Daniela Q.C.M. Barge-Schaapveld

What Is New in Dilatation of the Ascending Aorta? Review of Current Literature and Practical Advice for the Cardiologist

A 61-year-old woman presented with atypical chest complaints. Her sister and brother suffered from type A aortic dissection at 47 and 39 years of age, respectively.1 The diameter of the ascending aorta was 4.6 cm as measured with magnetic resonance imaging (Figure 1). Figure 1. Magnetic resonance angiography of the ascending aorta. The diameter at the level of the ascending aorta measures 4.6 cm. The diameter of the aortic root is normal. Acute dissection of the ascending aorta is often lethal. Even when emergency surgery can be performed, associated morbidity and mortality are high. To prevent dissection of the aorta, timely operation on a patient with a known dilatation of the ascending aorta (for normal values, see Table 1) is advised, along with other supportive measures. The guideline for the management of aortic dissection published by the European Society of Cardiology (ESC) task force in 20012 recommends the following for the prevention of aortic dissection in inherited diseases (Marfan syndrome [MFS], Ehlers-Danlos syndrome, annuloaortic ectasia): lifelong β-adrenergic blockade (Class IB), moderate restriction of physical activity (Class IC), periodic routine imaging of the aorta (Class IC), prophylactic replacement of the aortic root before diameter exceeds 5.5 cm (Class 2A), and prophylactic replacement of the aortic root before diameter exceeds 5.0 cm in patients with a family history of dissection (Class 2A). These ESC recommendations received endorsement by the American College of Cardiology (ACC) in 2001. In recent years, insights into the diagnosis and management of these patients have changed. The purpose of the present article is to summarize these changes, referring to this recent case presented at our clinic. View this table: Table 1. Normal Ascending Aortic Dimensions in Adults In patients with aortic dilatation, the aortic wall can be weakened by cystic media degeneration. The media displays loss of smooth muscle cells and fragmentation …

Prospective risk of cancer and the influence of tobacco use in carriers of the p16- Leiden germline variant

The p16-Leiden germline variant in the CDKN2A gene is associated with a high risk of melanoma and pancreatic cancer. The aims of this study were to assess the risk of developing other cancers and to determine whether tobacco use would alter cancer risk in carriers of such a variant. We therefore prospectively evaluated individuals with a p16-Leiden germline variant, participating in a pancreatic surveillance programme, for the occurrence of cancer (n=150). Tobacco use was assessed at the start of the surveillance programme. We found a significantly increased risk for melanoma (relative risk (RR) 41.3; 95% confidence interval (CI) 22.9–74.6) and pancreatic cancer (RR 80.8; 95% CI 44.7–146). In addition, increased risks were found for cancers of the lip, mouth and pharynx (RR 18.8; 95% CI 6.05–58.2) and respiratory tumours (RR 4.56; 95% CI 1.71–12.1). Current smokers developed significantly more cancers of the lip, mouth and pharynx, respiratory system and pancreas compared with former and never-smokers. In conclusion, this study shows that carriers of a p16-Leiden variant have an increased risk of developing various types of cancer, and smoking significantly increases the risk of frequently occurring cancers. Smoking cessation should be an integral part of the management of p16-Leiden variant carriers.

Lamin A/C-Related Cardiac Disease: Late Onset With a Variable and Mild Phenotype in a Large Cohort of Patients With the Lamin A/C p.(Arg331Gln) Founder Mutation

Background— Interpretation of missense variants can be especially difficult when the variant is also found in control populations. This is what we encountered for the LMNA c.992G>A (p.(Arg331Gln)) variant. Therefore, to evaluate the effect of this variant, we combined an evaluation of clinical data with functional experiments and morphological studies. Methods and Results— Clinical data of 23 probands and 35 family members carrying this variant were retrospectively collected. A time-to-event analysis was performed to compare the course of the disease with carriers of other LMNA mutations. Myocardial biopsies were studied with electron microscopy and by measuring force development of the sarcomeres. Morphology of the nuclear envelope was assessed with immunofluorescence on cultured fibroblasts. The phenotype in probands and family members was characterized by atrioventricular conduction disturbances (61% and 44%, respectively), supraventricular arrhythmias (69% and 52%, respectively), and dilated cardiomyopathy (74% and 14%, respectively). LMNA p.(Arg331Gln) carriers had a significantly better outcome regarding the composite end point (malignant ventricular arrhythmias, end-stage heart failure, or death) compared with carriers of other pathogenic LMNA mutations. A shared haplotype of 1 Mb around LMNA suggested a common founder. The combined logarithm of the odds score was 3.46. Force development in membrane-permeabilized cardiomyocytes was reduced because of decreased myofibril density. Structural nuclear LMNA-associated envelope abnormalities, that is, blebs, were confirmed by electron microscopy and immunofluorescence microscopy. Conclusions— Clinical, morphological, functional, haplotype, and segregation data all indicate that LMNA p.(Arg331Gln) is a pathogenic founder mutation with a phenotype reminiscent of other LMNA mutations but with a more benign course.

