We describe bi-allelic variants in TULP3 in 15 individuals from eight unrelated families and establish by further in vitro and in vivo experiments variants in TULP3 as a monogenic cause for a clinically distinct disorder of progressive degenerative liver fibrosis with variable fibrocystic kidney disease and hypertrophic cardiomyopathy. This evidence concerns the gene TULP3 and hypertrophic cardiomyopathy.