LAUSR

A rare disease (RD) is defined as a disorder affecting fewer than 1 in 2,000 people (European Union, 2000). Although each is rare, they cumulatively involve greater than 300 million people worldwide (Nguengang Wakap et al., 2020). There are approximately 7,000 RDs reported by the Online Mendelian Inheritance in Man (OMIM) database, and 6,172 unique RDs by Orphanet, 70% of whom have childhood onset (Amberger et al., 2015; Nguengang Wakap et al., 2020). One of the many challenges that persons living with an RD and their families face is the search for a diagnosis. Given their rarity, large number of disease entities and heterogeneous manifestation, patients often remain undiagnosed or misdiagnosed for years. The correct diagnosis has enormous implications for the patient and their family; it offers insight into the disease cause, natural history, and prognosis. It can facilitate contact with support groups and provides families with informed genetic counselling. Moreover, it can increase the understanding of the disease pathogenesis and thus improve therapeutic strategies. More than 70% of RDs are genetic in origin (Nguengang Wakap et al., 2020). In the last decade, next-generation sequencing (NGS) technologies such as whole-exome sequencing (WES) and whole-genome sequencing (WGS) have enabled the identification of disease-causing variants in RDs. The diagnostic yields of NGS in RDs varies (24–68%) depending on the technology employed, the disease group studied, the patient age groups, clinical indications, family structures and variant types analysed (Clark et al., 2018). Genome test interpretation and reporting represents one of the challenges to laboratories seeking to implement or maximize the diagnostic yield of NGS, OPEN ACCESS