TBX4 variants and pulmonary diseases:getting out of the 'Box'

Purpose of review In 2013, the association between T-Box factor 4 (TBX4) variants and pulmonary arterial hypertension (PAH) has first been described. Now - in 2020 - growing evidence is emerging indicating that TBX4 variants associate with a wide spectrum of lung disorders. Recent findings TBX4 variants are enriched in both children and adults with PAH. The clinical phenotype associated with a TBX4 variant seems to be milder than that in other PAH-associated gene mutations. Further, TBX4 variants have increasingly been associated with a variety of clinical and histopathological phenotypes, including lethal developmental parenchymal lung diseases such as not only acinar dysplasia in neonates, but also less outspoken parenchymal lung diseases in children and adults. Summary The clinical phenotype of a TBX4 variant has recently been recognised to expand from bone disorders to different types of lung diseases. Recent data suggest that variants of TBX4, a transcription factor known to be an important regulator in embryonic development, are not rare in both children and adults with PAH and/or developmental parenchymal lung diseases

Clinical and genetic aspects of bicuspid aortic valve:a proposed model for family screening based on a review of literature

Bicuspid aortic valve (BAV) is the most common congenital cardiac defect causing serious morbidity including valvular dysfunction and thoracic aortic aneurysms (TAA) in around 30% of BAV patients. Cardiological screening of first-degree relatives is advised in recent guidelines given the observed familial clustering of BAV. However, guidelines regarding screening of family members and DNA testing are not unequivocal. The aim of this review is to provide an overview of the literature on echocardiographic screening in first-degree relatives of BAV patients and to propose a model for family screening. In addition, we provide a flowchart for DNA testing. We performed a PubMed search and included studies providing data on echocardiographic screening in asymptomatic relatives of BAV patients. Nine studies were included. In 5.8-47.4% of the families BAV was shown to be familial. Of the screened first-degree relatives 1.8-11% was found to be affected with BAV. Results regarding a potential risk of TAA in first-degree relatives with a tricuspid aortic valve (TAV) were conflicting. The reported familial clustering of BAV underlines the importance of cardiological screening in relatives. After reviewing the available family history, patient characteristics and the results of cardiological screening in relatives, follow-up in relatives with a TAV and/or DNA testing may be advised in a subset of families. In this study we propose a model for the clinical and genetic work-up in BAV families, based on the most extensive literature review on family screening performed until now

Concordant Symptomatic Intracranial Aneurysm in a Monozygotic Twin:A Case Report and Review of the Literature

The development of an intracranial aneurysm (IA) is a multifactorial process, involving genetic and environmental factors. The presence of IA or aneurysmal subarachnoid hemorrhage (aSAH) in twins is particularly interesting, since both genetic and environmental factors can be studied. It also raises the question of whether, when one twin is affected, the other asymptomatic twin should be examined for an IA. We report on a monozygotic (MZ) twin-pair with aSAH in both twins and we review all reported cases of IA in MZ twins. Including our case, we found only 14 MZ twin-pairs in which both twins harbored an IA, suggesting a heavy underreporting in the medical literature. In this small group, a high concordance was noted in the sites of IAs. In MZ twins, the preferred sites for IAs are the branching arteries, while aneurysms arising from fusion arteries are rare. These sites differ from the preferential sites seen in series of familial IAs and series of sporadic IAs. We therefore hypothesize that the twinning process might play a significant role in the development of IAs in MZ twins. To further explore and substantiate this, the large twin registries should be studied. Although IAs in MZ twins with a negative family history for IAs should not be regarded as familial IAs, screening of the asymptomatic twin should be seriously considered if one MZ twin presents with an aSAH or an IA, because of the high fatality rates reported in asymptomatic (and not screened) MZ twin-halves

Maternal use of drug substrates of placental transporters and the effect of transporter-mediated drug interactions on the risk of congenital anomalies

Background A number of transporter proteins are expressed in the placenta, and they facilitate the placental transfer of drugs. The inhibition of P-glycoprotein (P-gp) was previously found to be associated with an increase in the risk of congenital anomalies caused by drug substrates of this transporter. We now explore the role of other placental transporter proteins. Methods A population-based case-referent study was performed using cases with congenital anomalies (N = 5,131) from EUROCAT Northern Netherlands, a registry of congenital anomalies. The referent population (N = 31,055) was selected from the pregnancy IADB. nl, a pharmacy prescription database. Results Ten placental transporters known to have comparable expression levels in the placenta to that of P-gp, were selected in this study. In total, 147 drugs were identified to be substrates, inhibitors or inducers, of these transporters. Fifty-eight of these drugs were used by at least one mother in our cases or referent population, and 28 were used in both. The highest user rate was observed for the substrates of multidrug resistance-associated protein 1, mainly folic acid (6% of cases, 8% of referents), and breast cancer resistance protein, mainly nitrofurantoin (2.3% of cases, 2.9% of referents). In contrast to P-gp, drug interactions involving substrates of these transporters did not have a significant effect on the risk of congenital anomalies. Conclusions Some of the drugs which are substrates or inhibitors of placental transporters were commonly used during pregnancy. No significant effect of transporter inhibition was found on fetal drug exposure, possibly due to a limited number of exposures

