GPNMB基因纯合变异导致色素异常性皮肤淀粉样变性一家系

Amyloidosis cutis dyschromica due to homozygous variants of the GPNMB gene in a pedigree

目的对1个色素异常性皮肤淀粉样变性家系的3例患者的GPNMB基因进行变异分析,明确其致病原因。方法对先证者行高通量测序,采用生物信息学方法寻找致病基因变异,并通过Sanger测序对家系内成员是否携带变异进行验证。结果先证者及其哥哥、妹妹GPNMB基因的第5外显子均存在c.565C>T(p.Arg189X)纯合无义变异,其变异后蛋白发生截短进而蛋白功能丧失。父亲携带c.565C>T(p.Arg189X)杂合变异,母亲因死亡无法验证。根据美国医学遗传学与基因组学学会遗传变异分类标准与指南,c.565C>T变异为可能致病性变异(PS3+PM2+PP1+PP3)。结论GPNMB基因第5外显子c.565C>T(p.Arg189X)纯合变异可能为该色素异常性皮肤淀粉样变性家系患者的致病原因,新变异的检出拓宽了GPNMB基因的变异谱。

Objective To explore the genetic basis for a Chinese pedigree affected with amyloidosis cutis dyschromica.Methods High throughput sequencing was carried out for the proband.Bioinformatic analysis was used to identify the pathogenic variants.The result was verified by Sanger sequencing.Results A homozygous nonsense variant c.565C>T(p.Arg189X)of the GPNMB gene was identified in the proband,his elder brother and younger sister,which resulted a truncated protein with loss of function.The father of the proband was a heterozygous carrier.The genotype of his mother was unknown since she had passed away.Based on the American College of Medical Genetics and Genomics standards and guidelines,the c.565C>T variant was predicted to be likely pathogenic(PS3+PM2+PP1+PP3).Conclusion The novel homozygous GPNMB variant probably underlay the amyloidosis cutis dyschromica in this pedigree.Above finding has expanded the variant spectrum of the GPNMB gene.