Compound heterozygosity for an expanded (GAA) and a (GAAGGA) repeat at FXN locus: from a diagnostic pitfall to potential clues to the pathogenesis of Friedreich ataxia

AbstractFriedreich ’s ataxia (FRDA) is usually due to a homozygous GAA expansion in intron 1 of the frataxin (FXN) gene. Rarely, uncommon molecular rearrangements at theFXN locus can cause pitfalls in the molecular diagnosis of FRDA. Here we describe a family whose proband was affected by late-onset Friedreich ’s ataxia (LOFA); long-range PCR (LR-PCR) documented two small expanded GAA alleles both in the proband and in her unaffected younger sister, who therefore received a diagnosis of pre-symptomatic LOFA. Later studies, however, revealed that the proband’s unaffected sister, as well as their health y mother, were both carriers of an expanded GAA allele and an uncommon (GAAGGA)66 –67 repeat mimicking a GAA expansion at the LR-PCR that was the cause of the wrong initial diagnosis of pre-symptomatic LOFA. Extensive studies in tissues from all the family members, including LR-PCR, assessment of methylation status ofFXN locus,MboII restriction analysis and direct sequencing of LR-PCR products, analysis ofFXN mRNA, and frataxin protein expression, support the virtual lack of pathogenicity of the rare (GAAGGA)66 –67 repeat, also providing significant data about the modulation of epigenetic modifications at theFXN locus. Overall, this report highlights a rare but possible pitfall in FRDA molecular diagnosis, emphasizing the need of further analysis in case of discrepancy between clinical and molecular data.

Source: Neurogenetics - July 6, 2020 Category: Genetics & Stem Cells Source Type: research