Analysis of a child with X-linked intellectual disability due to a maternal de novo splicing variant of thePAK3 gene
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目的 探讨1例具有严重智力障碍和明显行为异常的患儿的遗传学病因。 方法 采集2020年12月2日就诊于武汉大学中南医院的1例具有智力障碍和行为异常患儿及其父母的外周血样，进行全外显子组测序，并通过Sanger测序对其家系成员进行共分离验证。采用短串联重复序列分析对患儿母亲携带的变异进行溯源，并通过minigene实验对剪接变异进行体外功能验证。 结果 全外显子组测序发现患儿携带母源性PAK3基因c.176-2A>G剪接变异。Sanger测序及短串联重复序列分析证实其母亲携带的变异为新发变异。Minigene实验结果证实其第2外显子存在异常剪接。根据美国医学遗传学与基因组学学会变异相关指南，该变异评级为致病性变异(PVS1+PS3+PM2_Supporting+PP3) 结论 PAK3基因c.176-2A>G变异可能是患儿的遗传学病因。上述发现丰富了PAK3基因的变异谱，为患儿家庭的遗传咨询和产前诊断提供了依据。 Objective To explore the genetic etiology for a child with profound intellectual disabilities and obvious behavioral abnormalities. Methods A male child who had presented at the Zhongnan Hospital of Wuhan University on December 2, 2020 was selected as the study subject. Peripheral blood samples of the child and his parents were collected and subjected to whole exome sequencing (WES). Candidate variant was verified by Sanger sequencing. Short tandem repeat (STR) analysis was carried out to determine its parental origin. The splicing variant was also validated in vitro with a minigene assay. Results WES results revealed that the child had harbored a novel splicing variant of c. 176-2A>G in thePAK3 gene, which was inherited from his mother. The results of minigene assay have confirmed aberrant splicing of exon 2. According to the guidelines from the American College of Medical Genetics and Genomics, it was classified as a pathogenic variant (PVS1+ PM2_Supproting+ PP3). Conclusion The novel splicing variant c. 176-2A>G of thePAK3 gene probably underlay the disorder in this chlid. Above finding has expanded the variation spectrum of the PAK3 gene and provided a basis for genetic counseling and prenatal diagnosis for this family.
Objective To explore the genetic etiology for a child with profound intellectual disabilities and obvious behavioral abnormalities. Methods A male child who had presented at the Zhongnan Hospital of Wuhan University on December 2, 2020 was selected as the study subject. Peripheral blood samples of the child and his parents were collected and subjected to whole exome sequencing (WES). Candidate variant was verified by Sanger sequencing. Short tandem repeat (STR) analysis was carried out to determine its parental origin. The splicing variant was also validated in vitro with a minigene assay. Results WES results revealed that the child had harbored a novel splicing variant of c. 176-2A>G in thePAK3 gene, which was inherited from his mother. The results of minigene assay have confirmed aberrant splicing of exon 2. According to the guidelines from the American College of Medical Genetics and Genomics, it was classified as a pathogenic variant (PVS1+ PM2_Supproting+ PP3). Conclusion The novel splicing variant c. 176-2A>G of thePAK3 gene probably underlay the disorder in this chlid. Above finding has expanded the variation spectrum of the PAK3 gene and provided a basis for genetic counseling and prenatal diagnosis for this family.
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