United Laboratory of Fifth Affiliated Hospital and BGI, Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai 519000, China; Guangdong Provincial Key Laboratory of Biomedical Imaging, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province 519000, China.
Department of Cerebrovascular Disease, Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai 519000, China.
Clin Neurol Neurosurg. 2022 Dec;223:107524. doi: 10.1016/j.clineuro.2022.107524. Epub 2022 Nov 13.
PPP2R5D mutations are known to cause neurodevelopmental disorders in an autosomal-dominant manner. To date, the vast majority of the reported cases in the literature have been sporadic with de novo mutations. There are no data regarding PPP2R5D mutation penetrance. We aimed to unravel the underlying genetic defects in 3 generations of a family affected by intellectual disability, neurodevelopmental delay, and facial dysmorphology.
We performed detailed clinical examinations and whole-exome sequencing in the family.
We identified a novel mutation, c.1321 C>T (p.Arg441*), in PPP2R5D. The mutation cosegregated with affected family members I-2 and II-7 but not II-3, who bears the mutation but is phenotypically healthy. Our whole-exome sequencing also excluded the involvement of pathogenic mutations in other genes known to be related to neurodevelopmental disorders. The mutation was predicted to introduce a premature stop codon at position 441, thereby truncating the 162 amino acids at the C-terminus of the encoded protein.
We report a familial transmitted PPP2R5D-related neurodevelopmental disorder as well as a novel nonsense pathogenic mutation and its incomplete penetrance. Our study expands the mutational and phenotypic spectra of PPP2R5D-related neurodevelopmental disorders, broadens our understanding of these disorders, and will thus be valuable for mutation-based pre- and postnatal screening and genetic diagnosis of neurodevelopmental disorders.
PPP2R5D 突变以常染色体显性方式导致神经发育障碍。迄今为止，文献中报道的绝大多数病例都是散发的，具有新生突变。关于 PPP2R5D 突变的外显率尚无数据。我们旨在揭示受智力障碍、神经发育迟缓和面部畸形影响的 3 代家族的潜在遗传缺陷。
我们对该家族进行了详细的临床检查和全外显子组测序。
我们在 PPP2R5D 中发现了一个新的突变，c.1321C>T（p.Arg441*）。该突变与受影响的家族成员 I-2 和 II-7 共分离，但与 II-3 不共分离，后者携带突变但表型健康。我们的全外显子组测序还排除了其他已知与神经发育障碍相关的基因中致病性突变的参与。该突变预计会在 441 位引入一个提前终止密码子，从而导致编码蛋白的 C 末端 162 个氨基酸缺失。
我们报告了一种家族性 PPP2R5D 相关神经发育障碍，以及一种新的无义致病性突变及其不完全外显率。我们的研究扩展了 PPP2R5D 相关神经发育障碍的突变和表型谱，加深了我们对这些障碍的理解，因此对于神经发育障碍的基于突变的产前和产后筛查以及遗传诊断具有重要价值。