The first titin (c.59926 + 1G > A) founder mutation associated with dilated cardiomyopathy

Truncating variants in the gene encoding titin (TTNtv) are found in 13–25% of dilated cardiomyopathy (DCM) cases.1,2 In DCM patients, TTNtv are associated with early arrhythmic risk, composed of atrial fibrillation (AF), non-sustained and/or sustained ventricular tachycardia.3 TTNtv in the Aband region, or in constitutively expressed exons of TTN, are generally believed to be pathogenic, but assigning pathogenicity can be challenging because TTNtv are also found in control populations.4 Here we describe the TTN c.59926+1G >A splice-site variant located in the Aband (chr2:179456704C>T, build GRCh37; NM_001267550.2 reference sequence) that we have identified in multiple probands with DCM. Written informed consent was obtained from all participants following local medical ethics committee guidelines. Our study and all experiments conformed with the principles of the Declaration of Helsinki.

Toward an effective exome-based genetic testing strategy in pediatric dilated cardiomyopathy

PurposeWe evaluated the diagnostic yield in pediatric dilated cardiomyopathy (DCM) of combining exome sequencing (ES)-based targeted analysis and genome-wide copy-number variation (CNV) analysis. Based on our findings, we retrospectively designed an effective approach for genetic testing in pediatric DCM.MethodsWe identified 95 patients (in 85 families) with pediatric onset of DCM. We initially excluded 13 of these families because they already had a genetic diagnosis, leaving a total of 31 probands for single-nucleotide polymorphism (SNP) array and trio-ES. We used Human Phenotype Ontology (HPO)-based filtering for our data analysis.ResultsWe reached a genetic diagnosis in 15/31 (48.4%) families. ES yielded a diagnosis in 13 probands (13/15; 86.7%), with most variants being found in genes encoding structural cardiomyocyte components. Two large deletions were identified using SNP array. If we had included the 13 excluded families, our estimated yield would have been 54%.ConclusionWe propose a standardized, stepwise analysis of (i) well-known cardiomyopathy genes, (ii) CNVs, (iii) all genes assigned to HPO cardiomyopathy, and (iv) if appropriate, genes assigned to other HPO terms. This diagnostic approach yields the highest increase at each subsequent step and reduces analytic effort, cost, the number of variants of unknown clinical significance, and the chance of incidental findings.

The Tatton-Brown-Rahman Syndrome: A clinical study of 55 individuals with de novo constitutive DNMT3A variants

Tatton-Brown-Rahman syndrome (TBRS; OMIM 615879), also known as the DNMT3A-overgrowth syndrome, is an overgrowth intellectual disability syndrome first described in 2014 with a report of 13 individuals with constitutive heterozygous DNMT3A variants. Here we have undertaken a detailed clinical study of 55 individuals with de novo DNMT3A variants, including the 13 previously reported individuals. An intellectual disability and overgrowth were reported in >80% of individuals with TBRS and were designated major clinical associations. Additional frequent clinical associations (reported in 20-80% individuals) included an evolving facial appearance with low-set, heavy, horizontal eyebrows and prominent upper central incisors; joint hypermobility (74%); obesity (weight ³2SD, 67%); hypotonia (54%); behavioural/psychiatric issues (most frequently autistic spectrum disorder, 51%); kyphoscoliosis (33%) and afebrile seizures (22%). One individual was diagnosed with acute myeloid leukaemia in teenage years. Based upon the results from this study, we present our current management for individuals with TBRS

Putting genome-wide sequencing in neonates into perspective

PurposeSeveral studies have reported diagnostic yields up to 57% for rapid exome or genome sequencing (rES/GS) as a single test in neonatal intensive care unit (NICU) patients, but the additional yield of rES/GS compared with other available diagnostic options still remains unquantified in this population.MethodsWe retrospectively evaluated all genetic NICU consultations in a 2-year period.ResultsIn 132 retrospectively evaluated NICU consultations 27 of 32 diagnoses (84.4%) were made using standard genetic workup. Most diagnoses (65.6%) were made within 16 days. Diagnostic ES yield was 5/29 (17.2%). Genetic diagnoses had a direct effect on clinical management in 90.6% (29/32) of patients.ConclusionsOur study shows that exome sequencing has a place in NICU diagnostics, but given the associated costs and the high yield of alternative diagnostic strategies, we recommend to first perform clinical genetic consultation.