Frontiers in Neurology (Jan 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,
  • Emiliano Giardina,
  • Paola Mandich,
  • Paola Mandich,
  • Roberta Ghidoni,
  • Nicola Ticozzi,
  • Nicola Ticozzi,
  • Giacomina Rossi,
  • Chiara Fenoglio,
  • Chiara Fenoglio,
  • Francesco Danilo Tiziano,
  • Francesco Danilo Tiziano,
  • Federica Esposito,
  • Federica Esposito,
  • Sabina Capellari,
  • Sabina Capellari,
  • Benedetta Nacmias,
  • Benedetta Nacmias,
  • Rossana Mineri,
  • Rosa Campopiano,
  • Luana Di Pilla,
  • Federica Sammarone,
  • Stefania Zampatti,
  • Cristina Peconi,
  • Flavio De Angelis,
  • Flavio De Angelis,
  • Ilaria Palmieri,
  • Caterina Galandra,
  • Eleonora Nicodemo,
  • Paola Origone,
  • Paola Origone,
  • Fabio Gotta,
  • Clarissa Ponti,
  • Clarissa Ponti,
  • Roland Nicsanu,
  • Luisa Benussi,
  • Silvia Peverelli,
  • Antonia Ratti,
  • Antonia Ratti,
  • Martina Ricci,
  • Giuseppe Di Fede,
  • Stefania Magri,
  • Maria Serpente,
  • Serena Lattante,
  • Serena Lattante,
  • Teuta Domi,
  • Paola Carrera,
  • Elisa Saltimbanco,
  • Silvia Bagnoli,
  • Silvia Bagnoli,
  • Assunta Ingannato,
  • Assunta Ingannato,
  • Alberto Albanese,
  • Fabrizio Tagliavini,
  • Raffaele Lodi,
  • Carlo Caltagirone,
  • Stefano Gambardella,
  • Stefano Gambardella,
  • Enza Maria Valente,
  • Enza Maria Valente,
  • Vincenzo Silani,
  • Vincenzo Silani

DOI
https://doi.org/10.3389/fneur.2024.1284459
Journal volume & issue
Vol. 15

Abstract

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IntroductionHigh 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.MethodsA 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.ResultsAll 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.ConclusionThis 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.

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