Case Report: Novel LIM domain-binding protein 3 (LDB3) mutations associated with hypertrophic cardiomyopathy family.

Hypertrophic cardiomyopathy (HCM) is an autosomal dominant cardiomyopathy, which is one of the most common reasons for cardiac arrest in children or adolescents. It is characterized by ventricular hypertrophy (usually left ventricle), small ventricular cavity, and reduced ventricular diastolic compliance found by echocardiography in the absence of abnormal load (such as hypertension or aortic stenosis). HCM is usually caused by mutations in genes encoding sarcomere or sarcomere-related genes. Whole exome sequencing (WES) is performed to identify probable causative genes. Through WES, we identified LIM domain-binding protein 3 (LDB3) mutations (R547Q and P323S) respectively in an 11-year-old HCM girl and a 6-year-old HCM boy. Neural network analyses showed that the LDB3 (R547Q and P323S) mutation decreased its protein stability, with confidence scores of -0.9211 and -0.8967. The STRUM server also confirmed that the mutation decreased its protein stability. Thus, LDB3 mutation may be associated with heritable HCM. To our knowledge, this is the first time to report LDB3 heterozygous variants (R547Q and P323S) responsible for heritable HCM.

Generation of an induced pluripotent stem cell line from a Chinese Han child with catecholaminergic polymorphic ventricular tachycardia.

TECRL, first reported in a Sudanese family with catecholaminergic polymorphic ventricular tachycardia (CPVT) in 2016. TECRL, is an endoplasmic reticulum (ER) protein preferentially expressed in the heart, playing a role in cardiomyocyte calcium homeostasis. Using Sendaivirus-mediated reprogramming, we generated an induced pluripotent stem cell (iPSC) line from the CPVT patient's peripheral blood mononuclear cell. The iPSC exhibited stable amplification, expressed pluripotent markers, and differentiated spontaneously into three layers in vitro. Additionally, the iPSC line maintained a normal karyotype, retained the pathogenic TECRL mutation, and the cell resource facilitated a platform to explore the CPVT mechanisms related to TECRL mutations.

TECRL deficiency results in aberrant mitochondrial function in cardiomyocytes.

Sudden cardiac death (SCD) caused by ventricular arrhythmias is the leading cause of mortality of cardiovascular disease. Mutation in TECRL, an endoplasmic reticulum protein, was first reported in catecholaminergic polymorphic ventricular tachycardia during which a patient succumbed to SCD. Using loss- and gain-of-function approaches, we investigated the role of TECRL in murine and human cardiomyocytes. Tecrl (knockout, KO) mouse shows significantly aggravated cardiac dysfunction, evidenced by the decrease of ejection fraction and fractional shortening. Mechanistically, TECRL deficiency impairs mitochondrial respiration, which is characterized by reduced adenosine triphosphate production, increased fatty acid synthase (FAS) and reactive oxygen species production, along with decreased MFN2, p-AKT (Ser473), and NRF2 expressions. Overexpression of TECRL induces mitochondrial respiration, in PI3K/AKT dependent manner. TECRL regulates mitochondrial function mainly through PI3K/AKT signaling and the mitochondrial fusion protein MFN2. Apoptosis inducing factor (AIF) and cytochrome C (Cyc) is released from the mitochondria into the cytoplasm after siTECRL infection, as demonstrated by immunofluorescent staining and western blotting. Herein, we propose a previously unrecognized TECRL mechanism in regulating CPVT and may provide possible support for therapeutic target in CPVT.

A novel endoglin mutation in a family with hereditary hemorrhagic telangiectasia: a case report.

