神经相关基因甲基化和性别差异与家族性短QT综合征表型变异相关

Neuro-associated gene methylation and sex differences are associated with phenotypic variation in familial short QT syndrome

目的:探讨DNA甲基化在家族性短QT综合征遗传和表型变异中的作用。方法:对一个三代短QT综合征家系的7例患病个体和2名未患病个体的血液样本进行了研究。采用简化代表性亚硫酸氢盐测序来评估全基因组DNA甲基化模式,分析差异甲基化基因的遗传模式、差异甲基化区域和基因本体富集。结果:本研究没有发现可遗传的差异甲基化位点。我们在患病个体和未患病个体之间鉴定了2502个差异甲基化区域。高甲基化基因包括许多神经系统相关基因,如SYN1和NRXN1。对差异甲基化基因的基因本体富集分析进一步确定了神经系统的富集和激素水平的调节,这表明性别差异可能会影响表型。结论:与家族性短QT综合征相关的甲基化没有显著的遗传模式,差异甲基化区域富集分析提示短QT综合征表型差异可能具有跨代表观遗传效应。

Objective:To identify DNA methylation contributes to inheritance and phenotypic variation in family short QT syndrome.Methods:Blood samples from 7 affected and 2 unaffected individuals of a three-generation short QT syndrome family were investigated.The reduced representation bisulfite sequencing was performed to assess genome-wide patterns of DNA methylation.Inherited pattern,differentially methylated region and gene ontology enrichment for differentially methylated genes were investigated.Results:As a result,no differentially heritable methylated sites completely segregated with short QT syndrome phenotype and transmitted through three generations were observed.We identified 2502 differentially methylated regions between affected and unaffected individuals.The hypermethylated genes included many genes involved in nervous system,such as SYN1 and NRXN1.Gene ontology analysis of the differentially methylated genes further mainly identified enrichment of neuronal system and regulation of hormone levels,which indicated sex differences may influence an adverse phenotype.Conclusion:There is no significant genetic pattern of methylation associated with familial short QT syndrome,and enrichment analysis of differential methylation regions suggests that phenotypic differences in short QT syndrome may have intergenerational epigenetic inheritance.