Genetic diagnosis of polycystic kidney disease, Alport syndrome, and thalassemia minor in a large Chinese family

Polycystic kidney disease (PKD) and Alport syndrome (AS) are serious inherited disorders associated with renal disease, and thalassemia is a hereditary blood disease with a high prevalence in south China. Here, we report an exceptional PKD coincidence of thalassemia minor and AS (diagnosed genetically) in a large Chinese family. Whole genome next-generation sequencing (NGS) was performed on the proband, and all family members underwent clinical evaluation. Sanger sequencing was used to validate the mutations distinguished by NGS. The pathogenic potential of the variants were evaluated by Polymorphism Phenotyping v2 (PolyPhen-2), Sorting Intolerant From Tolerant (SIFT) algorithm, and MutationTaster. Immunohistochemical, Western blot, immunofluorescent, and TdT-mediated dUTP nick-end labeling (TUNEL) analyses were performed to investigate polycystin 1 (PC1) expression, and cell proliferation and apoptosis in kidney tissues from the proband and normal control. A novel frameshift polycystic kidney disease 1 (PKD1) mutation (c.3903delC, p.A1302Pfs) was identified to be responsible for renal disease in this family. PC1 expression, and cell proliferation and apoptosis were significantly increased in the kidney tissues of the proband. Moreover, a deletion of approximately 19.3 kb of DNA with alpha-globin genes (--(SEA)) was associated with thalassemia minor in the family. In addition, a collagen type IV alpha 5 chain (COL4A5) variant (c.2858G>T, rs78972735), annotated as a pathogenic mutation in dbSNP and human gene mutation database (HGMD), was found in four family members with no clinical traits of AS. A novel pathogenic PKD1 mutation (c.3903delC) and (--(SEA)) thalassemia deletion were found to be responsible for the clinical symptoms in this family. The reported pathogenic COL4a5 variant (c.2858G>T, rs78972735) was not pathogenic alone.