Mouse genetics reveals Barttin as a genetic modifier of Joubert syndrome

Significance Our current understanding of genetic disease is often inadequate, largely due to genetic background effects that modify disease presentation. This is particularly challenging for rare diseases that lack sufficient numbers of patients for genome-wide association studies. We show in a series of experiments using a murine model of Joubert syndrome, a multisystem ciliopathy, that a single locus is a modifier of cystic kidney disease. We go on to show that the human homolog plays a similar role in disease using a cohort of patients. These findings make a significant contribution to the underplayed (and often ignored) role of genetic background in murine models and how this can be exploited to understand further rare inherited disease. Genetic and phenotypic heterogeneity and the lack of sufficiently large patient cohorts pose a significant challenge to understanding genetic associations in rare disease. Here we identify Bsnd (alias Barttin) as a genetic modifier of cystic kidney disease in Joubert syndrome, using a Cep290-deficient mouse model to recapitulate the phenotypic variability observed in patients by mixing genetic backgrounds in a controlled manner and performing genome-wide analysis of these mice. Experimental down-regulation of Bsnd in the parental mouse strain phenocopied the severe cystic kidney phenotype. A common polymorphism within human BSND significantly associates with kidney disease severity in a patient cohort with CEP290 mutations. The striking phenotypic modifications we describe are a timely reminder of the value of mouse models and highlight the significant contribution of genetic background. Furthermore, if appropriately managed, this can be exploited as a powerful tool to elucidate mechanisms underlying human disease heterogeneity.