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

• Published in: American journal of medical genetics. Part B, Neuropsychiatric genetics Vol. 183; no. 6; pp. 341 - 351
• Main Authors: Piras, Ignazio Stefano, Picinelli, Chiara, Iennaco, Raffaele, Baccarin, Marco, Castronovo, Paola, Tomaiuolo, Pasquale, Cucinotta, Francesca, Ricciardello, Arianna, Turriziani, Laura, Nanetti, Lorenzo, Mariotti, Caterina, Gellera, Cinzia, Lintas, Carla, Sacco, Roberto, Zuccato, Chiara, Cattaneo, Elena, Persico, Antonio M.
• Format: Journal Article
• Language: English
• Published: Hoboken, USA John Wiley & Sons, Inc 01.09.2020; Wiley Subscription Services, Inc
• Subjects: Adult; Alleles; Apoptosis; Autism; autism spectrum disorder; Autism Spectrum Disorder - genetics; Autism Spectrum Disorder - metabolism; Autistic Disorder - genetics; Autistic Disorder - metabolism; Brain; CAG tract; Case-Control Studies; Cell migration; Child; Child, Preschool; Family; Female; Functional anatomy; Gene Frequency - genetics; Genetics; Homeostasis; Humans; Huntingtin; Huntingtin Protein - genetics; Huntingtin Protein - metabolism; Huntington Disease - genetics; Huntington's disease; Huntingtons disease; Male; Middle Aged; Nerve Tissue Proteins - genetics; Neural networks; Neurogenesis; Penetrance; Polyglutamine; Risk Factors; Siblings; Structure-function relationships; Synaptogenesis; Trinucleotide repeat diseases; Trinucleotide Repeat Expansion - genetics; Trinucleotide repeats; Trinucleotide Repeats - genetics; Huntington's disease; autism spectrum disorder; huntingtin; autism; CAG tract
• ISSN: 1552-4841; 1552-485X
• DOI: 10.1002/ajmg.b.32806

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.