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 CPVT. We sought to determine whether incidentally identified variants in genes associated with catecholaminergic polymorphic ventricular tachycardia (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 to 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 to 6.0% among controls and 60.0% among cases. There was a predominance of variants of undetermined significance (VUS, 97.7%). Following protein topology mapping, WES variants colocalized more frequently to residues with variants found in controls compared to 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 pre-test clinical suspicion for CPVT.
Conclusions
The prevalence of incidentally CPVT-associated variants is ~9% among WES tests. VUSs in CPVT-associated genes in WES genetic testing, in the absence of clinical suspicion for CPVT, are unlikely to represent markers of CPVT pathogenicity.
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.
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.
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ARS-CoV-2 infection has been associated with cardiovascular disease in children, but which children need cardiac evaluation is unclear
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We describe our experience evaluating 206 children for cardiac disease following
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ARS-CoV-2 infection (one of whom had ventricular ectopy) and propose a new guideline for management of these children. Routine cardiac screening after
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ARS-CoV-2 infection in children without any cardiac signs or symptoms does not appear to be high yield.
Introduction:
Neonates with tetralogy of Fallot and pulmonary atresia (TOF/PA) with pulmonary blood flow supplied by the ductus arteriosus require early intervention. This may be accomplished by: initial palliation (IP) followed by complete repair (CR) or initial primary repair (PR). The optimal approach for patients with TOF/PA has not been established.
Methods:
Neonates with TOF/PA who underwent IP or PR from 2005-17 were retrospectively reviewed from the Congenital Catheterization Research Collaborative. The primary outcome was mortality. Outcomes were compared as IP vs PR and IP+CR vs PR. Secondary outcomes included hospital and procedural complications and are listed in table 1. Propensity scoring was used to adjust for baseline differences between strategies.
Results:
Of 282 neonates with TOF/PA, 106 underwent PR and 176 underwent IP (144 surgical, 32 transcatheter). Prior to initial intervention, IP patients had higher rates of mechanical ventilation (83.9% vs 72.2%, p=0.023) and DiGeorge syndrome (14.77% vs 4.72%, p=0.009). Mortality was greater in the IP cohort (HR 2.7, 95% CI 1.02 - 7.1, p = 0.046), with no mortality in the PR cohort after 6 months post-repair. After adjustment, differences in survival were no longer significant (HR 1.4, 95% CI 0.7 - 3.1, p=0.39). Both cohorts had similar mechanical ventilation duration and inotrope use as well as procedural and hospital complications. Intensive care and hospital length of stay, cardiac bypass (CPB) and anesthesia time favored PR when compared to IP+CR (p=<0.001). Early reintervention was more common in patients undergoing IP (rate ratio 1.42, p 0.003), but post-complete repair rates were similar (p=0.837).
Conclusions:
In neonates with TOF/PA, the IP approach is more often utilized in higher-risk patients. Accounting for this difference, IP and PR strategies have similar adjusted survival rates. Perioperative morbidities and lower risk for reintervention generally favor PR.
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