P.76 Gene variant and neuromuscular findings from a long-chain fatty acid oxidation disorder gene panel program

Abstract

Long-chain fatty acid oxidation disorders (LC-FAOD) are rare, life-threatening, autosomal recessive conditions that can be diagnosed clinically with plasma acylcarnitine analysis and molecular testing. Undiagnosed LC-FAOD may present with hypoglycemia, cardiomyopathy, cardiac arrhythmias, and neuromuscular symptoms. Patients with a clinical diagnosis or suspicion of LC-FAOD are eligible for this no-charge, next-generation sequencing gene panel which includes 6 genes associated with LC-FAOD plus 18 genes associated with disorders that cause abnormal acylcarnitine profiles. As of 28 October 2021, LC-FAOD gene variants were identified in 153 (37%) of 417 patients tested, including 83 variants of uncertain significance (VUS), 8 likely pathogenic (LP), and 102 pathogenic (P) variants. Twenty-three patients had positive (2 P/LP) LC-FAOD results and 19 had potential positive (2 variants, at least 1 VUS) results. VUS resolution analysis led to the reclassification of 6 variants from VUS to LP or P. Five patients had variants in two or more LC-FAOD genes and 22 had variants in one LC-FAOD gene and one or more non-LC-FAOD genes. Fifty-one patients had only one LC-FAOD gene variant identified. The most common neuromuscular symptoms among patients ages ≥13 (76 reported) were myopathy (42), elevated creatine kinase (36), and rhabdomyolysis (30), and among patients <13 years (83 reported) were elevated creatine kinase (22), and myopathy (12). Program results demonstrate the diverse composition of gene variants in patients referred for LC-FAOD genetic testing. Approaches to resolve VUS and identify previously undetected variants in patients with suspected LC-FAOD are important and necessary.