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Primary cilia are cellular organelles which mediate key signaling pathways during development, such as the sonic hedgehog (SHH) pathway which is required for neuroepithelium and central nervous system development. Joubert syndrome is a primary ciliopathy characterized by cerebellar\/brain stem malformation, hypotonia, and developmental delays. At least 35 genes are associated with Joubert syndrome, including the gene <jats:italic>KIAA0753,<\/jats:italic> which is part of a complex required for primary ciliogenesis. The phenotypic spectrum associated with biallelic pathogenic variants in <jats:italic>KIAA0753<\/jats:italic> is broad and not well\u2010characterized. We describe four individuals with biallelic pathogenic <jats:italic>KIAA0753<\/jats:italic> variants, including five novel variants. We report in vitro results assessing the function of each variant indicating that mutant proteins are not fully competent to promote primary ciliogenesis. Ablation of KIAA0753 in vitro blocks primary ciliogenesis and SHH pathway activity. Correspondingly, <jats:italic>KIAA0753<\/jats:italic> patient fibroblasts have a deficit in primary ciliation and improper SHH and WNT signaling, with a particularly blunted response to SHH pathway stimulation. Our work expands the phenotypic spectrum of KIAA0753 ciliopathies and demonstrates the utility of patient\u2010focused functional assays for proving causality of genetic variants.<\/jats:p>","DOI":"10.1002\/ajmg.a.62497","type":"journal-article","created":{"date-parts":[[2021,9,15]],"date-time":"2021-09-15T11:33:58Z","timestamp":1631705638000},"page":"104-115","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Genetic and phenotypic heterogeneity in <scp>KIAA0753<\/scp>\u2010related ciliopathies"],"prefix":"10.1002","volume":"188","author":[{"given":"Katherine A.","family":"Inskeep","sequence":"first","affiliation":[{"name":"Division of Human Genetics Cincinnati Children's Hospital Medical Center  Cincinnati Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8235-6200","authenticated-orcid":false,"given":"Yuri A.","family":"Zarate","sequence":"additional","affiliation":[{"name":"Section of Genetics and Metabolism University of Arkansas for Medical Sciences  Little Rock Arkansas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danielle","family":"Monteil","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Naval Medical Center Portsmouth  Portsmouth Virginia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jurgen","family":"Spranger","sequence":"additional","affiliation":[{"name":"Children's Hospital University of Mainz  Mainz Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9377-028X","authenticated-orcid":false,"given":"Dan","family":"Doherty","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Center on Human Development and Disability University of Washington  Seattle Washington USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rolf W.","family":"Stottmann","sequence":"additional","affiliation":[{"name":"Division of Human Genetics Cincinnati Children's Hospital Medical Center  Cincinnati Ohio USA"},{"name":"Division of Developmental Biology Cincinnati Children's Hospital Medical Center  Cincinnati Ohio USA"},{"name":"Department of Pediatrics University of Cincinnati College of Medicine  Cincinnati Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3991-135X","authenticated-orcid":false,"given":"K. 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