Early genetic testing in pediatric epilepsy: Diagnostic and cost implications.

The identification of numerous genetically based epilepsies has resulted in the widespread use of genetic testing to inform epilepsy etiology. Our study aims to investigate whether a difference exists in the diagnostic evaluation and healthcare-related cost expenditures of pediatric patients with epilepsy of unknown etiology who receive a genetic diagnosis through multigene epilepsy panel (MEP) testing and comparing those who underwent early (EGT) versus late genetic testing (LGT). Testing was defined as early (less than 1 year), or late (more than 1 year), following clinical epilepsy diagnosis. A retrospective chart review of pediatric individuals (1-17 years) with epilepsy of unknown etiology who underwent multigene epilepsy panel (MEP) testing identified 28 of 226 (12%) individuals with a pathogenic epilepsy variant [EGT n = 8 (29%); LGT n = 20 (71%)]. The average time from clinical epilepsy diagnosis to genetic diagnosis was 0.25 years (EGT), compared with 7.1 years (LGT). The EGT cohort underwent fewer metabolic tests [EGT n = 0 (0%); LGT n = 16 (80%) (P < 0.01)] and invasive procedures [EGT n = 0 (0%); LGT n = 5 (25%) (P = 0.06)]. Clinical management changes implemented due to genetic diagnosis occurred in 10 (36%) patients [EGT n = 2 (25%); LGT n = 8 (40%) (P = 0.76)]. Early genetic testing with a MEP in pediatric patients with epilepsy of unknown etiology who receive a genetic diagnosis is associated with fewer non-diagnostic tests and invasive procedures and reduced estimated overall healthcare-related costs. PLAIN LANGUAGE SUMMARY: This study aims to investigate whether a difference exists in the diagnostic evaluation and cost expenditures of pediatric patients (1-17 years) with epilepsy of unknown cause who are ultimately diagnosed with a genetic cause of epilepsy through multigene epilepsy panel testing and comparing those who underwent early testing (less than 1 year) versus late testing (more than 1 year) after clinical epilepsy diagnosis. Of the 28 of 226 individuals with a confirmed genetic cause of epilepsy on multigene epilepsy panel testing, performing early testing was associated with fewer non-diagnostic tests, fewer invasive procedures and reduced estimated overall healthcare-related costs.

Assessment of the Diagnostic Yield of Combined Cardiomyopathy and Arrhythmia Genetic Testing.

Importance: Genetic testing can guide management of both cardiomyopathies and arrhythmias, but cost, yield, and uncertain results can be barriers to its use. It is unknown whether combined disease testing can improve diagnostic yield and clinical utility for patients with a suspected genetic cardiomyopathy or arrhythmia. Objective: To evaluate the diagnostic yield and clinical management implications of combined cardiomyopathy and arrhythmia genetic testing through a no-charge, sponsored program for patients with a suspected genetic cardiomyopathy or arrhythmia. Design, Setting, and Participants: This cohort study involved a retrospective review of DNA sequencing results for cardiomyopathy- and arrhythmia-associated genes. The study included 4782 patients with a suspected genetic cardiomyopathy or arrhythmia who were referred for genetic testing by 1203 clinicians; all patients participated in a no-charge, sponsored genetic testing program for cases of suspected genetic cardiomyopathy and arrhythmia at a single testing site from July 12, 2019, through July 9, 2020. Main Outcomes and Measures: Positive gene findings from combined cardiomyopathy and arrhythmia testing were compared with findings from smaller subtype-specific gene panels and clinician-provided diagnoses. Results: Among 4782 patients (mean [SD] age, 40.5 [21.3] years; 2551 male [53.3%]) who received genetic testing, 39 patients (0.8%) were Ashkenazi Jewish, 113 (2.4%) were Asian, 571 (11.9%) were Black or African American, 375 (7.8%) were Hispanic, 2866 (59.9%) were White, 240 (5.0%) were of multiple races and/or ethnicities, 138 (2.9%) were of other races and/or ethnicities, and 440 (9.2%) were of unknown race and/or ethnicity. A positive result (molecular diagnosis) was confirmed in 954 of 4782 patients (19.9%). Of those, 630 patients with positive results (66.0%) had the potential to inform clinical management associated with adverse clinical outcomes, increased arrhythmia risk, or targeted therapies. Combined cardiomyopathy and arrhythmia gene panel testing identified clinically relevant variants for 1 in 5 patients suspected of having a genetic cardiomyopathy or arrhythmia. If only patients with a high suspicion of genetic cardiomyopathy or arrhythmia had been tested, at least 137 positive results (14.4%) would have been missed. If testing had been restricted to panels associated with the clinician-provided diagnostic indications, 75 of 689 positive results (10.9%) would have been missed; 27 of 75 findings (36.0%) gained through combined testing involved a cardiomyopathy indication with an arrhythmia genetic finding or vice versa. Cascade testing of family members yielded 402 of 958 positive results (42.0%). Overall, 2446 of 4782 patients (51.2%) had only variants of uncertain significance. Patients referred for arrhythmogenic cardiomyopathy had the lowest rate of variants of uncertain significance (81 of 176 patients [46.0%]), and patients referred for catecholaminergic polymorphic ventricular tachycardia had the highest rate (48 of 76 patients [63.2%]). Conclusions and Relevance: In this study, comprehensive genetic testing for cardiomyopathies and arrhythmias revealed diagnoses that would have been missed by disease-specific testing. In addition, comprehensive testing provided diagnostic and prognostic information that could have potentially changed management and monitoring strategies for patients and their family members. These results suggest that this improved diagnostic yield may outweigh the burden of uncertain results.

Underdiagnosis of Hereditary Colorectal Cancers Among Medicare Patients: Genetic Testing Criteria for Lynch Syndrome Miss the Mark.

PURPOSE: Strict clinical criteria used by Medicare for germline testing for Lynch syndrome (LS) could lead to missed diagnoses of hereditary cancer syndromes given variable individual and family phenotypes. The aim of this study was to compare rates and spectrum of pathogenic or likely pathogenic (P/LP) variants in LS and other hereditary cancer genes on the basis of meeting Medicare LS testing criteria. METHODS: Retrospective review of Medicare beneficiaries who had multigene panel testing with an indication of personal or family history of colorectal cancer (CRC) was performed. Ordering providers determined if Medicare LS criteria were met. The results of genetic testing were compared on the basis of whether or not Medicare testing criteria were met. RESULTS: Among 639 Medicare beneficiaries, 495 (77.5%) met testing criteria. Overall rates of P/LP variant identification were similar between those meeting and not meeting testing criteria (18.4% v 11.8%; P = .06). LS was diagnosed more frequently among those meeting testing criteria (10.1% v 4.9%; P = .05). No statistical differences were found in rates of P/LP variant identification for non-LS CRC genes (5.3% v 5.6%; P = .89) or non-CRC genes (4.2% v 2.1%; P = .23). PMS2, MUTYH, and ATM P/LP variants were found at higher rates among those outside of criteria. CONCLUSION: Among Medicare beneficiaries undergoing genetic testing for suspected LS, rates of P/LP variants in actionable cancer genes were similar regardless of whether testing criteria were met. Current testing criteria fail to identify individuals with P/LP variants in PMS2 and other actionable cancer genes. Relaxing LS testing criteria could improve identification of individuals with hereditary cancer syndromes among Medicare beneficiaries.