Rare variants in NR2F2 cause congenital heart defects in humans

Congenital heart defects (CHDs) are the most common birth defect worldwide and are a leading cause of neonatal mortality. Nonsyndromic atrioventricular septal defects (AVSDs) are an important subtype of CHDs for which the genetic architecture is poorly understood. We performed exome sequencing in 13 parent-offspring trios and 112 unrelated individuals with nonsyndromic AVSDs and identified five rare missense variants (two of which arose de novo) in the highly conserved gene NR2F2, a very significant enrichment (p = 7.7 × 10?7) compared to 5,194 control subjects. We identified three additional CHD-affected families with other variants in NR2F2 including a de novo balanced chromosomal translocation, a de novo substitution disrupting a splice donor site, and a 3 bp duplication that cosegregated in a multiplex family. NR2F2 encodes a pleiotropic developmental transcription factor, and decreased dosage of NR2F2 in mice has been shown to result in abnormal development of atrioventricular septa. Via luciferase assays, we showed that all six coding sequence variants observed in individuals significantly alter the activity of NR2F2 on target promoters

Distinct genetic architectures for syndromic and nonsyndromic congenital heart defects identified by exome sequencing.

Congenital heart defects (CHDs) have a neonatal incidence of 0.8-1% (refs. 1,2). Despite abundant examples of monogenic CHD in humans and mice, CHD has a low absolute sibling recurrence risk (∼2.7%), suggesting a considerable role for de novo mutations (DNMs) and/or incomplete penetrance. De novo protein-truncating variants (PTVs) have been shown to be enriched among the 10% of 'syndromic' patients with extra-cardiac manifestations. We exome sequenced 1,891 probands, including both syndromic CHD (S-CHD, n = 610) and nonsyndromic CHD (NS-CHD, n = 1,281). In S-CHD, we confirmed a significant enrichment of de novo PTVs but not inherited PTVs in known CHD-associated genes, consistent with recent findings. Conversely, in NS-CHD we observed significant enrichment of PTVs inherited from unaffected parents in CHD-associated genes. We identified three genome-wide significant S-CHD disorders caused by DNMs in CHD4, CDK13 and PRKD1. Our study finds evidence for distinct genetic architectures underlying the low sibling recurrence risk in S-CHD and NS-CHD

Genetics of Congenital Heart Defects: Studies by Next-Generation Sequencing

TABLE OF CONTENTS SUMMARY/SAMENVATTING......................................9 GENERAL INTRODUCTION AND OBJECTIVES Chapter 1: Introduction..............................................13 Chapter 2: Research objectives...............................................31 RESULTS Chapter 3: The use of Next Generation Sequencing (NGS) in the detection of causal mutations of syndromic CHD in sporadic cases...................................................33 3.1: MEIS2 Involvement in Cardiac Development, Cleft Palate and Intellectual Disability.............................57 Chapter 4: Identification of the genetic cause of familial syndromic cardiopathies and rare types of cardiomyopathy...........................................71 4.1: Homozygous loss-of-function mutation in ALMS1 causes the lethal disorder mitogenic cardiomyopathy in two siblings.................................................91 4.2: Compound heterozygous loss-of-function mutations in KIF20A are associated with a novel lethal congenital cardiomyopathy in two siblings...............................................107 DISCUSSION Chapter 5: General discussion and future perspectives............................................137 APPENDICES List of abbreviations...........................................156 Curriculum Vitae...................................................157 List of publications............................................159nrpages: 173status: publishe

Lula’s Brazil in Africa: extending its middle power role?

