Abstract：
ANK3 encodes ankyrin-G, a protein involved in neuronal development and signaling. Alternative splicing gives rise to three ankyrin-G isoforms comprising different domains with distinct expression patterns. Mono- or biallelic ANK3 variants are associated with non-specific syndromic intellectual disability in 14 individuals (seven with monoallelic and seven with biallelic variants). In this study, we describe the clinical features of 13 additional individuals and review the data on a total of 27 individuals (16 individuals with monoallelic and 11 with biallelic ANK3 variants) and demonstrate that the phenotype for biallelic variants is more severe. The phenotypic features include language delay (92%), autism spectrum disorder (76%), intellectual disability (78%), hypotonia (65%), motor delay (68%), attention deficit disorder (ADD) or attention deficit hyperactivity disorder (ADHD) (57%), sleep disturbances (50%), aggressivity/self-injury (37.5%), and epilepsy (35%). A notable phenotypic difference was presence of ataxia in three individuals with biallelic variants, but in none of the individuals with monoallelic variants. While the majority of the monoallelic variants are predicted to result in a truncated protein, biallelic variants are almost exclusively missense. Moreover, mono- and biallelic variants appear to be localized differently across the three different ankyrin-G isoforms, suggesting isoform-specific pathological mechanisms.
摘要：
ANK3编码ankyrin-G，参与神经元发育和信号传导的蛋白质。选择性剪接产生三种包含具有不同表达模式的不同结构域的锚蛋白-G同种型。单等位基因或双等位基因ANK3变体与14个个体的非特异性综合征性智力障碍相关(7个具有单等位基因,7个具有双等位基因变体)。在这项研究中,我们描述了另外13个个体的临床特征,并回顾了总共27个个体(16个单等位基因个体和11个双等位基因ANK3变异体)的数据,并证明双等位基因变异体的表型更为严重.表型特征包括语言延迟(92%)，自闭症谱系障碍（76%），智力残疾（78%），低张力（65%），电机延迟(68%)，注意缺陷障碍（ADD）或注意缺陷多动障碍（ADHD）（57％），睡眠障碍（50%），攻击性/自我伤害（37.5%），癫痫（35%）。一个显著的表型差异是在三个具有双等位基因变异的个体中存在共济失调，但是在没有单等位基因变异的个体中。虽然预测大多数单等位基因变体会导致截短的蛋白质，双等位基因变体几乎完全是错义的。此外，单等位基因和双等位基因变体似乎在三种不同的锚蛋白-G亚型中定位不同，提示同工型特异性病理机制。
