challenges to establishing a maximally functional registry of this design were discussed, and a clear path forward was established.
The genetic basis of Turner syndrome aortopathy Corbitt, Holly; Gutierrez, Jacob; Silberbach, Michael ...
American journal of medical genetics. Part C, Seminars in medical genetics,
March 2019, Letnik:
181, Številka:
1
Journal Article
Odprti dostop
Our goal is to identify the genetic underpinnings of bicuspid aortic valve and aortopathy in Turner syndrome. We performed whole exome sequencing on 188 Turner syndrome study subjects from the GenTAC ...registry. A gene-based burden test, SKAT-O, was used to evaluate the data using bicuspid aortic valve (BAV) and aortic dimension z-scores as covariates. This revealed that TIMP3 was associated with BAV and increased aortic dimensions at exome-wide significance. It had been previously shown that genes on chromosome Xp contribute to aortopathy when hemizygous. Our analysis of Xp genes revealed that hemizygosity for TIMP1, a functionally redundant paralogue of TIMP3, increased the odds of having BAV aortopathy compared to individuals with more than one TIMP1 copy. The combinatorial effect of a single copy of TIMP1 and TIMP3 risk alleles synergistically increased the risk for BAV aortopathy to nearly 13-fold. TIMP1 and TIMP3 are tissue inhibitors of matrix metalloproteinases (TIMPs) which are involved in development of the aortic valve and protection from thoracic aneurysms. We propose that the combination of TIMP1 haploinsufficiency and deleterious variants in TIMP3 significantly increases the risk of BAV aortopathy in Turner syndrome, and suggest that TIMP1 hemizygosity may play a role in euploid male aortic disease.
About half of people with trisomy 21 have a congenital heart defect (CHD), whereas the remainder have a structurally normal heart, demonstrating that trisomy 21 is a significant risk factor but is ...not causal for abnormal heart development. Atrioventricular septal defects (AVSD) are the most commonly occurring heart defects in Down syndrome (DS), and ∼65% of all AVSD is associated with DS. We used a candidate-gene approach among individuals with DS and complete AVSD (cases = 141) and DS with no CHD (controls = 141) to determine whether rare genetic variants in genes involved in atrioventricular valvuloseptal morphogenesis contribute to AVSD in this sensitized population. We found a significant excess (p < 0.0001) of variants predicted to be deleterious in cases compared to controls. At the most stringent level of filtering, we found potentially damaging variants in nearly 20% of cases but fewer than 3% of controls. The variants with the highest probability of being damaging in cases only were found in six genes: COL6A1, COL6A2, CRELD1, FBLN2, FRZB, and GATA5. Several of the case-specific variants were recurrent in unrelated individuals, occurring in 10% of cases studied. No variants with an equal probability of being damaging were found in controls, demonstrating a highly specific association with AVSD. Of note, all of these genes are in the VEGF-A pathway, even though the candidate genes analyzed in this study represented numerous biochemical and developmental pathways, suggesting that rare variants in the VEGF-A pathway might contribute to the genetic underpinnings of AVSD in humans.
Down syndrome (DS) is a significant risk factor for congenital heart disease (CHD), increasing the incidence 50 times over the general population. However, half of people with DS have a normal heart ...and thus trisomy 21 is not sufficient to cause CHD by itself. Ts65Dn mice are trisomic for orthologs of >100 Hsa21 genes, and their heart defect frequency is significantly higher than their euploid littermates. Introduction of a null allele of Creld1 into Ts65Dn increases the penetrance of heart defects significantly. However, this increase was not seen when the Creld1 null allele was introduced into Ts1Cje, a mouse that is trisomic for about two thirds of the Hsa21 orthologs that are triplicated in Ts65Dn. Among the 23 genes present in three copies in Ts65Dn but not Ts1Cje, we identified Jam2 as necessary for the increased penetrance of Creld1-mediated septal defects in Ts65Dn. Thus, overexpression of the trisomic gene, Jam2, is a necessary potentiator of the disomic genetic modifier, Creld1 No direct physical interaction between Jam2 and Creld1 was identified by several methods. Regions of Hsa21 containing genes that are risk factors of CHD have been identified, but Jam2 (and its environs) has not been linked to heart formation previously. The complexity of this interaction may be more representative of the clinical situation in people than consideration of simple single-gene models.