Thesis (MA)--Stellenbosch University, 2016.ENGLISH ABSTRACT: Brazil-Africa relations date back to the trans-Atlantic slave trade of the sixteenth and nineteenth century. Despite the early onset of relations, it was only since the turn of the millennium, with the onset of President Luiz Inácio „Lula‟ da Silva‟s administration (2003-2010) that Brazil‟s expansion into Africa became noteworthy. This thesis sets out to analyse this period of unprecedented Brazilian expansion into the African continent. The research question that guides this study is: Do the reasons for Brazil‟s expansion of its political-economic interests in Africa during the Lula administration reflect Brazil‟s role as a neo-Gramscian middle power? The main objective of this thesis, as highlighted by the central research question, is thus to explain and describe the reasons behind Brazil‟s increased footprint on the continent during Lula‟s time in office and to describe how this expansion of Brazil into Africa does or does not reflect Brazil‟s role as a neo-Gramscian middle power. I argue that Brazil‟s involvement in Africa does indeed reflect its neo-Gramscian middle power role. This thesis thus makes use of neo-Gramscian middle power theory and a qualitative research methodology to guide research. To answer the central research question, this thesis looks at domestic and international reasons for Brazil‟s expansion of its political-economic interests in Africa by analysing the reasons for Brazil‟s political and economic expansion separately. The domestic reasons for Brazil‟s political expansion into Africa include, the overall positive and stable domestic (political-)economic context in Brazil during this period; the international-mindedness of the leftist „Partido dos Trabalhadores‟ (PT); the interests of the Afro-Brazilian domestic voter base; and Lula‟s personal interest in expanding to Africa. The international reasons include, the perception of Africa‟s rising international importance; Africa‟s strategic importance as a supporter base for Brazilian (inter)national interests; the changing world order; Brazil‟s search for autonomy; and geopolitical security in the South Atlantic. The domestic motivations for Brazil‟s expansion of its economic interests in Africa include, the necessity of a class compromise; Brazil‟s foreign policy of economic internationalisation and its increased diplomatic relations with Africa; the private agencies promoting Brazil-Africa economic relations; the need to secure strategic natural resources; and Brazil‟s domestic interest in promoting biofuels in Africa. The main international motivations for Brazil‟s increased economic interests in Africa include, the perception of Africa as the final economic frontier; the need to gain access to international market for Brazilian goods and services; the comparative advantage Brazil has in Africa; and Brazil‟s goal of establishing a new international trade geography. These reasons thus drove Brazil‟s expansion into Africa and the central argument that I make in this thesis is that Brazil‟s overarching motivation for expanding its relations with Africa lies within its need to increase its international status and that it used Africa as a stage from whence to display its strength and capability, thus fulfilling its international status-seeking ambition.AFRIKAANS ABSTRACT: Brasilië-Afrika verhoudinge strek terug na die trans-Atlantiese slawehandel van die sestiende en negentiende eeu. Ten spyte van die vroeë aanvang van verhoudinge, was dit eers sedert die administrasie van President Luiz Inácio „Lula‟ da Silva‟s (2003-2010) dat Brasilië se uitbreiding na Afrika noemenswaardig geword het. Hierdie tesis onderneem on hierdie tydperk van ongekende Brasiliaanse uitbreiding na Afrika te analiseer. Die kern navorsingsvraag wat hierdie studie lei is: Reflekteer die redes vir Brasilië se uitbreiding van sy politiese-ekonomiese belangstellings in Afrika gedurende die Lula administrasie Brasilië se rol as a neo-Gramsciaanse intermedïere moondheid („middle power‟)? Die kern doel van die tesis, soos uiteengesit in die kern navorsingsvraag, is dus om die redes agter Brasilië se toenemende voetspoor op die kontinent gedurende Lula se presidentskap te verduidelik en te beskryf, asook om te beskryf of díe uitbreiding Brasilië se rol as ʼn neo-Gramsciaanse intermedïere moondheid reflekteer, al dan nie. Ek argumenteer dat Brasilië se betrokkenheid in Afrika wel sy neo-Gramsciaanse intermedïere moondheid rol reflekteer. Hierdie tesis maak dus gebruik van neo-Gramsciaanse intermedïere moondheid teorie en ʼn kwalitatiewe navorsingsmetodologie. Om die kern navorsingsvraag te beantwoord, kyk hierdie tesis na binnelandse en internasionale redes vir Brasilië se uitbreiding van sy politiese-ekonomiese belangstellings in Afrika deur om die internasionale en binnelandse uitbreiding apart te bespreek. Die binnelandse redes vir Brasilië se politiese uitbreiding na Afrika sluit in: die stabiele en positiewe binnelandse ekonomiese konteks in Brasilie gedurende die Lula tydperk; die internasionale fokus van die linkse Brasiliaanse werkersparty (PT); die belange van die Afro-Brasiliaanse plaaslike stem; en Lula se persoonlike belangstelling om na Afrika uit te brei. Die internationale redes sluit in: die persepsie van Afrika se stygende internasionale belangrikheid; Afrika se strategiese ondersteuningsbasis vir Brasiliaanse (inter)nasionale belange; die veranderende wêreld orde; Brasilië se soeke na autonomie; en die geopolitiese sekuriteitsbelange in die Suid Atlanties. Die binnelandse redes vir Brasilië se uitbreiding van sy ekonomiese belange in Afrika sluit in: die noodsaaklikheid van ʼn kompromie tussen verskillende klasse in Brasilië; Brasilië se buitelandsebeleidsfokus op die internasionale uitbreiding van die ekonomie en Brasilië se toenemende diplomatieke verhoudinge met Afrika; die privaat agentskappe wat Brasilië-Afrika ekonomiese verhoudinge bevorder; die noodsaakliheid om strategiese natuurlike hulpbronne te verseker; en Brasilië se nasionale belange in die bevordering van biobrandstof in Afrika. Die kern internasionale motiverings is: die idee van Afrika as die laaste ekonomiese hawe; die soeke na nuwe markte vir Brasiliaanse goedere; die vergelykende voordeel wat Brasilië in Afrika het; en Brasilië se doelwit om n nuwe internasional handelsgeografie te stig. Hierdie redes het dus Brasilië se uitbreiding na Afrika gedryf en die sentrale argument wat ek in die tesis maak is dat Brasilië se oorhoofse motivering vir die uitbreiding na Afrika lê in sy soeke na internasionale status en dat Brasilië Afrika gebruik as ʼn verhoog vanwaar hy sy vermoë tentoonstel

