The PIDDosome is a multiprotein complex, composed by the p53-induced death domain protein 1 (PIDD1), the bipartite linker protein CRADD (also known as RAIDD) and the proform of caspase-2 that induces apoptosis in response to DNA damage. In the recent years, biallelic pathogenic variants in CRADD have been associated with a neurodevelopmental disorder (MRT34; MIM 614499) characterized by pachygyria with a predominant anterior gradient, megalencephaly, epilepsy and intellectual disability. More recently, biallelic pathogenic variants in PIDD1 have been described in a few families with apparently nonsydnromic intellectual disability. Here, we aim to delineate the genetic and radio-clinical features of PIDD1-related disorder. Exome sequencing was carried out in six consanguineous families. Thorough clinical and neuroradiological evaluation was performed for all the affected individuals as well as reviewing all the data from previously reported cases. We identified five distinct novel homozygous variants (c.2584C>T p.(Arg862Trp), c.1340G>A p.(Trp447*), c.2116_2120del p.(Val706Hisfs*30), c.1564_1565delCA p.(Gln522fs*44), and c.1804_1805del p.(Gly602fs*26) in eleven subjects displaying intellectual disability, behaviorial and psychiatric features, and a typical anterior-predominant pachygyria, remarkably resembling the CRADD-related neuroimaging pattern. In summary, we outline the phenotypic and molecular spectrum of PIDD1 biallelic variants supporting the evidence that the PIDD1/CRADD/caspase-2 signaling is crucial for normal gyration of the developing human neocortex as well as cognition and behavior.

PIDDosome 是一种多蛋白复合物，由 p53 诱导的死亡结构域蛋白 1 (PIDD1)、二分接头蛋白 CRADD（也称为 RAIDD）和 caspase-2 的前体组成，caspase-2 可诱导细胞凋亡以响应 DNA 损伤。近年来，CRADD中的双等位基因致病性变异与神经发育障碍（MRT34；MIM 614499）相关，其特征为以前梯度为主的巨脑回、巨脑畸形、癫痫和智力障碍。最近，PIDD1中的双等位基因致病变异已经在一些具有明显非综合征性智力障碍的家庭中进行了描述。在这里，我们旨在描述 PIDD1 相关疾病的遗传和放射临床特征。在六个近亲家庭中进行了外显子组测序。对所有受影响的个体进行了全面的临床和神经放射学评估，并审查了先前报告病例的所有数据。我们确定了五部不同的小说纯合变体 (c.2584C>T p.(Arg862Trp)、c.1340G>A p.(Trp447*)、c.2116_2120del p.(Val706Hisfs*30)、c.1564_1565delCA p.(Gln522fs*44) 和 c .1804_1805del p.(Gly602fs*26) in 11 subjects showing intellectual disability,behavioral and psychiatric features,and a typical anterior-predominant pachygyria,非常类似于CRADD相关的神经影像学模式。总之，我们概述了PIDD1的表型和分子谱双等位基因变体支持 PIDD1/CRADD/caspase-2 信号对于发育中的人类新皮质的正常旋转以及认知和行为至关重要的证据。