Amy R. Shikany

Aortopathy in the 7q11.23 microduplication syndrome

The 7q11.23 microduplication syndrome, caused by the reciprocal duplication of the Williams‐Beuren syndrome deletion region, is a genomic disorder with an emerging clinical phenotype. Dysmorphic features, congenital anomalies, hypotonia, developmental delay highlighted by variable speech delay, and autistic features are characteristic findings. Congenital heart defects, most commonly patent ductus arteriosus, have been reported in a minority of cases. Included in the duplicated region is elastin (ELN), implicated as the cause of supravalvar aortic stenosis in patients with Williams–Beuren syndrome. Here we present a series of eight pediatric patients and one adult with 7q11.23 microduplication syndrome, all of whom had aortic dilation, the opposite vascular phenotype of the typical supravalvar aortic stenosis found in Williams–Beuren syndrome. The ascending aorta was most commonly involved, while dilation was less frequently identified at the aortic root and sinotubular junction. The findings in these patients support a recommendation for cardiovascular surveillance in patients with 7q11.23 microduplication syndrome.

Clinically relevant variants identified in thoracic aortic aneurysm patients by research exome sequencing

Thoracic aortic aneurysm (TAA) is a genetically heterogeneous disease involving subclinical and progressive dilation of the thoracic aorta, which can lead to life‐threatening complications such as dissection or rupture. Genetic testing is important for risk stratification and identification of at risk family members, and clinically available genetic testing panels have been expanding rapidly. However, when past testing results are normal, there is little evidence to guide decision‐making about the indications and timing to pursue additional clinical genetic testing. Results from research based genetic testing can help inform this process. Here we present 10 TAA patients who have a family history of disease and who enrolled in research‐based exome testing. Nine of these ten patients had previous clinical genetic testing that did not identify the cause of disease. We sought to determine the number of rare variants in 23 known TAA associated genes identified by research‐based exome testing. In total, we found 10 rare variants in six patients. Likely pathogenic variants included a TGFB2 variant in one patient and a SMAD3 variant in another. These variants have been reported previously in individuals with similar phenotypes. Variants of uncertain significance of particular interest included novel variants in MYLK and MFAP5, which were identified in a third patient. In total, clinically reportable rare variants were found in 6/10 (60%) patients, with at least 2/10 (20%) patients having likely pathogenic variants identified. These data indicate that consideration of re‐testing is important in TAA patients with previous negative or inconclusive results.

Twins with progressive thoracic aortic aneurysm, recurrent dissection and ACTA2 mutation.

Thoracic aortic aneurysm (TAA) is a genetically mediated disease with variable age of onset. In the pediatric age range, nonsyndromic TAA frequently has a milder course than syndromic forms of TAA, such as Marfan syndrome or Loeys-Dietz syndrome. Herein, we describe 17-year-old identical twin brothers with severe progressive TAA due to a novel de novo ACTA2 mutation. Interestingly, both boys were diagnosed at age 11 with congenital mydriasis, a recently recognized manifestation of some ACTA2 mutations due to smooth muscle dysfunction. One of the brothers presented with acute-onset lower back pain that was identified as dissection of an abdominal aortic aneurysm. Imaging of the chest at this time showed severe fusiform TAA. Cardiac imaging in his twin showed similar TAA, but no abdominal aortic aneurysm. Both brothers underwent valve-sparing aortic root replacement, but have had progressive aortic disease with recurrent dissection requiring multiple surgeries. This case emphasizes the importance of identifying physical stigmata of smooth muscle dysfunction, such as mydriasis, as potential markers for associated aortopathy and vascular diseases.

Clinical Stratification of Pediatric Patients with Idiopathic Thoracic Aortic Aneurysm

