Laboratory diagnosis of disorders of peroxisomal biogenesis and function: a technical standard of the American College of Medical Genetics and Genomics (ACMG)

Peroxisomal disorders are a clinically and genetically heterogeneousgroup of diseases caused by defects in peroxisomal biogenesis or function, usuallyimpairing several metabolic pathways. Peroxisomal disorders are rare; however, theincidence may be underestimated due to the broad spectrum of clinical presentations.The inclusion of X-linked adrenoleukodystrophy to the Recommended Uniform ScreeningPanel for newborn screening programs in the United States may increase detection ofthis and other peroxisomal disorders. The current diagnostic approach relies heavilyon biochemical genetic tests measuring peroxisomal metabolites, including verylong–chain and branched-chain fatty acids in plasma and plasmalogens in red bloodcells. Molecular testing can confirm biochemical findings and identify the specificgenetic defect, usually utilizing a multiple-gene panel or exome/genome approach.When next-generation sequencing is used as a first-tier test, evaluation ofperoxisome metabolism is often necessary to assess the significance of unknownvariants and establish the extent of peroxisome dysfunction. This document providesa resource for laboratories developing and implementing clinical biochemical genetictesting for peroxisomal disorders, emphasizing technical considerations for samplecollection, test performance, and result interpretation. Additionally,considerations on confirmatory molecular testing are discussed.