Submission Details

The *PIBF1 (CEP90, C13orf24) *gene is located on chromosome 13 at 13q21.33-q22.1 and encodes the progesterone immunomodulatory binding factor 1(Pibf1) protein. Pibf1 is induced by the steroid hormone progesterone and overexpressed in highly proliferating cells. Pibf1 is a core component of the centrosome and encodes a centrosomal protein crucial for the accumulation of centriolar satellites, eventually forming the primary cilia. Depletion of Pibf1 is known to cause mitotic arrest, misaligned chromosomes, and spindle pole fragmentation. Pibf1 is expressed in many organs, including the brain, kidney, and liver, with the highest expression in the testis and thyroid. Additionally, the protein regulates the immune system to maintain a normal pregnancy.

Multiple disease entities have been reported in association with this gene. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, there was no evidence of differences in their molecular mechanism, inheritance pattern, and phenotypic spectrum. Therefore, the following disease entities have been lumped into one disease Joubert Syndrome (JBST) MIM 617767, the mode of inheritance being autosomal recessive. PIBF1 was first reported in relation to JBST, a classic ciliopathy, in 2015 with an autosomal recessive mode of inheritance, by Wheway et al., PMID: 26167768. The mechanism of pathogenicity reported is loss of function. PIBF1 is associated with marked phenotypic variability. JBST is a neurodevelopmental disease which is characterized by malformation in the cerebellum and brainstem, recognizable on axial brain magnetic resonance imaging (MRI) as a “molar tooth sign”, the diagnostic hallmark. Patients typically present as infants with hypotonia, abnormal eye movement, respiratory problems, and ataxia. JBST is manifested in multiple body systems including the eyes, kidney, liver, and skeleton.

Ten variants (missense (5), nonsense (1), frameshift (3), insertion (1) have been reported in 5 families (11 individuals) in 5 publications (PMIDs: 26167768, 29695797,30858804, 33004012, 34592808) included in this curation. A total of 7.4/12 pts. genetic evidence was reached, considering case-level and segregation data.This gene-disease relationship is also supported by functional and expression studies, in vitro assays of non-patient cells, animal models, and rescue assays. Wheway, et al, (PMID: 26167768) used siRNA knockdown to screen for ciliogenesis genes across the genome. They demonstrated that exogenous expression of human wild-type PIBF1 rescued ciliogenesis defects in mIMCD3 cells following siRNA knockdown of endogenous Pibf1, while expression of PIBF1 containing the p.Asp637Ala Hutterite variant was unable to rescue normal ciliogenesis. Ott et al., 2019 (PMID: 30858804) conducted functional analysis of wildtype and mutant pidf1 alleles in Xenopus embryos demonstrating no rescue with the nonsense variant, p.Gln485Ter but partial rescue with the missense variant, p.Tyr503Cys. Their analysis of pibf1 alleles demonstrated a role of Pibf1 in motile cilia of larval skin in the Xenopus, and generating a phenotype consistent with that seen in human JBST. Additionally, Ott et al., demonstrated Pibf1protein was expressed in both cells and tissue (motile cilia cells of the larval skin). Kim and Rhee, 2019 (PMID 23110211) examined the biological function of PIBF1 in interphase cells, by performing rescue experiments and demonstrated that PIBF1 physically interacts with PCM-1 at centriolar satellites; The interaction of PIBF1 with PCM-1 is important for centrosomal accumulation of the centriolar satellites, which is essential for primary cilia formation. Finally, a mouse model (PMID: 3421634) was reported with several phenotypes that overlap with JBST, including abnormal neural tube closure, abnormal lens morphology, embryonic growth retardation, and abnormal sleep behaviors. A total of 3.5/6 pts. experimental evidence was reached.

In summary, there is Moderate evidence supporting the relationship between PIBF1 and autosomal recessive JBST 33. This has been demonstrated in both the research and clinical diagnostic settings and has been upheld over time.This classification was approved by the ClinGen Kidney Cystic GCEP on the meeting date 09/27/2023(SOP Version 9).