PRICKLE2 encodes a member of a highly conserved family of proteins that are involved in the non-canonical Wnt and planar cell polarity signaling pathway. Prickle2 localizes to the post-synaptic density, and interacts with post-synaptic density protein 95 and the NMDA receptor. Loss-of-function variants in prickle2 orthologs cause seizures in flies and mice but evidence for the role of PRICKLE2 in human disease is conflicting. Our goal is to provide further evidence for the role of this gene in humans and define the phenotypic spectrum of PRICKLE2-related disorders. We report a cohort of six subjects from four unrelated families with heterozygous rare PRICKLE2 variants (NM_198859.4). Subjects were identified through an international collaboration. Detailed phenotypic and genetic assessment of the subjects were carried out and in addition, we assessed the variant pathogenicity using bioinformatic approaches. We identified two missense variants (c.122 C > T; p.(Pro41Leu), c.680 C > G; p.(Thr227Arg)), one nonsense variant (c.214 C > T; p.(Arg72*) and one frameshift variant (c.1286_1287delGT; p.(Ser429Thrfs*56)). While the p.(Ser429Thrfs*56) variant segregated with disease in a family with three affected females, the three remaining variants occurred de novo. Subjects shared a mild phenotype characterized by global developmental delay, behavioral difficulties ± epilepsy, autistic features, and attention deficit hyperactive disorder. Computational analysis of the missense variants suggest that the altered amino acid residues are likely to be located in protein regions important for function. This paper demonstrates that PRICKLE2 is involved in human neuronal development and that pathogenic variants in PRICKLE2 cause neurodevelopmental delay, behavioral difficulties and epilepsy in humans.

PRICKLE2编码一个高度保守的蛋白质家族成员，该家族参与非经典 Wnt 和平面细胞极性信号通路。Prickle2 定位于突触后密度，并与突触后密度蛋白 95 和 NMDA 受体相互作用。prickle2 直系同源物中的功能丧失变异导致果蝇和小鼠癫痫发作，但PRICKLE2在人类疾病中的作用的证据相互矛盾。我们的目标是为该基因在人类中的作用提供进一步的证据，并定义PRICKLE2相关疾病的表型谱。我们报告了来自四个无关家庭的六名受试者的队列，这些受试者具有杂合的罕见PRICKLE2变体（NM_198859.4）。受试者是通过国际合作确定的。对受试者进行了详细的表型和遗传评估，此外，我们还使用生物信息学方法评估了变异致病性。我们确定了两个错义变体 (c.122 C > T; p.(Pro41Leu), c.680 C > G; p.(Thr227Arg))，一个无义变体 (c.214 C > T; p.(Arg72*)和一个移码变体 (c.1286_1287delGT; p.(Ser429Thrfs*56))。虽然 p.(Ser429Thrfs*56) 变体在一个有三名受影响女性的家庭中与疾病分离，但其余三个变体从头发生。受试者共享一个以整体发育迟缓、行为困难±癫痫、自闭症特征和注意力缺陷多动障碍为特征的轻度表型。错义变异的计算分析表明，改变的氨基酸残基可能位于对功能重要的蛋白质区域。本文证明PRICKLE2参与人类神经元发育，PRICKLE2的致病变异导致人类神经发育迟缓、行为困难和癫痫。