Clinical Genetics Department, Human Genetics and Genome Research Institute, National Research Centre, Cairo, Egypt.
Medical Molecular Department, Human Genetics and Genome Research Institute, National Research Centre, Cairo, Egypt.
Clin Genet. 2023 Sep;104(3):356-364. doi: 10.1111/cge.14357. Epub 2023 May 15.
Biallelic variants in PPIL1 have been recently found to cause a very rare type of pontocerebellar hypoplasia and congenital microcephaly in which simplified gyral pattern was not observed in all of the patients. Here, we describe a series of nine patients from eight unrelated Egyptian families in whom whole exome sequencing detected a previously reported homozygous missense variant (c.295G>A, p.Ala99Thr) in PPIL1. Haplotype analysis confirmed that this variant has a founder effect in our population. All our patients displayed early onset drug-resistant epilepsy, profound developmental delay, and visual impairment. Remarkably, they presented with recognizable imaging findings showing profound microcephaly, hypoplastic frontal lobe and posteriorly predominant pachygyria, agenesis of corpus callosum with colpocephaly, and pontocerebellar hypoplasia. In addition, Dandy-Walker malformation was evident in three patients. Interestingly, four of our patients exhibited hematopoietic disorder (44% of cases). We compared the phenotype of our patients with other previously reported PPIL1 patients. Our results reinforce the hypothesis that the alterative splicing of PPIL1 causes a heterogeneous phenotype. Further, we affirm that hematopoietic disorder is a common feature of the condition and underscore the role of major spliceosomes in brain development.
PPIL1 的双等位基因突变最近被发现可导致一种非常罕见的桥脑小脑发育不良和先天性小头畸形，并非所有患者的脑回模式都简化。在这里，我们描述了来自 8 个无关埃及家庭的 9 名患者，他们的外显子组测序检测到 PPIL1 中先前报道的纯合错义变异（c.295G>A，p.Ala99Thr）。单体型分析证实，该变异在我们人群中具有一个起源效应。我们所有的患者均表现为早发性耐药性癫痫、严重的发育迟缓以及视力损害。值得注意的是，他们表现出可识别的影像学表现，包括严重的小头畸形、额叶发育不良和后部优势性脑回肥厚、胼胝体发育不全合并尖头畸形，以及桥脑小脑发育不良。此外，3 名患者存在 Dandy-Walker 畸形。有趣的是，我们的 4 名患者表现出造血障碍（44%的病例）。我们将我们患者的表型与其他先前报道的 PPIL1 患者进行了比较。我们的结果证实了替代性剪接的 PPIL1 可导致异质性表型的假说。此外，我们证实造血障碍是该病症的一个常见特征，并强调了主要剪接体在大脑发育中的作用。
