Mouse genetics reveals Barttin as a genetic modifier of Joubert syndrome.

Abstract

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 <i>Bsnd</i> (alias <i>Barttin</i>) as a genetic modifier of cystic kidney disease in Joubert syndrome, using a <i>Cep290</i>-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 <i>Bsnd</i> in the parental mouse strain phenocopied the severe cystic kidney phenotype. A common polymorphism within human <i>BSND</i> significantly associates with kidney disease severity in a patient cohort with <i>CEP290</i> 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.