Primary cilia are critical sensing and signaling hubs that extend from nearly all mammalian cell types. Ciliopathies are a spectrum of human disorders associated with defects in cilia formation and function that result in a wide and variable range of clinical features, often with low genotype to phenotype correlation. This phenotypic variability may stem from the presence of multiple modifier alleles causing different degrees of primary cilia dysfunction. To identify modifier alleles, we conducted a mutagenesis screen in C. elegans with a primary mutation in the ciliary transition zone component,
nphp-4(
tm925), and looked for secondary mutations that caused ciliary dysfunction. From this screen, we identified a mutation in the BBSome component,
bbs-5(
yhw62), as a genetic modifier of
nphp-4(
tm925) mutants. By assessing a variety of behaviors associated with ciliated sensory neuron function, including chemotaxis and egg laying, we find that our novel
bbs-5(
yhw62) mutation causes enhanced ciliary defects when compared to an existing mutation,
bbs-5(
gk537). In addition, we observe that
bbs-5;
nphp-4 double mutants carrying either
bbs-5 mutation display dye filling defects in ciliated sensory neurons and defects in dauer formation not seen in single mutants alone. We have also investigated whether the genetic interaction between
bbs-5 and
nphp-4 is conserved in two vertebrate models, zebrafish and mouse. In adult Bbs5; Nphp4 zebrafish, we observe scoliosis and disorganization of the outer nuclear layer of the retinal photoreceptor cells, although these phenotypes are also observed in adult Bbs5 single mutant animals. In contrast to zebrafish, mice with congenital expression of both Bbs5 and Nphp4 do not survive to weaning age. Juvenile induction of Bbs5 loss in an Nphp4 mutant background is associated with seizure-like activity and early mortality. These results suggest that the genetic interaction between
bbs-5 and
nphp-4 identified in C. elegans that causes enhanced ciliary dysfunction may be conserved in mice, but not in zebrafish. The mammalian conservation of this genetic interaction provides excellent rationale to pursue further mechanistic studies in C. elegans.