Robert M. Gow

An accurate diagnosis is an integral component of patient care for children with rare genetic disease. Recent advances in sequencing, in particular whole-exome sequencing (WES), are identifying the genetic basis of disease for 25-40% of patients. The diagnostic rate is probably influenced by when in the diagnostic process WES is used. The Finding Of Rare Disease GEnes (FORGE) Canada project was a nation-wide effort to identify mutations for childhood-onset disorders using WES. Most children enrolled in the FORGE project were toward the end of the diagnostic odyssey. The two primary outcomes of FORGE were novel gene discovery and the identification of mutations in genes known to cause disease. In the latter instance, WES identified mutations in known disease genes for 105 of 362 families studied (29%), thereby informing the impact of WES in the setting of the diagnostic odyssey. Our analysis of this dataset showed that these known disease genes were not identified prior to WES enrollment for two key reasons: genetic heterogeneity associated with a clinical diagnosis and atypical presentation of known, clinically recognized diseases. What is becoming increasingly clear is that WES will be paradigm altering for patients and families with rare genetic diseases.

BACKGROUND: Myocardial bridging may cause compression of a coronary artery, and it has been suggested that myocardial ischemia may result. The clinical significance and prognostic value of myocardial bridging of the left anterior descending coronary artery in children with hypertrophic cardiomyopathy are unknown. We sought to determine the prevalence and clinical effects of myocardial bridging in children with hypertrophic cardiomyopathy who underwent cardiac catheterization. METHODS: Angiograms from 36 children with hypertrophic cardiomyopathy were reviewed to determine whether myocardial bridging was present and, if so, to assess the characteristics of systolic narrowing of the left anterior descending coronary artery caused by myocardial bridging and the duration of residual diastolic compression. We also reviewed clinical data on these patients. RESULTS: Myocardial bridging was present in 10 (28 percent) of the patients. Compression of the left anterior descending coronary artery persisted for a mean (+/-SD) of 50+/-17 percent of diastole. As compared with patients without bridging, patients with bridging had a greater incidence of chest pain (60 percent vs. 19 percent, P=0.04), cardiac arrest with subsequent resuscitation (50 percent vs. 4 percent, P=0.004), and ventricular tachycardia (80 percent vs. 8 percent, P<0.001). On average, the patients with bridging had a reduction in systolic blood pressure with exercise of 17+/-27 mm Hg, as compared with an elevation of 43+/-31 mm Hg in those without bridging (P<0.001). The patients with bridging also had greater ST-segment depression with exercise (median, 5 vs. 0 mm, P=0.004) and a shorter duration of exercise (mean, 6.6+/-2.4 vs. 9.1+/-1.4 minutes, P=0.008). The degree of dispersion of the QT interval corrected for heart rate on the electrocardiogram was greater in patients with bridging than in those without bridging (104+/-46 vs. 48+/-31 msec, P=0.002). Kaplan-Meier estimates of the proportions of patients who had not died or had cardiac arrest with subsequent resuscitation five years after the diagnosis of hypertrophic cardiomyopathy were 67 percent among patients with bridging and 94 percent among those without bridging (P=0.004). CONCLUSIONS: Myocardial bridging is associated with a poor outcome in children with hypertrophic cardiomyopathy. Our observations suggest that bridging is associated with myocardial ischemia