Compound heterozygosity for an expanded (GAA) and a (GAAGGA) repeat at FXN locus: from a diagnostic pitfall to potential
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ORIGINAL ARTICLE
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 Massimo Santoro 1 & Alessia Perna 2 & Piergiorgio La Rosa 3 & Sara Petrillo 3 & Fiorella Piemonte 3 & Salvatore Rossi 2 & Vittorio Riso 2,4 & Tommaso Filippo Nicoletti 2,4 & Anna Modoni 4 & Maria Grazia Pomponi 5 Pietro Chiurazzi 5 & Gabriella Silvestri 2,4
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Received: 30 March 2020 / Accepted: 14 June 2020 # Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Friedreich’s ataxia (FRDA) is usually due to a homozygous GAA expansion in intron 1 of the frataxin (FXN) gene. Rarely, uncommon molecular rearrangements at the FXN 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 presymptomatic LOFA. Later studies, however, revealed that the proband’s unaffected sister, as well as their healthy mother, were both carriers of an expanded GAA allele and an uncommon (GAAGGA)66–67 repeat mimicking a GAA expansion at the LRPCR 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 of FXN locus, MboII restriction analysis and direct sequencing of LR-PCR products, analysis of FXN 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 the FXN 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. Keywords Friedreich’s ataxia . Molecular testing . Frataxin . FXN methylation . FXN intronic array
Introduction Massimo Santoro and Alessia Perna wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors. * Gabriella Silvestri [email protected] 1
IRCCS Fondazione Don Carlo Gnocchi, Piazzale Morandi, 6, 20121 Milan, Italy
2
Dept of Neuroscience, Faculty of Medicine and Surgery, Università Cattolica del Scaro Cuore, L.go F. Vito 1, 000168 Rome, Italy
3
Unit of Muscular and Neurodegenerative Diseases, Ospedale Pediatrico Bambino Gesù, IRCCS, Viale San Paolo, 15, 00146 Rome, Italy
4
Institute of Neurology, Neuroscience Area, Neurology Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, Largo Agostino Gemelli, 8, 00168 Rome, Italy
5
Institute of Genomic Medicine, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario A. Gemelli IRCCS, Largo Agostino Gemelli, 8, 00168 Rome, Italy
Friedreich ataxia (FRDA, OMIM #229300) is the most frequent autosomal recessive ataxia in wester
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