PDF(Pubmed)
Abstract：
Prune exopolyphosphatase-1 (PRUNE1) encodes a member of the aspartic acid-histidine-histidine (DHH) phosphodiesterase superfamily that regulates cell migration and proliferation during brain development. In 2015, biallelic PRUNE1 loss-of-function variants were identified to cause the neurodevelopmental disorder with microcephaly, hypotonia, and variable brain abnormalities (NMIHBA, OMIM#617481). NMIHBA is characterized by the namesake features and structural brain anomalies including thinning of the corpus callosum, cerebral and cerebellar atrophy, and delayed myelination. To date, 47 individuals have been reported in the literature, but the phenotypic spectrum of PRUNE1-related disorders and their causative variants remains to be characterized fully. Here, we report a novel homozygous PRUNE1 NM_021222.2:c.933G>A synonymous variant identified in a 6-year-old boy with intellectual and developmental disabilities, hypotonia, and spastic diplegia, but with the absence of microcephaly, brain anomalies, or seizures. Fibroblast RNA sequencing revealed that the PRUNE1 NM_021222.1:c.933G>A variant resulted in an in-frame skipping of the penultimate exon 7, removing 53 amino acids from an important protein domain. This case represents the first synonymous variant and the third pathogenic variant known to date affecting the DHH-associated domain (DHHA2 domain). These findings extend the genotypic and phenotypic spectrums in PRUNE1-related disorders and highlight the importance of considering synonymous splice site variants in atypical presentations.
摘要：
修剪外聚磷酸酶-1（PRUNE1）编码天冬氨酸-组氨酸-组氨酸（DHH）磷酸二酯酶超家族的成员，该家族在大脑发育过程中调节细胞迁移和增殖。2015年，双等位基因PRUNE1功能丧失变体被鉴定为导致小头畸形的神经发育障碍，低张力,和可变的大脑异常(NMIHBA，OMIM#617481)。NMIHBA的特征是同名特征和结构性脑异常，包括call体变薄，大脑和小脑萎缩,髓鞘形成延迟。迄今为止,文献中已经报道了47个人，但PRUNE1相关疾病的表型谱及其致病变异仍有待充分表征.这里,我们报告了一个新的纯合PRUNE1NM_021222.2：c.933G>在一个有智力和发育障碍的6岁男孩中发现的同义变体，低张力,痉挛型双瘫,但是在没有小头畸形的情况下，大脑异常,或癫痫发作。成纤维细胞RNA测序显示，PRUNE1NM_021222.1：c.933G>A变体导致倒数第二个外显子7的框内跳跃，从重要的蛋白质结构域中去除53个氨基酸。该病例代表迄今为止已知的影响DHH相关结构域(DHHA2结构域)的第一同义变体和第三致病变体。这些发现扩展了PRUNE1相关疾病的基因型和表型谱，并强调了在非典型表现中考虑同义剪接位点变异的重要性。
