It’s well known that FXN variants cause Friedreich’s ataxia – a progressive form of ataxia that usually affects individuals before 25 years of age1. Because Friedreich’s ataxia is a recessive disorder, both alleles must be affected.
It’s also well known that the most frequent form of variation is an abnormally expanded GAA repeat. In the vast majority of Friedreich’s ataxia cases, both alleles contain a repeat expansion. But in certain cases, the affected individual is compound heterozygous for a repeat expansion on one allele and a different pathogenic variant within the FXN gene on the other allele.
Recently, we worked on just such a case.
We received an order for testing for a 17 year old male presenting with clinical symptoms consistent with a motor neuropathy. His diagnostic journey began at age five when he was first evaluated for leg pain. By age 12 he was showing evidence of an abnormal gate, heavy footprint, muscle weakness and foot drop. A further decrease in muscle strength was observed at age 14 and EMG/NCV studies at age 15 suggested a demyelinating sensory motor neuropathy.
The patient had undergone extensive previous genetic testing including three separate comprehensive panel tests for Charcot-Marie-Tooth, hereditary spastic paraplegia and neuropathies.
Our whole genome-based testing methodology determined that the patient was compound heterozygous for an FXN GAA repeat expansion on one allele and a pathogenic FXN sequence variant on the other allele.
Of note, orthogonal testing of the heterozygous repeat expansion using traditional Southern blot methodology failed confirmation by the first outside lab the sample was sent to. Upon closer examination, it appeared that the reason for the failure was that a polymorphism interfered with the restriction enzyme digestion site. The heterozygous repeat expansion was confirmed by a second outside lab using a PCR assay.
The take home message?
Actually, there are three.
First, clinical symptoms can sometimes be misleading. Leg pain and foot drop in a pediatric patient reasonably suggests Charcot-Marie-Tooth as a cause. It would be less likely to consider ataxia as the cause.
Second, only a test capable of detecting both repeat expansions and additional types of variants (SNVs, indels, structural variants) has the ability to directly diagnose the subset of Friedreich’s ataxia patients with compound heterozygous FXN variants.
Third, even the commonly accepted gold standard method of detecting FXN repeat expansions can return a false negative result when the sample contains a polymorphism within the restriction enzyme digestion site.
In conclusion, it takes a PCR-free whole genome-based testing approach to provide a broad test and to cover both categories of Friedreich’s ataxia patients.
Interested to read the case study?
Download it here.