Background: Variant interpretation can change over time as new knowledge emerges. Our aim was to determine the frequency and causes of variant reinterpretation on systematic reevaluation in pediatric patients with cardiomyopathy. Methods: Overall, 227 unrelated pediatric patients with cardiomyopathy enrolled in the Heart Centre Biobank harbored a pathogenic/likely pathogenic (P/LP) variant or a variant of uncertain significance (VUS) on clinical genetic testing (2005–2022). Variant pathogenicity was reevaluated using the American College of Medical Genetics and Genomics guidelines. Additional extension cohorts (n=4547, cases) were analyzed to assess variant burden in cases versus controls (gnomAD 4.1.0). Results: A total of 382 variants (110 P/LP, 272 VUS) in 227 patients were reevaluated. Forty‐nine variants in 49 patients (21.6%) changed classification. Twelve (10.9%) P/LP variants were downgraded to VUS in 14 patients. Leading criteria were high population allele frequency and variant not located in mutational hotspot or critical functional gene domain. Thirty‐seven (13.6%) VUS were upgraded to P/LP in 35 patients. Leading criteria were variant location in mutational hotspot for gene and deleteriousness on in silico prediction. Only 8 reclassified variants had been reported back by the clinical genetic testing laboratory at the time of the study. Ten of the 37 VUS upgraded to P/LP were significantly enriched in cardiomyopathy cases (n=4796) versus controls. Conclusions: One in 5 patients with cardiomyopathy had a clinically relevant change in variant pathogenicity on systematic reevaluation that would require modifying family clinical screening and cascade genetic testing. These findings underscore the clinical importance of regular variant reinterpretation on follow‐up.

Purpose: Atlantoaxial rotatory fixation (AARF) is a rare complication of acute Kawasaki disease (KD). Early diagnosis and intervention are important for AARF because delayed diagnoses may incur neurological sequelae. However, previous studies on AARF associated with KD are limited, and its clinical characteristics and course are unknown. This study aimed to examine the clinical features and treatment course of KD with AARF using a Japanese national inpatient database. Methods: Using the Diagnosis Procedure Combination database, we identified KD patients who received intravenous immunoglobulin (IVIG) treatment between July 2010 and March 2020. The clinical characteristics of KD patients with AARF and their risk factors were evaluated using multivariable logistic regression analysis. We also examined the relationship between AARF, the proportion of coronary artery abnormalities (CAAs), IVIG resistance, length of stay and medical costs. Results: We identified 71,913 patients with KD, 166 of whom had AARF. The AARF group had older age, heavier bodyweight and atypical KD. In multivariable analysis, AARF was associated with older age [odds ratio (OR): 1.24; 95% confidence interval (CI): 1.19–1.29], lower body mass index (OR: 0.89; 95% CI: 0.82–0.96) and atypical KD (OR: 1.95; 95% CI: 1.12–3.40). AARF was not associated with CAAs (OR: 0.73; 95% CI, 0.23–2.32) and IVIG resistance (OR: 1.05; 95% CI, 0.74–1.49). However, AARF was associated with higher medical costs (difference, US$1064; 95% CI: 346–1781) and longer hospital stay (difference, 3.1 days; 95% CI: 1.7–4.4). Conclusion: AARF in patients with acute KD should be considered if cervical symptoms present in older patients with atypical KD.