Novel intragenic deletion within the FXN gene in a patient with typical phenotype of Friedreich ataxia: may be more prevalent than we think?

Abstract

Background: Friedreich ataxia is the most common inherited ataxia in Europe and is mainly caused by biallelic pathogenic expansions of the GAA trinucleotide repeat in intron 1 of the FXN gene that lead to a decrease in frataxin protein levels. Rarely, affected individuals carry either a large intragenic deletion or whole-gene deletion of FXN on one allele and a full-penetrance expanded GAA repeat on the other allele.

Case presentation: We report here a patient that presented the typical clinical features of FRDA and genetic analysis of FXN intron 1 led to the assumption that the patient carried the common biallelic expansion. Subsequently, parental sample testing led to the identification of a novel intragenic deletion involving the 5'UTR upstream region and exons 1 and 2 of the FXN gene by MLPA.

Conclusions: With this case, we want to raise awareness about the potentially higher prevalence of intragenic deletions and underline the essential role of parental sample testing in providing accurate genetic counselling.

Keywords: Biallelic expansion; Deletion; FXN; Friedreich ataxia (FRDA); Parental testing.

Fig. 1

Pedigree and genetic analysis of the FXN polymorphic region performed on the proband and his family. The results of PCR fragment analysis show an allele of 7 GAA repeats in the father’s sample (II-3) and an allele of 9 GAA repeats in the mother’s sample (II-4). The sibling (III-1) presents two normal alleles of 7 and 9 GAA repeats, respectively. No peaks were observed in the proband’s sample (III-2). To detect expanded alleles, TP-PCR was performed and, as a result, the father (II-3) and the proband’s (III-2) samples showed an expansion while non-expanded alleles were observed in the mother’s sample (II-4). The affected individuals are marked in black

Fig. 2

Deletion/duplication analysis of FXN gene and summary of intragenic deletions reported to date. (A) MLPA analysis with the kit P316-B4 showed a deletion of FXN exons 1 and 2 in the mother (II-4) and the proband’s (III-2) samples. The deleted probes are highlighted in red. (B) Summary of FXN gene deletions in the literature and this report