Comparison of treatment strategies for neonates with tetralogy of Fallot and pulmonary atresia.

OBJECTIVE: Neonates with tetralogy of Fallot and pulmonary atresia (TOF/PA) but no major aorta-pulmonary collaterals are dependent on the arterial duct for pulmonary blood flow and require early intervention, either by primary (PR) or staged repair (SR) with initial palliation (IP) followed by complete repair (CR). The optimal approach has not been established. METHODS: Neonates with TOF/PA who underwent PR or SR were retrospectively reviewed from the Congenital Cardiac Research Collaborative. Outcomes were compared between PR and SR (IP + CR) strategies. Propensity scoring was used to adjust for baseline differences. The primary outcome was mortality. Secondary outcomes included complications, length of stay, cardiopulmonary bypass and anesthesia times, reintervention (RI), and pulmonary artery (PA) growth. RESULTS: Of 282 neonates, 106 underwent PR and 176 underwent SR (IP: 144 surgical, 32 transcatheter). Patients who underwent SR were more likely to have DiGeorge syndrome and greater rates of mechanical ventilation before the initial intervention. Mortality was not significantly different. Duration of mechanical ventilation, inotrope use, and complication rates were similar. Cumulative length of stay, cardiopulmonary bypass, and anesthesia times favored PR (P ≤ .001). Early RI was more common in patients who underwent SR (rate ratio, 1.42; P = .003) but was similar after CR (P = .837). Conduit size at the time of CR was larger with SR. Right PA growth was greater with PR. CONCLUSIONS: In neonates with TOF/PA, SR is more common in greater-risk patients. Accounting for this, SR and PR strategies have similar mortality. Perioperative morbidities, RI, and right PA growth generally favor PR, whereas SR allows for larger initial conduit implantation.

Implementation of a practice plan for the outpatient cardiac evaluation of children after acute SARS-CoV-2 infection and a report of outcomes.

SARS-CoV-2 infection has been associated with cardiovascular disease in children, but which children need cardiac evaluation is unclear. We describe our experience evaluating 206 children for cardiac disease following SARS-CoV-2 infection (one of whom had ventricular ectopy) and propose a new guideline for management of these children. Routine cardiac screening after SARS-CoV-2 infection in children without any cardiac signs or symptoms does not appear to be high yield.

Copy Number Variants of Undetermined Significance Are Not Associated with Worse Clinical Outcomes in Hypoplastic Left Heart Syndrome.

OBJECTIVE: To determine the prevalence, spectrum, and prognostic significance of copy number variants of undetermined significance (cnVUS) seen on chromosomal microarray (CMA) in neonates with hypoplastic left heart syndrome (HLHS). STUDY DESIGN: Neonates with HLHS who presented to Texas Children's Hospital between June 2008 and December 2016 were identified. CMA results were abstracted and compared against copy number variations (CNVs) in ostensibly healthy individuals gathered from the literature. Findings were classified as normal, consistent with a known genetic disorder, or cnVUS. Survival was then compared using Kaplan-Meier analysis. Secondary outcomes included tracheostomy, feeding tube at discharge, cardiac arrest, and extracorporeal membrane oxygenation (ECMO). RESULTS: Our study cohort comprised 105 neonates with HLHS, including 70 (66.7%) with normal CMA results, 9 (8.6%) with findings consistent with a known genetic disorder, and 26 (24.7%) with a cnVUS. Six of the 26 (23.0%) neonates with a cnVUS had a variant that localized to a specific region of the genome seen in the healthy control population. One-year survival was 84.0% in patients with a cnVUS, 68.3% in those with normal CMA results, and 33.3% in those with a known genetic disorder (P = .003). There were no significant differences in secondary outcomes among the groups, although notably ECMO was used in 15.7% of patients with normal CMA and was not used in those with cnVUS and abnormal results (P = .038). CONCLUSIONS: Among children with HLHS, cnVUSs detected on CMA are common. The cnVUSs do not localize to specific regions of the genome, and are not associated with worse outcomes compared with normal CMA results.

Amino acid-level signal-to-noise analysis of incidentally identified variants in genes associated with long QT syndrome during pediatric whole exome sequencing reflects background genetic noise.

BACKGROUND: Due to rapid expansion of clinical genetic testing, an increasing number of genetic variants of undetermined significance and unclear diagnostic value are being identified in children. Variants found in genes associated with heritable channelopathies, such as long QT syndrome (LQTS), are particularly difficult to interpret given the risk of sudden cardiac death associated with pathologic mutations. OBJECTIVE: The purpose of this study was to determine whether variants in LQTS-associated genes from whole exome sequencing (WES) represent disease-associated biomarkers or background genetic "noise." METHODS: WES variants from Baylor Genetics Laboratories were obtained for 17 LQTS-associated genes. Rare variants from healthy controls were obtained from the GnomAD database. LQTS case variants were extracted from the literature. Amino acid-level mapping and signal-to-noise calculations were conducted. Clinical history and diagnostic studies were analyzed for WES subjects evaluated at our institution. RESULTS: Variants in LQTS case-associated genes were present in 38.3% of 7244 WES probands. There was a similar frequency of variants in the WES and healthy cohorts for LQTS1-3 (11.2% and 12.9%, respectively) and LQTS4-17 (27.1% and 38.4%, respectively). WES variants preferentially localized to amino acids altered in control individuals compared to cases. Based on amino acid-level analysis, WES-identified variants are indistinguishable from healthy background variation, whereas LQTS1 and 2 case-identified variants localized to clear pathologic "hotspots." No individuals who underwent clinical evaluation had clinical suspicion for LQTS. CONCLUSION: The prevalence of incidentally identified LQTS-associated variants is ∼38% among WES tests. These variants most likely represent benign healthy background genetic variation rather than disease-associated mutations.

Interpreting Incidentally Identified Variants in Genes Associated With Catecholaminergic Polymorphic Ventricular Tachycardia in a Large Cohort of Clinical Whole-Exome Genetic Test Referrals.

BACKGROUND: The rapid expansion of genetic testing has led to increased utilization of clinical whole-exome sequencing (WES). Clinicians and genetic researchers are being faced with assessing risk of disease vulnerability from incidentally identified genetic variants which is typified by variants found in genes associated with sudden death-predisposing catecholaminergic polymorphic ventricular tachycardia (CPVT). We sought to determine whether incidentally identified variants in genes associated with CPVT from WES clinical testing represent disease-associated biomarkers. METHODS AND RESULTS: CPVT-associated genes RYR2 and CASQ2 variants were identified in one of the world's largest collections of clinical WES referral tests (N=6517, Baylor Miraca Genetics Laboratories) and compared with a control cohort of ostensibly healthy individuals (N=60 706) and a case cohort of CPVT cases (N=155). Within the WES cohort, the rate of rare variants in CPVT-associated genes was 8.8% compared with 6.0% among controls and 60.0% among cases. There was a predominance of variants of undetermined significance (97.7%). After protein topology mapping, WES variants colocalized more frequently to residues with variants found in controls compared with cases. Retrospective clinical evaluation of individuals referred to our institution with WES-positive variants demonstrated no evidence of clinical CPVT in individuals with a low pretest clinical suspicion for CPVT. CONCLUSIONS: The prevalence of incidentally identified CPVT-associated variants is ≈9% among WES tests. Variants of undetermined significances in CPVT-associated genes in WES genetic testing, in the absence of clinical suspicion for CPVT, are unlikely to represent markers of CPVT pathogenicity.