We present ARL3 as a ciliopathy- and JBTS-associated gene. LdARL-3A, a Leishmania homolog of ARL3, is an essential component of flagellum formation.24 Arl3 knockdown has previously been investigated in a gene-trap murine model, where Arl3 was disrupted after the first exon.25 These Arl3−/− mice, which represent a null allele, developed a severe ciliopathy phenotype with pronounced cystic kidney disease, pancreatic hypoplasia, ductal plate malformation within the liver, and retinal dystrophy with impaired photoreceptor development.25 The mice died within 3 weeks of age, indicating a severe phenotype, which is much more detrimental than that of our human subjects, who carry a missense mutation. We speculate that nonsense mutations in ARL3 in humans could cause more pronounced ciliopathy phenotypes, such as the perinatally lethal ciliopathy Meckel syndrome,26 and could go some way to explaining why such a fundamental gene has previously not been identified in ciliopathy syndromes. It is noteworthy that the ExAC Browser and gnomAD do not have any homozygous pathogenic variants reported within ARL3 and that the gene is relatively intolerant to variation (positive Z score of 0.44). We did not identify any additional ARL3 pathogenic variants in our WES databases, which are relatively enriched with autozygosity, or in a cohort of 35 unsolved JBTS-affected individuals.