An Optimized Diagnostic Approach for Adults With Suspected Inherited Metabolic Disorders

Abstract

Inherited metabolic disorders (IMDs) arise from defects in metabolic pathways essential for normal biochemical function. Although the pathogenic genetic variants are present at birth, clinical manifestations may not emerge until adolescence or adulthood. Symptoms may be more subtle compared to those of childhood onset IMDs and may have overlap with signs and symptoms of acquired disorders. This makes diagnosing IMDs in adulthood challenging. To identify how routine diagnostic care for adults suspected of having an IMD could be improved, we conducted a reanalysis study in a cohort of 31 adult participants. The participants, who remained undiagnosed after standard diagnostic care, were seen by a clinical geneticist, adult metabolic specialist and neurologist for deep phenotyping and data collection. Subsequently, exome sequencing data were reanalyzed and possible disease‐causing variants were prioritized for further evaluation by a multidisciplinary team including both clinicians and geneticists (biochemical and molecular). This approach led to a (partial) diagnosis for nine participants from six families, giving a 25% diagnostic yield. We could distinguish four possible reasons why the identified disease‐associated variants were not detected during routine diagnostic care. Beyond the expected impact of technical advancements and emerging knowledge of disease genes, we found that the most impactful factor was of organizational nature. Our findings underscore the value of reviewing all strong genetic variants within a multidisciplinary team setting, facilitating a bidirectional exchange of expertise. This approach enhances diagnostic accuracy, particularly when the underlying cause of the disease is not immediately apparent.