AUTHOR=Giardina Emiliano , Mandich Paola , Ghidoni Roberta , Ticozzi Nicola , Rossi Giacomina , Fenoglio Chiara , Tiziano Francesco Danilo , Esposito Federica , Capellari Sabina , Nacmias Benedetta , Mineri Rossana , Campopiano Rosa , Di Pilla Luana , Sammarone Federica , Zampatti Stefania , Peconi Cristina , De Angelis Flavio , Palmieri Ilaria , Galandra Caterina , Nicodemo Eleonora , Origone Paola , Gotta Fabio , Ponti Clarissa , Nicsanu Roland , Benussi Luisa , Peverelli Silvia , Ratti Antonia , Ricci Martina , Di Fede Giuseppe , Magri Stefania , Serpente Maria , Lattante Serena , Domi Teuta , Carrera Paola , Saltimbanco Elisa , Bagnoli Silvia , Ingannato Assunta , Albanese Alberto , Tagliavini Fabrizio , Lodi Raffaele , Caltagirone Carlo , Gambardella Stefano , Valente Enza Maria , Silani Vincenzo TITLE=Distribution of the C9orf72 hexanucleotide repeat expansion in healthy subjects: a multicenter study promoted by the Italian IRCCS network of neuroscience and neurorehabilitation JOURNAL=Frontiers in Neurology VOLUME=15 YEAR=2024 URL=https://www.frontiersin.org/journals/neurology/articles/10.3389/fneur.2024.1284459 DOI=10.3389/fneur.2024.1284459 ISSN=1664-2295 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.