Haploinsufficiency of elastin gene may lead to familial cardiopathy and pulmonary emphysema

status: publishe

MEIS2 involvement in cardiac development, cleft palate, and intellectual disability

MEIS2 has been associated with cleft palate and cardiac septal defects as well as varying degrees of intellectual disability. We present a female patient with a more severe phenotype compared to previous reported patients. She has multiple congenital malformations; cleft palate and congenital heart defect characterized by septal defects and aortic coarctation. She has severe feeding problems, facial dysmorphism, severely delayed gross motor and verbal development, and autism spectrum disorder. Facial dysmorphism consisting of bitemporal narrowing, arched and laterally extended eyebrows, mild upslanting palpebral fissures, deep-set eyes, a tented upper lip, thin upper vermilion, full lower vermilion, broad first ray of hands and feet, a gap between the first and second toes, and syndactyly of toe II-III. Exome sequencing revealed a non-frameshift deletion (c.998_1000del:p.Arg333del) of three base pairs in the MEIS2 homeodomain. The more severe phenotype is most probably due to dominant-negative mechanisms. This is the first report showing a de novo small intragenic mutation in MEIS2 and further confirms the important role of this gene in normal development. © 2015 Wiley Periodicals, Inc.status: publishe

Homozygous loss-of-function mutation in ALMS1 causes the lethal disorder mitogenic cardiomyopathy in two siblings

Two siblings from consanguineous parents of Turkish descent presented with isolated dilated cardiomyopathy, leading to early death in infancy. The diagnosis of mitogenic cardiomyopathy was made histologically.publisher: Elsevier articletitle: Homozygous loss-of-function mutation in ALMS1 causes the lethal disorder mitogenic cardiomyopathy in two siblings journaltitle: European Journal of Medical Genetics articlelink: http://dx.doi.org/10.1016/j.ejmg.2014.06.004 content_type: article copyright: Copyright © 2014 Published by Elsevier Masson SASstatus: publishe

Can a volume challenge pinpoint the limiting factor in a Fontan circulation?

OBJECTIVE: It is difficult to indicate whether the limitation in a failing Fontan circulation lies within the pulmonary vasculature or the heart. Such differentiation is crucial to direct adequate therapy. This study was set out to determine if a volume challenge could identify the limiting factor. METHODS AND STUDY POPULATION: Thirty-two catheterizations in 28 patients with a Fontan circulation were included. Pressures and oxygen saturations were measured before and after volume challenge (NaCl 0.9%; 15 cc/Kg). The changes in data were grouped based on the location of the major pressure increase. Ventricular function was measured in the resting state. RESULTS: The majority of the patients showed an increase in aortic oxygen saturation, mixed venous oxygen saturation, systolic, pulmonary and systemic venous pressures. The arterio-venous oxygen gradient decreased, suggesting an increase in cardiac output. Different patterns in pressure changes were observed. Most (n=17) showed a similar increase of ventricular end-diastolic pressure and mean venous pressure (MVP); some (n=7) showed a lower increase of MVP, suggesting pulmonary reserve and recruitment; others (n=8) showed a significant higher increase in MVP, suggesting increased pulmonary vascular resistance. All volume challenge was well tolerated. CONCLUSION: Most patients were preload-responsive. The pressure changes following volume load showed patterns with a potential of differentiating between patients with a major pulmonary or cardiac limiting factor.status: publishe

Neonatal Circulatory failure due to acute hypertensive crisis:Clinical and echocardiographic clues

Objective: Circulatory failure due to acute arterial hypertension in the neonatal period is rare. This study was undertaken to assess the clinical and echocardiographic manifestations of circulatory failure resulting from acute neonatal hypertensive crisis. Methods: Neonatal and cardiology databases from 2007 to 2010 were reviewed. An established diagnosis of circulatory failure due to neonatal hypertension before the age of 14 days was required for inclusion. Six patients were identified. Results: Five patients presented with circulatory failure due to an acute hypertensive crisis. The median age at presentation was 8.5 days (range: 6.0-11.0) with a median body weight of 3.58 kg (range: 0.86-4.70). Echocardiography demonstrated mild left ventricular dysfunction [median shortening fraction (SF) 25%, range 10-30) and mild aortic regurgitation in 83% (5/6) of patients. One patient with left ventricular dysfunction (SF = 17%) had a large apical thrombus. Two patients were hypotensive, and hypertension only became evident after restoration of cardiac output. Administration of intravenous milrinone was successful, with rapid improvement of the clinical condition. Left ventricular function normalised in all survivors. Conclusion: Early neonatal circulatory collapse due to arterial hypertension is a rare but potentially life-threatening condition. At presentation, hypotension, especially in the presence of a dysfunctional left ventricle, does not exclude a hypertensive crisis being the cause of circulatory failure. The echocardiographic presence of mild aortic regurgitation combined with left ventricular hypocontractility in a structurally normal heart should alert the physician to the presence of underlying hypertension.</p