一个婴儿神经轴索营养不良家系的基因变异分析

目的对1个临床拟诊婴儿神经轴索营养不良(infantile neuroaxonal dystrophy,INAD)家系的患儿及父母进行基因变异分析,明确其致病原因为遗传咨询及产前诊断提供依据。方法应用高通量测序方法对患儿相关致病基因进行初步筛查,再通过直接测序对患儿及父母可疑致病基因进行验证,寻找可能的致病突变位点,采用SIFT及PolyPhen-2生物信息学软件对变异位点进行致病性预测。结果高通量测序筛查显示患儿PLA2G6基因第5和第16外显子存在可疑致病突变;Sanger测序结果显示患儿PLA2G6基因第5外显子c.668C>A(p.Pro223Gln)和第16外显子c.2266C>T(p.Gln756Ter)复合杂合变异,父亲携带c.668C>A杂合变异,母亲携带c.2266C>T杂合变异。c.668C>A变异导致PLA2G6基因编码的第223位脯氨酸被谷氨酰胺替代,为已报道的致病变异;c.2266C>T变异导致编译第756位谷氨酰胺的密码子变为终止密码,使肽链合成提前终止,该变异尚未见文献报道,蛋白功能预测为有害变异;患儿的复合杂合变异分别来自父母。结论PLA2G6基因第5外显子c.668C>A(p.Pro223Gln)和第16外显子c.2266C>T(p.Gln756Ter)变异可能是患儿的致病原因,新变异的发现丰富了PLA2G6基因变异谱。

Analysis of PLA2G6 gene variant in a family affected with infantile neuroaxonal dystrophy

Objective To identify potential variant in a child diagnosed as infantile neuroaxonal dystrophy.Methods Genomic DNA was extracted from peripheral blood samples from the patient and his parents and subjected to next generation sequencing.Suspected variant was verified by PCR and Sanger sequencing.Pathogenicity of the mutation was predicted by using bioinformatic software including SIFT and PolyPhen-2.Results The child was found to carry compound heterozygous variations c.668C>A(p.Pro223Gln)and c.2266C>T(p.Gln756Ter)of the PLA2G6 gene,which were respectively inherited from his father and mother.c.2266C>T has changed codon 756(glutamine)into a stop codon,resulting premature termination of peptide chain synthesis.c.2266C>T has not been reported previously and was predicted to be harmful.Conclusion The compound variants of c.668C>A(p.Pro223Gln)and c.2266C>T(p.Gln756Ter)of the PLA2G6 gene probably underlies the disease in the child.Above finding has enriched the variant spectrum of the PLA2G6 gene.