TGFBR1 Variants Can Associate with Non-Syndromic Congenital Heart Disease without Aortopathy.

BACKGROUND: Congenital heart diseases (CHD) are the most common congenital malformations in newborns and remain the leading cause of mortality among infants under one year old. Molecular diagnosis is crucial to evaluate the recurrence risk and to address future prenatal diagnosis. Here, we describe two families with various forms of inherited non-syndromic CHD and the genetic work-up and resultant findings. METHODS: Next-generation sequencing (NGS) was employed in both families to uncover the genetic cause. In addition, we performed functional analysis to investigate the consequences of the identified variants in vitro. RESULTS: NGS identified possible causative variants in both families in the protein kinase domain of the TGFBR1 gene. These variants occurred on the same amino acid, but resulted in differently substituted amino acids (p.R398C/p.R398H). Both variants co-segregate with the disease, are extremely rare or unique, and occur in an evolutionary highly conserved domain of the protein. Furthermore, both variants demonstrated a significantly altered TGFBR1-smad signaling activity. Clinical investigation revealed that none of the carriers had (signs of) aortopathy. CONCLUSION: In conclusion, we describe two families, with various forms of inherited non-syndromic CHD without aortopathies, associated with unique/rare variants in TGFBR1 that display altered TGF-beta signaling. These findings highlight involvement of TGFBR1 in CHD, and warrant consideration of potential causative TGFBR1 variants also in CHD patients without aortopathies.

The Role of the Disrupted Podosome Adaptor Protein (SH3PXD2B) in Frank-Ter Haar Syndrome.

Frank-Ter Haar syndrome (FTHS), sometimes referred to as Ter Haar syndrome, is a rare hereditary disorder that manifests in skeletal, cardiac, and ocular anomalies, including hypertelorism, glaucoma, prominent eyes, and facial abnormalities. In this study, we performed whole-exome sequencing (WES) to identify the genetic component responsible for the phenotype of the index patient, a male infant born to a consanguineous family from Saudi Arabia. The analysis revealed a homozygous missense variant, c.280C>G, in the SH3PXD2B gene, which cosegregates with the familial phenotype with a plausible autosomal-recessive mode of inheritance, indicating a potential disease-causing association. The SH3PXD2B gene encodes a TKS4 podosome adaptor protein that regulates the epidermal growth factor signaling pathway. This study validates the critical function of the TKS4 podosome protein by suggesting a common mechanism underlying the pathogenesis of FTHS.

Neurological complications in children with infective endocarditis: Incidence, risk factors, and outcome: A 10-year single-center experience.

BACKGROUND AND OBJECTIVE: Despite improvement in medical management, infective endocarditis (IE) remains a serious disease that may affect children with and without preexisting cardiac conditions with significant morbidity and mortality. Neurological complications of IE represent the worst with guarded prognosis. The aim of this study is to describe the incidence, etiology, characteristics, risk factors, and outcome of children with neurological complications associated with IE. MATERIAL AND METHODS: A retrospective cohort study was conducted from 2009 to 2019 where all pediatric patients who fulfilled the modified Duke criteria for IE were included. We divided the cases into 2 groups: IE with neurological complications and IE without neurological complications control group. We compared the two groups statistically and analyzed the results. RESULTS: We identified 31 (17 male, 14 female) patients with IE. Neurological complications occurred in 7/31 (23%) patients, mainly in the form of a stroke. Gram-positive microbes were the main causative agents for IE (52%) followed by gram-negative (14%), then fungal organisms (3%). Univariate analysis identified the following risk factors for neurological complications: lower body weight, higher C- reactive protein (CRP) level, and left-sided valvular lesions with P values of (0.0003, 0.0001, and 0.04), respectively.Although mortality was higher in the neurological complications group, it was 43% in comparison to 21% in the control group and it did not reach statistical significance (P = .49). Large vegetation size (more than 10 mm) was seen in 57% of patients with neurological complications as compared to 16% in the control group (P = .052). CONCLUSION: Neurological complications occurred in almost a quarter of children with IE. Possible risk factors include lower body weight, left-sided valvular lesion, and higher levels of inflammatory markers (CRP). Stroke was the most common neurological complication encountered with possible increased risk of mortality.

Novel Autosomal Recessive Splice-Altering Variant in PRKD1 Is Associated with Congenital Heart Disease.

Congenital heart defects (CHDs) are the most common types of birth defects, and global incidence of CHDs is on the rise. Despite the prevalence of CHDs, the genetic determinants of the defects are still in the process of being identified. Herein, we report a consanguineous Saudi family with three CHD affected daughters. We used whole exome sequencing (WES) to investigate the genetic cause of CHDs in the affected daughters. We found that all affected individuals were homozygous for a novel splice-altering variant (NM_001330069.1: c.265-1G>T) of PRKD1, which encodes a calcium/calmodulin-dependent protein kinase in the heart. The homozygous variant was found in the affected patients with Pulmonary Stenosis (PS), Truncus Arteriosis (TA), and Atrial Septal Defect (ASD). Based on the family's pedigree, the variant acts in an autosomal recessive manner, which makes it the second autosomal recessive variant of PRKD1 to be identified with a link to CHDs, while all other previously described variants act dominantly. Interestingly, the father of the affected daughters was also homozygous for the variant, though he was asymptomatic of CHDs himself. Since both of his sisters had CHDs as well, this raises the possibility that the novel PRKD1 variant may undergo autosomal recessive inheritance mode with gender limitation. This finding confirms that CHD can be associated with both dominant and recessive mutations of the PRKD1 gene, and it provides a new insight to genotype-phenotype association between PRKD1 and CHDs. To our knowledge, this is the first report of this specific PRKD1 mutation associated with CHDs.

ADAMTS19-associated heart valve defects: Novel genetic variants consolidating a recognizable cardiac phenotype.

Recently, ADAMTS19 was identified as a novel causative gene for autosomal recessive heart valve disease (HVD), affecting mainly the aortic and pulmonary valves. Exome sequencing and data repository (CentoMD) analyses were performed to identify patients with ADAMTS19 variants (two families). A third family was recognized based on cardiac phenotypic similarities and SNP array homozygosity. Three novel loss of function (LoF) variants were identified in six patients from three families. Clinically, all patients presented anomalies of the aortic/pulmonary valves, which included thickening of valve leaflets, stenosis and insufficiency. Three patients had (recurrent) subaortic membrane, suggesting that ADAMTS19 is the first gene identified related to discrete subaortic stenosis. One case presented a bi-commissural pulmonary valve. All patients displayed some degree of atrioventricular valve insufficiency. Other cardiac anomalies included atrial/ventricular septal defects, persistent ductus arteriosus, and mild dilated ascending aorta. Our findings confirm that biallelic LoF variants in ADAMTS19 are causative of a specific and recognizable cardiac phenotype. We recommend considering ADAMTS19 genetic testing in all patients with multiple semilunar valve abnormalities, particularly in the presence of subaortic membrane. ADAMTS19 screening in patients with semilunar valve abnormalities is needed to estimate the frequency of the HVD related phenotype, which might be not so rare.

Infective endocarditis in children with normal heart: Indication for surgical intervention.

Although infective endocarditis is an uncommon condition, it can be fatal if not treated. The new era of infective endocarditis in children with structurally normal heart has become apparent entity. Duke criteria has been established for a long time and gives clear guidelines for diagnosis; however, surgical indication in pediatric population needs to be tailored to individual patients.