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Huntingtin gene CAG repeat size affects autism risk: Family-based and case-control association study.
American Journal of Medical Genetics Part B: Neuropsychiatric Genetics ( IF 2.8 ) Pub Date : 2020-07-11 , DOI: 10.1002/ajmg.b.32806
Ignazio Stefano Piras 1 , Chiara Picinelli 2 , Raffaele Iennaco 3, 4 , Marco Baccarin 2 , Paola Castronovo 2 , Pasquale Tomaiuolo 5 , Francesca Cucinotta 5 , Arianna Ricciardello 5 , Laura Turriziani 5 , Lorenzo Nanetti 6 , Caterina Mariotti 6 , Cinzia Gellera 6 , Carla Lintas 7 , Roberto Sacco 7 , Chiara Zuccato 3, 4 , Elena Cattaneo 3, 4 , Antonio M Persico 5
Affiliation  

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.

中文翻译:

亨廷顿基因CAG重复序列的大小会影响自闭症的风险:基于家庭和病例对照的研究。

Huntingtin(HTT)基因的第1外显子包含一个CAG重复序列,其第39外显子的扩增始终导致亨廷顿舞蹈病(HD),而正常至中等等位基因似乎在调节大脑的结构,功能和行为。研究了CAG重复在自闭症谱系障碍(ASD)中的作用,同时应用了基于家族的病例对照设计,并以SCA3重复作为阴性对照。自闭症儿童的“长” CAG等位基因(≥17个重复)显着过量传播,而未受影响的同胞“短”等位基因(≤16个重复)显着过量传播(所有p  <10 -5在612个ASD系列(548个单工和64个多工)中观察到)。令人惊讶的是,与185个未受影响的兄弟姐妹相比,与548个来自同一家庭的ASD患者相比,与185个未受影响的兄弟姐妹相比,193个人群对照和1188个神经系统非HD对照的频率明显较低,而“长”等位基因的发生率更高(p <.05–.001)。SCA3 CAG重复未显示任何关联。“短” HTT等位基因似乎对具有ASD遗传易感性的家庭的临床自闭症具有保护作用,而“长”等位基因可能会增加自闭症的风险。自闭症诱发的遗传/表观遗传变异的差异渗透可能暗示与HTT功能相关的非典型发育轨迹,包括兴奋/抑制失衡,皮质神经发生和凋亡,神经元迁移,突触形成,连接性和体内平衡。
更新日期:2020-08-08
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