Turner syndrome is a rare disorder resulting from complete or partial loss of the second sex chromosome. Common manifestations include delayed growth, premature ovarian failure, congenital heart ...defects, endocrine disorders, lymphedema, and webbed neck. People with Turner syndrome have significantly increased mortality risk primarily due to cardiovascular abnormalities. The mechanisms that lead to these defects are not completely understood and are obscured by the significant variability of both karyotype and phenotype without consistent correlation between the two. This paper presents a review of the recent literature surrounding the symptoms, mechanisms, diagnosis, and treatment of Turner syndrome with a focus on cardiovascular manifestations. With technological advancements in genetics, the molecular processes of Turner syndrome have begun to be dissected. Certain genes on the X chromosome that typically escape inactivation have been implicated in both specific manifestations and broader risk categories. Recently identified genome-wide epigenetic changes may help explain the variability in presentation. It remains unclear as to how the combination of these factors results in the overall clinical picture, but advances in genomic, genetic, epigenetic, and -omics technology hold promise for providing insights that will improve the medical management of individuals with Turner syndrome.
Although patients with various types of heritable aortopathy often require distal aortic repair, data are limited regarding the most extensive operations—open thoracoabdominal aortic aneurysm (TAAA) ...repairs. The objective of this multicenter registry study was to characterize TAAA repairs in a large cohort of patients with different heritable aortic diseases.
From the 3699 patients enrolled at 8 participating centers in the Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions (GenTAC) Registry, we identified 155 open TAAA repairs in 142 unique patients. We examined data related to clinical characteristics, surgical techniques, and outcomes.
The primary diagnoses included Marfan syndrome (n = 76; 54%), familial thoracic aortic aneurysm and dissections (n = 31; 22%), and Loeys-Dietz syndrome (n = 10; 7%). Most repairs were performed for aneurysms associated with aortic dissection (n = 110; 71%). The most common repairs involved the entire descending thoracic aorta with distal extension (21% Crawford extent I and 36% extent II). Adjuncts used during repair varied substantially. The operative mortality rate was 1.3%. Other complications included paraplegia (4%), acute renal failure (5%), and vocal cord paralysis (21%). Reoperation after TAAA repair was required in a subset of cases for early bleeding (n = 15; 10%) and late repair failure (n = 7; 5%).
Open TAAA repairs are necessary in a variety of heritable aortic diseases. These patients often require extensive surgical repair, and a variety of adjunctive techniques are utilized. The risk of repair failure and the need for reoperation in a subset of patients support the need for vigilant long-term surveillance after repair.
Turner Syndrome (TS) is a rare cytogenetic disorder caused by the complete loss or structural variation of the second sex chromosome. The most common cause of early mortality in TS results from a ...high incidence of left-sided congenital heart defects, including bicuspid aortic valve (BAV), which occurs in about 30% of individuals with TS. BAV is also the most common congenital heart defect in the general population with a prevalence of 0.5–2%, with males being three-times more likely to have a BAV than females. TS is associated with genome-wide hypomethylation when compared to karyotypically normal males and females. Alterations in DNA methylation in primary aortic tissue are associated with BAV in euploid individuals. Here we show significant differences in DNA methylation patterns associated with BAV in TS found in peripheral blood by comparing TS BAV (
n
= 12), TS TAV (
n
= 13), and non-syndromic BAV (
n
= 6). When comparing TS with BAV to TS with no heart defects we identified a differentially methylated region encompassing the BAV-associated gene
MYRF
, and enrichment for binding sites of two known transcription factor contributors to BAV. When comparing TS with BAV to euploid women with BAV, we found significant overlapping enrichment for ChIP-seq transcription factor targets including genes in the
NOTCH1
pathway, known for involvement in the etiology of non-syndromic BAV, and other genes that are essential regulators of heart valve development. Overall, these findings suggest that altered DNA methylation affecting key aortic valve development genes contributes to the greatly increased risk for BAV in TS.
Retrotransposition of processed mRNAs is a common source of novel sequence acquired during the evolution of genomes. Although the vast majority of retroposed gene copies, or retrogenes, rapidly ...accumulate debilitating mutations that disrupt the reading frame, a small percentage become new genes that encode functional proteins. By using a multibreed association analysis in the domestic dog, we demonstrate that expression of a recently acquired retrogene encoding fibroblast growth factor 4 (fgf4) is strongly associated with chondrodysplasia, a short-legged phenotype that defines at least 19 dog breeds including dachshund, corgi, and basset hound. These results illustrate the important role of a single evolutionary event in constraining and directing phenotypic diversity in the domestic dog.
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