一例DYM基因移码变异所致Dyggve-Melchior-Clausen综合征患儿的临床及遗传学分析

Clinical and genetic analysis of a Chinese pedigree affected with Dyggve-Melchior-Clausen syndrome due to a novel frameshift variant of DYM gene

目的对1个Dyggve-Melchior-Clausen综合征家系进行基因变异检测,明确其遗传学病因。方法应用全外显子及Sanger测序对家系成员进行致病变异检测,并通过蛋白免疫印迹法(Western blotting)对变异位点进行功能分析。结果测序结果显示家系的两例患儿DYM基因均存在c.1222delG纯合变异,其父母均为杂合变异携带者。该变异为未报道的新变异,导致DYM蛋白第408位氨基酸由Asp变为Met,并在移码10个氨基酸后提前终止(p.Asp408Metfs*10)。蛋白免疫印迹法结果显示,c.1222delG变异导致DYM突变型蛋白被降解,为功能丧失型变异。结论DYM基因c.1222delG纯合变异可能为该家系患儿的致病原因,可为临床诊断和遗传咨询提供依据。

Objective To explore the genetic basis of a Chinese pedigree affected with Dyggve-Melchior-Clausen syndrome.Methods Whole exome sequencing and Sanger sequencing were carried out to detect potential pathogenic variants associated with the syndrome.The function of candidate variant was verified by Western blotting.Results A novel homozygous variant,c.1222delG of the DYM gene was detected in the two affected siblings,for which both parents were heterozygous carriers.The variant has caused replacement of Asp by Met at amino acid 408 and generate a premature stop codon p.Asp408Metfs*10.Western blotting confirmed that the variant can result in degradation of the mutant DYM protein,suggesting that it is a loss of function variant.Conclusion The homozygous c.1222delG frameshift variant of the DYM probably underlay the Dyggve-Melchior-Clausen syndrome in the two affected siblings.Above findings has enabled clinical diagnosis and genetic counseling for the family.