锚蛋白是一个蛋白质家族,将完整的膜蛋白连接到潜在的血影蛋白-肌动蛋白细胞骨架,并在细胞运动等活动中起关键作用,激活,扩散,细胞-细胞接触,和维护专门的膜结构域。AnkyrinG,由ANK3基因编码,是锚蛋白家族的三种主要亚型之一。Ankryin基因普遍表达,但是他们的表达在大脑中最高。在中枢神经系统中,锚蛋白在轴突初始段具有关键作用,Ranvier的节点,和突触。迄今为止,ANK3的致病变异已在神经精神病患者中报道,认知,和神经发育障碍。在观察到常染色体隐性遗传和常染色体显性遗传模式的这些个体中,临床严重程度是可变的。这些发现表明了基因型-表型相关性,甚至对具有ANK3致病性变体的个体的同工型特异性影响。这里我们报告一个说话延迟的病人,自闭症谱系障碍和一种语言障碍,其中通过外显子组测序发现了从头无意义的ANK3改变。有趣的是,下一代测序数据表明,这种变化是受影响儿童的马赛克,并通过数字PCR在22%的等位基因部分得到证实。据我们所知,这是患有致病性马赛克ANK3变体的个体的第一例。这一发现扩展了可用于ANK3基因的现有基因型-表型信息,同时还突出了潜在的基因表达与表型的相关性。
Ankyrins are a family of proteins that link integral membrane proteins to the underlying spectrin-actin cytoskeleton and play a key role in activities such as cell motility, activation, proliferation, cell-cell contact, and the maintenance of specialized membrane domains. Ankyrin 3 (ANK3) is one of the three major subtypes of the ankyrin protein family. Ankryin genes are ubiquitously expressed, but their expression is highest in the brain. In the central nervous system,
ankyrins have critical roles at the axonal initial segment, the nodes of Ranvier, and at synapses. To date, pathogenic variants in ANK3 have been reported in individuals with neuropsychiatric, cognitive, and neurodevelopmental disorders. The clinical severity is variable in these individuals with both autosomal recessive and autosomal dominant patterns of inheritance observed. These findings have suggested genotype-phenotype correlations and even isoform-specific implications for individuals with ANK3 pathogenic variants. Here, we report a patient with speech delay, autism spectrum disorder, and a language disorder in which a de novo nonsense ANK3 alteration was discovered by exome sequencing. Interestingly, the next-generation sequencing data suggested the change was mosaic in the affected child, and it was confirmed by digital polymerase chain reaction (dPCR) at 22% allelic fraction. To our knowledge, this is the first
case of an individual with a pathogenic mosaic ANK3 variant. This finding expands upon the existing genotype-phenotype information available for the ANK3 gene while also highlighting potential gene expression correlations with phenotype.