Unraveling the genetic causes in large pedigrees with gout by whole-exome sequencing

Gout is a common type of inflammatory arthritis that is clinically and genetically heterogeneous. The genetic aetiology remains unclear, and mainly relies on previous genome-wide association studies focused on sporadic cases. The present study aimed to identify the genetic basis of gout in three families using whole-exome sequencing (WES). WES was performed in the probands, and family members were involved in the co-segregation analysis. In total, three deleterious rare or novel missense mutations were identified in ATP-binding cassette super-family G member 2 (ABCG2), protein kinase CGMP-dependent 2 (PRKG2) and adrenoceptor beta 3 (ADRB3) genes in three different families. In addition, certain gout-associated candidate genes were revealed to be shared among the co-expression and protein-protein interaction (PPI) networks of ABCG2, PRKG2 and ADRB3. Furthermore, the disease ontology analysis of the genes present in the co-expression network exhibited significant (P<0.05) enrichment in hyperuricemia, gout, cardiovascular system disease and metabolic disease. In addition, genes involved in the PPI network were significantly enriched in the purine nucleoside monophosphate biosynthetic process, urate transport and biological processes associated with glycose metabolism. Collectively, to the best of our knowledge, the present study was the first to use WES to identify three candidate rare or novel deleterious mutations in three families with gout. The present results provided novel insights that may improve the current understanding of the molecular genetic basis underlying gout. Importantly, the present results may facilitate the improvement of clinical diagnosis and the development of novel personalized therapies.