Huntingtin gene CAG repeat size affects autism risk: Family-based and case-control association study.

Autor: Piras IS; Neurogenomics Division, The Translational Genomics Research Institute, Phoenix, Arizona, USA., Picinelli C; Mafalda Luce Center for Pervasive Developmental Disorders, Milan, Italy., Iennaco R; Department of Biosciences, Università degli Studi di Milano, Milan, Italy.; Istituto Nazionale di Genetica Molecolare 'Romeo ed Enrica Invernizzi', Milan, Italy., Baccarin M; Mafalda Luce Center for Pervasive Developmental Disorders, Milan, Italy., Castronovo P; Mafalda Luce Center for Pervasive Developmental Disorders, Milan, Italy., Tomaiuolo P; Interdepartmental Program 'Autism 0-90', 'Gaetano Martino' University Hospital, University of Messina, Messina, Italy., Cucinotta F; Interdepartmental Program 'Autism 0-90', 'Gaetano Martino' University Hospital, University of Messina, Messina, Italy., Ricciardello A; Interdepartmental Program 'Autism 0-90', 'Gaetano Martino' University Hospital, University of Messina, Messina, Italy., Turriziani L; Interdepartmental Program 'Autism 0-90', 'Gaetano Martino' University Hospital, University of Messina, Messina, Italy., Nanetti L; Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy., Mariotti C; Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy., Gellera C; Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy., Lintas C; Unit of Child and Adolescent NeuroPsychiatry & Laboratory of Molecular Psychiatry and Neurogenetics, University Campus Bio-Medico, Rome, Italy., Sacco R; Unit of Child and Adolescent NeuroPsychiatry & Laboratory of Molecular Psychiatry and Neurogenetics, University Campus Bio-Medico, Rome, Italy., Zuccato C; Department of Biosciences, Università degli Studi di Milano, Milan, Italy.; Istituto Nazionale di Genetica Molecolare 'Romeo ed Enrica Invernizzi', Milan, Italy., Cattaneo E; Department of Biosciences, Università degli Studi di Milano, Milan, Italy.; Istituto Nazionale di Genetica Molecolare 'Romeo ed Enrica Invernizzi', Milan, Italy., Persico AM; Interdepartmental Program 'Autism 0-90', 'Gaetano Martino' University Hospital, University of Messina, Messina, Italy.
Jazyk: angličtina
Zdroj: American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics [Am J Med Genet B Neuropsychiatr Genet] 2020 Sep; Vol. 183 (6), pp. 341-351. Date of Electronic Publication: 2020 Jul 11.
DOI: 10.1002/ajmg.b.32806
Abstrakt: 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.
(© 2020 Wiley Periodicals LLC.)
Databáze: MEDLINE
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