Genetic testing is routinely performed on infants with critical congenital heart disease (CHD). This project reviewed the effect of implementing a genetic testing protocol in this population. Charts of infants with critical CHD were reviewed for genetic testing and results across two time periods: the time before implementation of a genetic testing protocol (pre-protocol) and the time after implementation (post-protocol). The use of karyotype, 22q11.2 Deletion testing, and chromosomal microarray were compared across these two time periods. Records of 891 infants were reviewed. 562 (63%) had at least one of the target genetic tests completed. During the pre-protocol time period, 66% of patients who had genetic testing underwent multiple tests versus 24% during the post-protocol time period (p < 0.01). The rate of patients who underwent genetic testing increased from 60% in the pre-protocol time period to 77% in the post-protocol time period (p < 0.01). The rate of diagnosis of genetic conditions during the pre-protocol period was 26% versus 36% during the post-protocol period (p = 0.01). There was a reduction in cost to patients by $5105.59 per diagnosis during the post-protocol period. Patients with critical CHD in the post-protocol period were less likely to undergo multiple genetic tests and more likely to have a diagnosis of genetic disease. In addition there was a significant reduction in cost per diagnosis during the post-protocol time period. Genetic testing protocols for infants with critical CHD promoted more efficient use of genetic testing and increased the rate of diagnosis of genetic conditions in this population.
Studies of mitochondrial redox signaling predict that the colonial hydroids Eirene viridula and Podocoryna carnea should respond to manipulations of reactive oxygen species (ROS). Both species encrust surfaces with feeding polyps connected by networks of stolons; P. carnea is more 'sheet-like' with closely spaced polyps and short stolons, while E. viridula is more 'runner-like' with widely spaced polyps and long stolons. Treatment with the chemical antioxidant vitamin C diminishes ROS in mitochondrion-rich epitheliomuscular cells (EMCs) and produces phenotypic effects (sheet-like growth) similar to uncouplers of oxidative phosphorylation. In peripheral stolon tips, treatment with vitamin C triggers a dramatic increase of ROS that is followed by tissue death and stolon regression. The enzymatic anti-oxidant catalase is probably not taken up by the colony but, rather, converts hydrogen peroxide in the medium to water and oxygen. Exogenous catalase does not affect ROS in mitochondrion-rich EMCs, but does increase the amounts of ROS emitted from peripheral stolons, resulting in rapid, runner-like growth. Treatment with exogenous hydrogen peroxide increases ROS levels in stolon tips and results in somewhat faster colony growth. Finally, untreated colonies of E. viridula exhibit higher levels of ROS in stolon tips than untreated colonies of P. carnea. ROS may participate in a number of putative signaling pathways: (1) high levels of ROS may trigger cell and tissue death in peripheral stolon tips; (2) more moderate levels of ROS in stolon tips may trigger outward growth, inhibit branching and, possibly, mediate the redox signaling of mitochondrion-rich EMCs; and (3) ROS may have an extra-colony function, perhaps in suppressing the growth of bacteria.
Restrictive cardiomyopathy (RCM) is a rare and distinct form of cardiomyopathy characterized by normal ventricular chamber dimensions, normal myocardial wall thickness, and preserved systolic function. The abnormal myocardium, however, demonstrates impaired relaxation. To date, dominant variants causing RCM have been reported in a small number of sarcomeric or cytoskeletal genes, but the genetic causes in a majority of cases remain unexplained, especially in early childhood. Here, we describe two RCM families with childhood onset: one in a large family with a history of autosomal dominant RCM and the other a family with affected monozygotic, dichorionic/diamniotic twins. Exome sequencing found a pathogenic filamin C (FLNC) variant in each: p.Pro2298Leu, which segregates with disease in the large autosomal dominant RCM family, and p.Tyr2563Cys in both affected twins. In vitro expression of both mutant proteins yielded aggregates of FLNC containing actin in C2C12 myoblast cells. Recently, a number of variants in FLNC have been described that cause hypertrophic, dilated, and restrictive cardiomyopathies. Our data presented here provide further evidence for the role of FLNC in pediatric RCM, and suggest the need to include FLNC in genetic testing of cardiomyopathy patients including those with early ages of onset.
SUMMARYAs with many colonial animals, hydractiniid hydroids display a range of morphological variation. Sheet-like forms exhibit feeding polyps close together with short connecting stolons, whereas runner-like forms have more distant polyps and longer connecting stolons. These morphological patterns are thought to derive from rates of stolon growth and polyp formation. Here, stolon regression is identified and characterized as a potential process underlying this variation. Typically, regression can be observed in a few stolons of a normally growing colony. For detailed studies, many stolons of a colony can be induced to regress by pharmacological manipulations of reactive oxygen species (e.g. hydrogen peroxide) or reactive nitrogen species (e.g. nitric oxide). The regression process begins with a cessation of gastrovascular flow to the distal part of the stolon. High levels of endogenous H 2 O 2 and NO then accumulate in the regressing stolon. Remarkably, exogenous treatments with either H 2 O 2 or an NO donor equivalently trigger endogenous formation of both H 2 O 2 and NO. Cell death during regression is suggested by both morphological features, detected by transmission electron microscopy, and DNA fragmentation, detected by TUNEL. Stolon regression may occur when colonies detect environmental signals that favor continued growth in the same location rather than outward growth.
Standard assessment of patients with CHD, including adult survivors, is indicated. The best first-line genetic assessment for most patients with CHD is a chromosomal microarray, and this will soon evolve to be genomic sequencing with copy number variant analysis. Due to lack of medical geneticists, creative solutions to maximize the number of patients with CHD who undergo assessment with standard protocols and plans for support with result interpretation need to be explored.
Heterotaxy (HTX) is a laterality defect resulting in abnormal arrangement of the thoracic and abdominal organs across the right-left axis, and is associated with multiple anatomic and physiologic disruptions. HTX often occurs in association with complex congenital heart disease. Splenic abnormalities are also common and convey an increased risk of bacteremia (bacteremia) with a high associated mortality. We performed a systematic review of the literature studying the risk of infection in HTX patients and strategies that can be utilized to prevent such infections. Studies were identified for inclusion using PubMed, EMBASE, and OVID, as well as hand search of references from previously identified papers. Published studies specifically investigating bacteremia in HTX were identified and included as long as they were in English. Data were extracted by two separate authors independently with review of any findings that differed between the two authors. There were 42 documented cases of bacteremia in 32 patients. Approximately, 79% of these had absence of a spleen. The average age of bacteremia was 17 months. HTX patients are at high risk for bacteremia leading to mortality, regardless of anatomic splenic type. We propose strategies for the evaluation of splenic function in HTX patients, and review management practices to reduce the impact of infection risk in the HTX population.
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