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. 2024 Jan 31:15:1284459.
doi: 10.3389/fneur.2024.1284459. eCollection 2024.

Distribution of the C9orf72 hexanucleotide repeat expansion in healthy subjects: a multicenter study promoted by the Italian IRCCS network of neuroscience and neurorehabilitation

Emiliano Giardina  1   2 , Paola Mandich  3   4 , Roberta Ghidoni  5 , Nicola Ticozzi  6   7 , Giacomina Rossi  8 , Chiara Fenoglio  9   10 , Francesco Danilo Tiziano  11   12 , Federica Esposito  13   14 , Sabina Capellari  15   16 , Benedetta Nacmias  17   18 , Rossana Mineri  19 , Rosa Campopiano  20 , Luana Di Pilla  20 , Federica Sammarone  20 , Stefania Zampatti  1 , Cristina Peconi  1 , Flavio De Angelis  21   22 , Ilaria Palmieri  23 , Caterina Galandra  23 , Eleonora Nicodemo  24 , Paola Origone  3   4 , Fabio Gotta  3 , Clarissa Ponti  3   4 , Roland Nicsanu  5 , Luisa Benussi  5 , Silvia Peverelli  6 , Antonia Ratti  6   25 , Martina Ricci  8 , Giuseppe Di Fede  8 , Stefania Magri  26 , Maria Serpente  9 , Serena Lattante  11   27 , Teuta Domi  28 , Paola Carrera  29 , Elisa Saltimbanco  15 , Silvia Bagnoli  17   18 , Assunta Ingannato  17   18 , Alberto Albanese  30 , Fabrizio Tagliavini  31 , Raffaele Lodi  32 , Carlo Caltagirone  33 , Stefano Gambardella  20   34 , Enza Maria Valente  23   24 , Vincenzo Silani  6   7
Affiliations

Distribution of the C9orf72 hexanucleotide repeat expansion in healthy subjects: a multicenter study promoted by the Italian IRCCS network of neuroscience and neurorehabilitation

Emiliano Giardina et al. Front Neurol. .

Abstract

Introduction: High repeat expansion (HRE) alleles in C9orf72 have been linked to both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD); ranges for intermediate allelic expansions have not been defined yet, and clinical interpretation of molecular data lacks a defined genotype-phenotype association. In this study, we provide results from a large multicenter epidemiological study reporting the distribution of C9orf72 repeats in healthy elderly from the Italian population.

Methods: A total of 967 samples were collected from neurologically evaluated healthy individuals over 70 years of age in the 13 institutes participating in the RIN (IRCCS Network of Neuroscience and Neurorehabilitation) based in Italy. All samples were genotyped using the AmplideXPCR/CE C9orf72 Kit (Asuragen, Inc.), using standardized protocols that have been validated through blind proficiency testing.

Results: All samples carried hexanucleotide G4C2 expansion alleles in the normal range. All samples were characterized by alleles with less than 25 repeats. In particular, 93.7% of samples showed a number of repeats ≤10, 99.9% ≤20 repeats, and 100% ≤25 repeats.

Conclusion: This study describes the distribution of hexanucleotide G4C2 expansion alleles in an Italian healthy population, providing a definition of alleles associated with the neurological healthy phenotype. Moreover, this study provides an effective model of federation between institutes, highlighting the importance of sharing genomic data and standardizing analysis techniques, promoting translational research. Data derived from the study may improve genetic counseling and future studies on ALS/FTD.

Keywords: C9orf72; GGGGCC hexanucleotide repeat; allele distribution; amyotrophic lateral sclerosis; frontotemporal dementia.

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Conflict of interest statement

VS received compensation for consulting services and/or speaking activities from AveXis, Cytokinetics, Italfarmaco, Liquidweb S.r.l., Novartis Pharma AG, Zambon Biotech SA, and Asuragen. He receives or has received research supports form the Italian Ministry of Health, AriSLA, E-Rare Joint Transnational Call, and the ERN Euro-NMD. He is in the Editorial Board of Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, European Neurology, American Journal of Neurodegenerative Diseases, Frontiers in Neurology, and Exploration of Neuroprotective Therapy. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.

Figures

Figure 1
Figure 1
Organizational model of RIN.
Figure 2
Figure 2
Allelic distribution of C9orf72 alleles in our cohort.
See this image and copyright information in PMC

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