Detection of COL4A3, COL4A4, and COL4A5 gene mutations in Chinese families with Alport syndrome

Objective To analyse the mutations of COL4A3, COL4A4, and COL4A5 genes in Chinese families with Alport syndrome, and to explore the possibility that Alport syndrome is under a new genetic model. Methods We were to determine the genetic defects in proband with Alport syndrome by next-generation sequencing to capture exons of COL4A3, COL4A4, COL4A5 genes. The gene mutations of the related family members were identified by Sanger method. The SIFT and Polyphen softwares were applied for protein function prediction. We collected the clinical data and analysed the association between genotype and phenotype. Results The heterozygous COL4A4 mutation c.2840C>T (p.947R>Q) and COL4A5 mutation c.3246G>A (p.1082K>K) were detected in proband of Family 1. The COL4A3 missense mutation c.3627G>A (1209M>I) and a homozygous COL4A5 mutation in splice site IVS21-2A>G were identified in proband of Family 2. The proband of Family 3 were found with COL4A3 missense mutation c.3476G>A(p.1159R>H) and COL4A5 missense mutation c.3517G>A(p.1173G>S). The same mutations with proband were found in some members of the three families respectively. With different genotypes, there was wide phenotypic variability of family members. Conclusion Digenic inheritance may be an alternative genetic model of Alport syndrome. We found a close connection between genotype and phenotype. Key words: Alport syndrome; Genetic model; Genotype; Phenotype