Diagnostic strategies in patients with undiagnosed and rare diseases

Abstract Rare diseases are life-threatening or chronically debilitating conditions affecting millions of people worldwide. In many instances, the patients experience a delay in their diagnosis or remain undiagnosed despite extensive investigations carried out by specialists. There are several explanations to account for this phenomenon including the socioeconomic context and the lack of an established consensus for diagnostic testing. Nonetheless, the widespread use of genetic and genomic tests in the past decades has had a major impact on clinical reasoning paradigms, and new troves of data are constantly being generated and analyzed. This requires constantly updating tools to match the discovery rate and allow reanalysis. In this review, we summarize the latest international recommendations and guidelines to address the problem of diagnostic deficit as well as present the current diagnostic workflows. Increasing access to exome and genome sequencing technologies and biological validation, gaining insight into the interpretation of multi-omics datasets, and fostering data sharing would reduce the long diagnostic odyssey and diagnostic gap.