KATNIP was first reported in relation to autosomal recessive ciliopathy-KATNIP (MONDO:0005308) in 2015 (Sanders AA et al., PMID: 26714646). Individuals with ciliopathy KATNIP presented with Joubert syndrome and abnormalities of the anterior and posterior pituitary gland and sometimes retinal dystrophy, cleft lip/palate, agenesis of the corpus callosum, and hypothalamic hamartoma. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no differences in molecular mechanism and inheritance pattern and no significant phenotypic variability. KATNIP has previously been associated with only one disease entity: autosomal recessive Joubert syndrome 26 (MIM #616784). Eight variants (nonsense, frameshift, splice-site) that have been reported in 6 probands in 6 publications (PMIDs: 26714646, 27245168, 31197031, 36580738, 32164589, 30982090) are included in this curation. The mechanism of pathogenicity is reported to be loss of function. This gene-disease relationship is also supported by experimental evidence, most importantly protein interaction studies showing KATNIP interacting with ciliary components and microtubule-regulating katanins, patient-derived fibroblasts showing primary cilium alterations, and a knockdown zebrafish model presenting a ciliopathy phenotype (PMIDs: 27245168 & 26714646).
In summary, there is “Definitive” evidence supporting the relationship between KATNIP and autosomal recessive ciliopathy- KATNIP (MONDO:0005308). This has been repeatedly demonstrated in both the research and clinical diagnostic settings and upheld over time. This classification was approved by the ClinGen Kidney Cystic and Ciliopathy Disorders GCEP on 07/10/2023.
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