Common arterial trunk and ventricular non-compaction in Lrp2 knockout mice indicate a crucial role of LRP2 in cardiac development

Lipoprotein-related receptor protein 2 (LRP2) is important for development of the embryonic neural crest and brain in both mice and humans. Although a role in cardiovascular development can be expected, the hearts of Lrp2 knockout (KO) mice have not yet been investigated. We studied the cardiovascular development of Lrp2 KO mice between embryonic day 10.5 (E10.5) and E15.5, applying morphometry and immunohistochemistry, using antibodies against Tfap2α (neural crest cells), Nkx2.5 (second heart field), WT1 (epicardium derived cells), tropomyosin (myocardium) and LRP2. The Lrp2 KO mice display a range of severe cardiovascular abnormalities, including aortic arch anomalies, common arterial trunk (persistent truncus arteriosus) with coronary artery anomalies, ventricular septal defects, overriding of the tricuspid valve and marked thinning of the ventricular myocardium. Both the neural crest cells and second heart field, which are essential for the lengthening and growth of the right ventricular outflow tract, are abnormally positioned in the Lrp2 KO. T hi s explains the absence of the aorto-pulmonary septum, which leads to common arterial trunk and ventricular septal defects. Severe blebbing of the epicardial cells covering the ventricles is seen. Epithelial-mesenchymal transition does occur; however, there are fewer WT1-positive epicardium-derived cells in the ventricular wall as compared to normal, coinciding with the myocardial thinning and deep intertrabecular spaces. LRP2 plays a crucial role in cardiovascular development in mice. This corroborates findings of cardiac anomalies in humans with LRP2 mutations. Future studies should reveal the underlying signaling mechanisms in which LRP2 is involved during cardiogenesis

Strategies in Rapid Genetic Diagnostics of Critically Ill Children:Experiences From a Dutch University Hospital

Background: Genetic disorders are a substantial cause of infant morbidity and mortality and are frequently suspected in neonatal intensive care units. Non-specific clinical presentation or limitations to physical examination can result in a plethora of genetic testing techniques, without clear strategies on test ordering. Here, we review our 2-years experiences of rapid genetic testing of NICU patients in order to provide such recommendations. Methods: We retrospectively included all patients admitted to the NICU who received clinical genetic consultation and genetic testing in our University hospital. We documented reasons for referral for genetic consultation, presenting phenotypes, differential diagnoses, genetic testing requested and their outcomes, as well as the consequences of each (rapid) genetic diagnostic approach. We calculated diagnostic yield and turnaround times (TATs). Results: Of 171 included infants that received genetic consultation 140 underwent genetic testing. As a result of testing as first tier, 13/14 patients received a genetic diagnosis from QF-PCR; 14/115 from SNP-array; 12/89 from NGS testing, of whom 4/46 were diagnosed with a small gene panel and 8/43 with a large OMIM-morbid based gene panel. Subsequent secondary or tertiary analysis and/or additional testing resulted in five more diagnoses. TATs ranged from 1 day (QF-PCR) to a median of 14 for NGS and SNP-array testing, with increasing TAT in particular when many consecutive tests were performed. Incidental findings were detected in 5/140 tested patients (3.6%). Conclusion: We recommend implementing a broad NGS gene panel in combination with CNV calling as the first tier of genetic testing for NICU patients given the often unspecific phenotypes of ill infants and the high yield of this large panel

A homozygous variant in growth and differentiation factor 2(GDF2)may cause lymphatic dysplasia with hydrothorax and nonimmune hydrops fetalis

The etiology of nonimmune hydrops fetalis is extensive and includes genetic disorders. We describe a term-born female neonate with late onset extensive nonimmune hydrops, that is, polyhydramnios, edema, and congenital bilateral chylothorax. This newborn was successfully treated with repetitive thoracocentesis, total parenteral feeding, octreotide intravenously and finally surgical pleurodesis and corticosteroids. A genetic cause seemed plausible as the maternal history revealed a fatal nonimmune hydrops fetalis. A homozygous truncating variant inGDF2(c.451C>T, p.(Arg151*)) was detected with exome sequencing. Genetic analysis of tissue obtained from the deceased fetal sibling revealed the same homozygous variant. The parents and two healthy siblings were heterozygous for theGDF2variant. Skin and lung biopsies in the index patient, as well as the revised lung biopsy of the deceased fetal sibling, showed lymphatic dysplasia and lymphangiectasia. To the best of our knowledge, this is the first report of an association between a homozygous variant inGDF2with lymphatic dysplasia, hydrothorax and nonimmune hydrops fetalis