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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.
Neurogenetics. 2020 10; 21(4):279-287.N

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 pre-symptomatic 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 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 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.

Authors+Show Affiliations

IRCCS Fondazione Don Carlo Gnocchi, Piazzale Morandi, 6, 20121, Milan, Italy.Dept of Neuroscience, Faculty of Medicine and Surgery, Università Cattolica del Scaro Cuore, L.go F. Vito 1, 000168, Rome, Italy.Unit of Muscular and Neurodegenerative Diseases, Ospedale Pediatrico Bambino Gesù, IRCCS, Viale San Paolo, 15, 00146, Rome, Italy.Unit of Muscular and Neurodegenerative Diseases, Ospedale Pediatrico Bambino Gesù, IRCCS, Viale San Paolo, 15, 00146, Rome, Italy.Unit of Muscular and Neurodegenerative Diseases, Ospedale Pediatrico Bambino Gesù, IRCCS, Viale San Paolo, 15, 00146, Rome, Italy.Dept of Neuroscience, Faculty of Medicine and Surgery, Università Cattolica del Scaro Cuore, L.go F. Vito 1, 000168, Rome, Italy.Dept of Neuroscience, Faculty of Medicine and Surgery, Università Cattolica del Scaro Cuore, L.go F. Vito 1, 000168, Rome, Italy. Institute of Neurology, Neuroscience Area, Neurology Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, Largo Agostino Gemelli, 8, 00168, Rome, Italy.Dept of Neuroscience, Faculty of Medicine and Surgery, Università Cattolica del Scaro Cuore, L.go F. Vito 1, 000168, Rome, Italy. Institute of Neurology, Neuroscience Area, Neurology Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, Largo Agostino Gemelli, 8, 00168, Rome, Italy.Institute of Neurology, Neuroscience Area, Neurology Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, Largo Agostino Gemelli, 8, 00168, Rome, Italy.Institute of Genomic Medicine, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario A. Gemelli IRCCS, Largo Agostino Gemelli, 8, 00168, Rome, Italy.Institute of Genomic Medicine, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario A. Gemelli IRCCS, Largo Agostino Gemelli, 8, 00168, Rome, Italy.Dept of Neuroscience, Faculty of Medicine and Surgery, Università Cattolica del Scaro Cuore, L.go F. Vito 1, 000168, Rome, Italy. gabriella.silvestri@unicatt.it. Institute of Neurology, Neuroscience Area, Neurology Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, Largo Agostino Gemelli, 8, 00168, Rome, Italy. gabriella.silvestri@unicatt.it.

Pub Type(s)

Case Reports
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

32638185

Citation

Santoro, Massimo, et al. "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." Neurogenetics, vol. 21, no. 4, 2020, pp. 279-287.
Santoro M, Perna A, La Rosa P, et al. 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. Neurogenetics. 2020;21(4):279-287.
Santoro, M., Perna, A., La Rosa, P., Petrillo, S., Piemonte, F., Rossi, S., Riso, V., Nicoletti, T. F., Modoni, A., Pomponi, M. G., Chiurazzi, P., & Silvestri, G. (2020). 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. Neurogenetics, 21(4), 279-287. https://doi.org/10.1007/s10048-020-00620-7
Santoro M, et al. 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. Neurogenetics. 2020;21(4):279-287. PubMed PMID: 32638185.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Santoro,Massimo, AU - Perna,Alessia, AU - La Rosa,Piergiorgio, AU - Petrillo,Sara, AU - Piemonte,Fiorella, AU - Rossi,Salvatore, AU - Riso,Vittorio, AU - Nicoletti,Tommaso Filippo, AU - Modoni,Anna, AU - Pomponi,Maria Grazia, AU - Chiurazzi,Pietro, AU - Silvestri,Gabriella, Y1 - 2020/07/07/ PY - 2020/03/30/received PY - 2020/06/14/accepted PY - 2020/7/9/pubmed PY - 2021/6/16/medline PY - 2020/7/9/entrez KW - FXN intronic array KW - FXN methylation KW - Frataxin KW - Friedreich’s ataxia KW - Molecular testing SP - 279 EP - 287 JF - Neurogenetics JO - Neurogenetics VL - 21 IS - 4 N2 - 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 pre-symptomatic 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 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 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. SN - 1364-6753 UR - https://www.unboundmedicine.com/medline/citation/32638185/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_ L2 - https://dx.doi.org/10.1007/s10048-020-00620-7 DB - PRIME DP - Unbound Medicine ER -