OBJECTIVES To describe the global phenotypes of pediatric patients with thoracic aortic aneurysm (TAA) who do not have a clinical diagnosis of Marfan syndrome (MFS) or related connective tissue disorders. We hypothesized that the presence of noncardiovascular abnormalities correlate with TAA severity and that medical therapy reduces TAA progression. STUDY DESIGN This is a retrospective case series of patients with TAA age ≤ 21 years evaluated in a cardiovascular genetics clinic. Patients meeting clinical criteria for MFS or related disorders were excluded. Repeated measures analyses of longitudinal echocardiographic measurements of the aorta were used to test associations between TAA severity and noncardiovascular phenotype and to assess the impact of medical therapy. RESULTS Sixty-nine patients with TAA at mean age 12.5 ± 5.3 years were included. Noncardiovascular abnormalities, including skeletal (65%) or craniofacial (54%) findings, were frequently observed. Increased rate of aortic root enlargement was associated with ocular (P = .002) and cutaneous (P = .003) abnormalities, and increased rate of ascending aorta enlargement was associated with craniofacial (P < .001) abnormalities. Beta blocker or angiotensin receptor blocker therapy (n = 41) was associated with reduction in the rate of aortic root growth (P = .018). CONCLUSIONS Children with TAA not satisfying diagnostic criteria for MFS or related disorders frequently have noncardiovascular findings, some of which are associated with TAA progression. Because therapy initiation may reduce risk of progression and long-term complications, comprehensive assessment of noncardiovascular findings may facilitate early risk stratification and improve outcomes.

Genetic Testing in Pediatric Left Ventricular NoncompactionCLINICAL PERSPECTIVE

Background— Left ventricular noncompaction (LVNC) can occur in isolation or can co-occur with a cardiomyopathy phenotype or cardiovascular malformation. The yield of cardiomyopathy gene panel testing in infants, children, and adolescents with a diagnosis of LVNC is unknown. By characterizing a pediatric population with LVNC, we sought to determine the yield of cardiomyopathy gene panel testing, distinguish the yield of testing for LVNC with or without co-occurring cardiac findings, and define additional factors influencing genetic testing yield. Methods and Results— One hundred twenty-eight individuals diagnosed with LVNC at ⩽21 years of age were identified, including 59% with idiopathic etiology, 32% with familial disease, and 9% with a syndromic or metabolic diagnosis. Overall, 75 individuals had either cardiomyopathy gene panel (n=65) or known variant testing (n=10). The yield of cardiomyopathy gene panel testing was 9%. The severity of LVNC by imaging criteria was not associated with positive genetic testing, co-occurring cardiac features, etiology, family history, or myocardial dysfunction. Individuals with isolated LVNC were significantly less likely to have a positive genetic testing result compared with those with LVNC and co-occurring cardiomyopathy (0% versus 12%, respectively; P<0.01). Conclusions— Genetic testing should be considered in individuals with cardiomyopathy co-occurring with LVNC. These data do not suggest an indication for cardiomyopathy gene panel testing in individuals with isolated LVNC in the absence of a family history of cardiomyopathy.

Erratum to: At the Heart of the Pregnancy: What Prenatal and Cardiovascular Genetic Counselors Need to Know about Maternal Heart Disease

1 Department of Internal Medicine, The Ohio State University, Columbus, OH, USA 2 Human Genetics Division, The Ohio State University, 306 BRT, 460 W. 12th Ave, Columbus, OH 43210, USA 3 Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA 4 Allegheny General Hospital, Pittsburgh, PA, USA 5 Institute of Genetic Medicine, Johns Hopkins University, Baltimore, MD, USA 6 Division of Cardiology, Johns Hopkins University, Baltimore, MD, USA 7 Heart Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

Hypertrophic Cardiomyopathy Genotype Prediction Models in a Pediatric Population

The Toronto Hypertrophic Cardiomyopathy (HCM) Genotype Score and Mayo HCM Genotype Predictor are risk assessment models developed to estimate a patient’s likelihood of testing positive for a pathogenic variant causative of HCM. These models were developed from adult populations with HCM based on factors that have been associated with a positive genotype and have not been validated in external populations. The purpose of this study was to evaluate the overall predictive abilities of these models in a clinical pediatric HCM setting. A retrospective medical record review of 77 pediatric patients with gene panel testing for HCM between September 2005 and June 2015 was performed. Clinical and echocardiographic variables used in the developed models were collected and used to calculate scores for each patient. To evaluate model performance, the ability to discriminate between a carrier and non-carrier was assessed by area under the ROC curve (AUC) and overall calibration was evaluated by the Hosmer–Lemeshow goodness-of-fit statistic. Discrimination assessed by AUC was 0.72 (P < 0.001) for the Toronto model and 0.67 (P = 0.004) for the Mayo model. The Toronto model and the Mayo model showed P values of 0.36 and 0.82, respectively, for model calibration. Our findings suggest that these models are useful in predicting a positive genetic test result in a pediatric HCM setting. They may be used to aid healthcare providers in communicating risk and enhance patient decision-making regarding pursuit of genetic testing.