Researchers from Germany demonstrated that short-read genome sequencing (SR-GS) could be useful to identify cases of atypical Friedreich ataxia (FA).

“Our findings demonstrate that SR-GS allows to identify ataxia subjects with biallelic GAA expansions in FXN, where FA had not been part of the initial differential diagnosis, despite the fact that they were seen by ataxia experts with > 10 years of genetics ataxia experience,” the study’s authors said.

In a letter to the editor published in the Journal of Neurology, the researchers explained that SR-GS could detect even intronic short-tandem repeat-expansions “en route,” that is, without requiring any primary direct gene analysis, and in a phenotype- and family history-independent way.

The conclusion was drawn from the analysis of a series of 3 distinct cases of FA presenting with atypical phenotype and atypical age of onset.

Read more about FA etiology

SR-GS identified a biallelic intronic FXN repeat expansion in the 3 subjects. The exact lengths of the alleles were subsequently confirmed by classical fragment length analysis and long range polymerase chain reaction, confirming the diagnosis of FA.

All subjects experienced late disease onset (older than 40 years) and had prominent pyramidal tract symptoms, rather than the typical afferent ataxia. Moreover, they did not show other typical neurological and non-neurological signs and symptoms of the disease, such as absent Achilles tendon reflexes, Babinski sign, scoliosis, pes cavus, or hypertrophic cardiomyopathy.

In addition, 2 subjects had misleading family history that suggested a different mode of inheritance.

Prior to SR-GS, genetic studies using standard next-generation sequencing panel-based approaches or exome sequencing-based short-tandem repeat-expansion analyses have suggested other diagnoses as the identification of strong variants in other genes could explain the phenotype.

For instance, 1 subject had a variant of unknown significance in the PLEKHG4 gene, which had been associated with an autosomal-dominant form of cerebellar ataxia. The same variant was detected in his father who also presented with gait impairment and, therefore, it was considered disease causing.

Such genetic studies failed to identify FA because the identification of FXN repeats requires specific and direct analysis of fragment length.


Fleszar Z, Dufke C, Sturm M, et al. Short-read genome sequencing allows ‘en route’ diagnosis of patients with atypical Friedreich ataxia. J Neurol. Published online April 29, 2023. doi:10.1007/s00415-023-11745-8