Hereditary hemorrhagic telangiectasis (HHT) is an autosomal dominant vascular disease, and approximately 80% of all HHT cases are caused by gene mutation. In this report, we analyzed the case of an 11-year-old girl who had intracranial bleeding when she was 7 years old. Her brain computed tomography (CT) scans and craniocerebral angiography results revealed that she had multiple cerebral arteriovenous malformations (CAVMs). Cardiac computed tomography angiography (CTA) revealed a pulmonary arteriovenous malformation (PAVM) located in a segment of the left lung. This patient's primary diagnosis was of CAVMs and PAVMs. Both cerebral vascular embolization therapy and interventional treatment for PAVMs were performed to treat these respective conditions. The operations were successful and the patient's prognosis was good. To confirm the patient's diagnosis and the cause of her conditions, peripheral blood was collected from her and her family for whole-exome sequencing (WES). Sanger sequencing was used to verify these results and STRUM software was used to predict the presence of mutant proteins. We found a new mutation of the endoglin (ENG) gene present in this family; this mutation is known as c.1466del (p.Gln489Argfs*2). The patient's mother was a carrier of this heterozygous mutation. STRUM software confirmed that the configuration of the ENG protein p.Gln489Argfs2 site changed with this mutation. We believe this c.1466del (p.Gln489Argfs*2) mutation affects ENG protein function, and the resultant ENG protein dysfunction leads to HHT. When a child has multiple vascular malformation, HHT should be considered as a primary diagnosis.

A compound heterozygosity of Tecrl gene confirmed in a catecholaminergic polymorphic ventricular tachycardia family.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is one of the most common causes of sudden cardiac death (SCD) during childhood and in adolescence. Trans-2, 3-enoyl-CoA reductase-like (Tecrl) gene mutations (Arg196Gln and c.331+1G > A splice site mutation) were first reported in CPVT. Tecrl homozygous c.331+1G > A splice site mutation in iPSCs revealed a definite correlation between Tecrl and Ca2+ transport in cardiomyocytes. However, no other researchers have confirmed Tecrl mutations in CPVT with literature review. In this study, a case of compound heterozygosity in the Tecrl gene (Arg196Gln and c.918+3T > G splice site mutation) was first identified in a 13-year-old boy with CPVT by whole-exome sequencing (WES) and confirmed by Sanger sequence. Support vector machine and neural network analysis predicted that Arg196Gln mutation could decrease the stability of Tecrl structure, the confidence scores were -0.8929 and -0.9930. A STRUM server also confirmed that Arg196Gln mutation may decrease the binding capacity of the substrate and cause an amino acid substitution immediately upstream of the 3-oxo-5-alpha steroid 4-dehydrogenase domain. According to the "human splicing finder" indication and Alamut Visual Splicing Prediction, the c.918 + 3T > G mutation could influence Tecrl variable splicing. Thus, we confirmed that Tecrl as a new gene which is associated with CPVT.

A 10-year-old boy with dyspnea and hypoxia: abernathy malformation masquerading as pulmonary arteriovenous fistula.

BACKGROUND: Abernethy malformation is an extremely rare congenital malformation characterised by an extrahepatic portosystemic shunt. Children with Abernathy malformation can develop hepatopulmonary syndrome (HPS) with pulmonary arteriovenous fistulas (PAVF) or pulmonary hypertension. PAVF manifests as central cyanosis with effort intolerance. We report a case of PAVF in a Ten-year-old Boy. Persistent symptoms identified Abernathy malformation as the cause of progressive symptoms and current understanding of this rare malformation is reviewed. CASE PRESENTATION: A case of 10-year-old boy with Abernethy malformation complicated with HPS initially managed as PAVF was presented. Selective lung angiography showed a typical diffuse reticular pattern on right lower lung, which suggested PAVF. However, cyanosis was not improved post transcatheter coil embolization. Then, liver disease was considered although the patient had normal aspartate aminotransferase and alanine aminotransferase. The significantly elevated serum ammonia was attracted our attention. Abdominal computed tomography also exhibited enlarged main portal vein (MPV), cirsoid spleen vein, and superior mesenteric vein (SMV). Angiography with direct opacification of the SMV with a catheter coming from the inferior vena cava (IVC) and going to the SMV via the shunt vessel (SHUNT) between the MPV and IVC. Occlusion the IVC with an inflated balloon, injection of contrast medium via a catheter placed in the SMV, MPV was showed and absence of intrahepatic branches. Abernethy malformation IB type is finally confirmed. CONCLUSIONS: Abernethy malformation is an unusual cause for development of PAVF and cyanosis in children. Clinicians must be suspicious of Abernethy malformation complicated with HPS. If patients have abnormal serum ammonia and enlarged MPV in abdominal CT, cathether angiography should be done to rule out Abernethy malformation.