Pitt-Hopkins syndrome is a rare neurodevelopment disorder caused by haploinsufficiency of the transcription factor 4 (TCF4). The main clinical symptoms of Pitt-Hopkins syndrome are severe development delay, intellectual disability, characteristic facial phenotype, and breathing abnormalities, including episodic hyperventilation. Different pathogenic variants can lead to Pitt-Hopkins syndrome. The most common are large deletions at 18q21 encompassing the TCF4 gene and frameshifting/nonsense single nucleotide variants. However, variants in noncoding regions can also lead to Pitt-Hopkins syndrome by disrupting the normal pre-mRNA splicing machinery. Here we describe three patients with Pitt-Hopkins syndrome caused by a large deletion in chromosome 18, a nonsense variant, and a novel variant located in intron 11 of TCF4 c.922+5G > A. Using RT-PCR analysis and minigene splicing assay we showed that this intronic variant leads to exon 11 skipping resulting in a formation of a premature stop codon. To our knowledge, this is the first functional annotation of a splicing variant in Pitt-Hopkins syndrome.

Pitt-Hopkins综合征是一种罕见的神经发育障碍，由转录因子4（TCF4）的单倍缺乏引起。皮特-霍普金斯综合征的主要临床症状是严重的发育迟缓，智力残疾，面部特征性表型和呼吸异常，包括发作性换气过度。不同的致病变异可以导致皮特-霍普金斯综合征。最常见的是包含TCF4的18q21大缺失基因和移码/无意义单核苷酸变体。但是，非编码区的变异也可能通过破坏正常的前mRNA剪接机制而导致Pitt-Hopkins综合征。在这里，我们描述了三位因18号染色体上的大缺失，无意义变异和位于TCF4 c.922 + 5G> A的内含子11中的新变异而导致的Pitt-Hopkins综合征患者。使用RT-PCR分析和小基因剪接测定法我们表明，该内含子变异导致外显子11跳跃，导致过早终止密码子的形成。据我们所知，这是皮特-霍普金斯综合征中一个剪接变体的第一个功能注释。