Pre-selection of the correct genetic diagnostic method according to the presumed underlying mutational mechanism has been key in current ataxia routine diagnostics: short-tandem repeat-expansions (STRs) are missed by standard next-generation sequencing (NGS) panel-based approaches; and while exome sequencing (ES)-based STR analyses are now being considered standard for clinical routine, they still show only moderate specificity for exonic STRs and—by design—fail almost completely for most of the intronic STRs in ataxias. This pre-selection of genetic diagnostics, e.g. direct fragment length analysis for FA, however, is led by clinical suspicion based on the main clinical phenotype and additional relevant information (such as e.g. the supposed inheritance mode). However, this pre-selection is vulnerable to bias. By a series of three distinct cases of atypical FA, the authors here showcase how the introduction of short-read genome sequencing (SR-GS) allows to overcome these biases in the work-up of complex ataxias, as it allows to detect even intronic STRs (i) “en route”, i.e. with detection not requiring any primary direct gene analysis; and (ii) in a phenotype-independent fashion”, i.e. also for those atypical phenotypic presentations where the corresponding gene and mutational mechanism had not been part of the prior differential clinical diagnosis. 

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