The Huntingtin (HTT) gene contains a CAG repeat in exon 1, whose expansion beyond 39 repeats consistently leads to Huntington's disease (HD), whereas normal-to-intermediate alleles seemingly modulate brain structure, function and behavior. The role of the CAG repeat in Autism Spectrum Disorder (ASD) was investigated applying both family-based and case–control association designs, with the SCA3 repeat as a negative control. Significant overtransmission of “long” CAG alleles (≥17 repeats) to autistic children and of “short” alleles (≤16 repeats) to their unaffected siblings (all p < 10−5) was observed in 612 ASD families (548 simplex and 64 multiplex). Surprisingly, both 193 population controls and 1,188 neurological non-HD controls have significantly lower frequencies of “short” CAG alleles compared to 185 unaffected siblings and higher rates of “long” alleles compared to 548 ASD patients from the same families (p <.05–.001). The SCA3 CAG repeat displays no association. “Short” HTT alleles seemingly exert a protective effect from clinically overt autism in families carrying a genetic predisposition for ASD, while “long” alleles may enhance autism risk. Differential penetrance of autism-inducing genetic/epigenetic variants may imply atypical developmental trajectories linked to HTT functions, including excitation/inhibition imbalance, cortical neurogenesis and apoptosis, neuronal migration, synapse formation, connectivity and homeostasis.
Huntingtin gene CAG repeat size affects autism risk: Family-based and case–control association study / I.S. Piras, C. Picinelli, R. Iennaco, M. Baccarin, P. Castronovo, P. Tomaiuolo, F. Cucinotta, A. Ricciardello, L. Turriziani, L. Nanetti, C. Mariotti, C. Gellera, C. Lintas, R. Sacco, C. Zuccato, E. Cattaneo, A.M. Persico. - In: AMERICAN JOURNAL OF MEDICAL GENETICS. PART B, NEUROPSYCHIATRIC GENETICS. - ISSN 1552-4841. - (2020). [Epub ahead of print]
Titolo: | Huntingtin gene CAG repeat size affects autism risk: Family-based and case–control association study |
Autori: | CATTANEO, ELENA (Penultimo) |
Parole Chiave: | autism; autism spectrum disorder; CAG tract; huntingtin; Huntington's disease |
Settore Scientifico Disciplinare: | Settore BIO/14 - Farmacologia |
Data di pubblicazione: | 2020 |
Rivista: | |
Tipologia: | Article (author) |
Data ahead of print / Data di stampa: | 11-lug-2020 |
Digital Object Identifier (DOI): | http://dx.doi.org/10.1002/ajmg.b.32806 |
Appare nelle tipologie: | 01 - Articolo su periodico |
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