Research Centre for Medical Genetics, Moscow, Russia.
Research Centre for Medical Genetics, Moscow, Russia.
Eur J Med Genet. 2020 Dec;63(12):104088. doi: 10.1016/j.ejmg.2020.104088. Epub 2020 Oct 15.
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.
皮特-霍普金斯综合征是一种由转录因子 4（TCF4）单倍剂量不足引起的罕见神经发育障碍。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、特征性面部表型和呼吸异常，包括发作性过度通气。不同的致病性变异可导致皮特-霍普金斯综合征。最常见的是包含 TCF4 基因的 18q21 大片段缺失和移码/无义单核苷酸变异。然而，非编码区域的变异也可以通过破坏正常的前体 mRNA 剪接机制导致皮特-霍普金斯综合征。在这里，我们描述了三个由 18 号染色体大片段缺失、无义变异和位于 TCF4 c.922+5G>A 内含子 11 的新型变异引起的皮特-霍普金斯综合征患者。通过 RT-PCR 分析和小基因剪接试验，我们表明该内含子变异导致第 11 外显子跳跃，从而形成提前终止密码子。据我们所知，这是对皮特-霍普金斯综合征剪接变异的首次功能注释。
