Tetralogy of Fallot (TOF), the most common severe congenital heart malformation, occurs sporadically, without other anomaly, and from unknown cause in 70% of cases. A genome-wide survey of 114 TOF patients and their unaffected parents identified 11 de novo copy number variants (CNVs) that were absent or extremely rare (<0.1%) in 2,265 controls. A second, independent TOF cohort (n = 398) was then examined for additional CNVs at these loci. In 1% (5/512, p = 0.0002, OR = 22.3) of non-syndromic sporadic TOF cases we identified CNVs at chromosome 1q21.1. Recurrent CNVs were also identified at 3p25.1, 7p21.3 and 22q11.2. CNVs in a single TOF case occurred at six loci, two that encode known (NOTCH1, JAG1) disease genes. Our data predicts that at least 10% (4.5–15.5, 95% CI) of sporadic, non-syndromic TOF reflects de novo CNVs and implicates mutations within these loci as etiologic in other cases of TOF.

Exome and whole genome sequencing (ES/WGS) offer potential advantages over traditional approaches to diagnostic genetic testing. Consequently, use of ES/WGS in clinical settings is rapidly becoming commonplace. Yet there are myriad moral, ethical, and perhaps legal implications attached to the use of ES and health care professionals and institutions will need to consider these implications in the context of the varied practices and policies of ES service providers. We developed "core elements" of content and procedures for informed consent, data sharing, and results management and a quantitative scale to assess the extent to which research protocols met the standards established by these core elements. We then used these tools to evaluate the practices and policies of each of the 6 U.S. CLIA-certified labs offering clinical ES. Approaches toward informed consent, data sharing, and results return vary widely among ES providers as do the overall potential merits and disadvantages of each, and more importantly, the balance between the two.

Context.-Tests that are performed outside of the ordering institution, send-out tests, represent an area of risk to patients because of complexity associated with sending tests out. Risks related to send-out tests include increased number of handoffs, ordering the wrong or unnecessary test, specimen delays, data entry errors, preventable delays in reporting and acknowledging results, and excess financial liability. Many of the most expensive and most misunderstood tests are send-out genetic tests.Objective.-To design and develop an active utilization management program to reduce the risk to patients and improve value of genetic send-out tests.Design.-Send-out test requests that met defined criteria were reviewed by a rotating team of doctoral-level consultants and a genetic counselor in a pediatric tertiary care center.Results.-Two hundred fifty-one cases were reviewed during an 8-month period. After review, nearly onequarter of genetic test requests were modified in the downward direction, saving a total of 2% of the entire send-out bill and 19% of the test requests under management. Ultimately, these savings were passed on to patients.Conclusions.-Implementing an active utilization strategy for expensive send-out tests can be achieved with minimal technical resources and results in improved value of testing to patients.