Genetic mutations associated with brain malformations can lead to a spectrum of severity and it is often difficult to determine whether there are additional pathogenic variants contributing to the phenotype. Here, we present a family affected by a severe brain malformation including bilateral polymicrogyria, hydrocephalus, patchy white matter signal changes, and cerebellar and pontine hypoplasia with elongated cerebellar peduncles leading to the molar tooth sign. While the malformation is reminiscent of bilateral frontoparietal polymicrogyria (BFPP), the phenotype is more severe than previously reported and also includes features of Joubert syndrome (JBTS). Via exome sequencing, we identified homozygous truncating mutations in both ADGRG1/GPR56 and KIAA0556, which are known to cause BFPP and mild brain-specific JBTS, respectively. This study shows how two independent mutations can interact leading to complex brain malformations.

中文翻译：

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一个在ADGRG1 / GPR56和KIAA0556中出现新的截断突变的家庭中的多小神经生殖系统，脑积水和Joubert综合征的重叠。

与脑畸形相关的遗传突变会导致一系列严重性，通常很难确定是否有其他致病性变体影响该表型。在这里，我们介绍了一个受严重脑畸形影响的家庭，其中包括双侧多毛小脑，脑积水，斑块状白质信号变化以及小脑和桥脑发育不全，小脑柄长而导致磨牙。尽管该畸形使人联想到双边额叶前部多菌质性小胶质细胞增多症（BFPP），但该表型比以前报道的更为严重，并且还具有Joubert综合征（JBTS）的特征。通过外显子组测序，我们在ADGRG1 / GPR56和KIAA0556中鉴定出纯合的截短突变，已知分别导致BFPP和轻度的大脑特异性JBTS。这项研究显示了两个独立的突变如何相互作用，从而导致复杂的大脑畸形。