Identifying the genetic causality of familial IgAN by a new analysis system

为了确定家族性IgAN的遗传因果关系，我们对一个由四个活检证实的IgAN患者组成的家庭进行了外显子组测序。同时进行全基因组连锁分析。13个仅由家族中受影响个体共享的变异体被选为家族性IgAN的候选基因。该家族的连锁分析揭示了9个位点的连锁信号，在候选基因中，EEA1中有一个新的错义变体F161Y，编码早期内核体抗原1。此外，F161Y变体在家族中完全共分离，并且该变体存在于斑马鱼到人类的高度保守区域。EEA1的重排序分析显示，在另外27个家族性IgAN中，有6个家族携带EEA1中另外3个变体。这些EEA1基因在家族性IgAN中的变异频率显著高于The Human Genetic Variation Database，表明EEA1基因是日本家族性IgAN的易感基因。

To identify the genetic causality of familial IgAN, we applied exome sequencing to a family comprising four biopsy-proven IgAN patients. Genome-wide linkage analysis was concurrently carried out. Thirteen variants which were shared only by affected individuals in the family were selected as candidate genes for familial IgAN. Linkage analysis of the family revealed linkage signals at nine loci, and among the candidates, a novel missense variant F161Y in EEA1, encoding Early Endosome Antigen 1. Furthermore, the F161Y variant completely co-segregated in the family and this variant is existed in the highly conserved region across zebrafish to human. Resequence analysis of EEA1 revealed that among additional 27 familial IgAN, six families carried the other three variants within EEA1. Frequencies of these EEA1 variants in familial IgAN was significantly higher than those in The Human Genetic Variation Database, indicating that EEA1 gene is a susceptibility gene for Japanese familial IgAN.