PIBF1 – Joubert syndrome

PIBF1 has emerged as a critical gene underlying Joubert syndrome, a disorder characterized by global developmental delay, hypotonia, abnormal facial features, and the distinctive molar tooth sign on brain imaging (PMID:29695797). Several independent studies report biallelic pathogenic variants in PIBF1 in affected patients, reinforcing its role in this clinically heterogeneous ciliopathy.

The clinical validity of the PIBF1–Joubert syndrome association is rated as Strong. Evidence stems from at least five unrelated probands in distinct case reports and series, with autosomal recessive inheritance patterns consistently observed (PMID:29695797; PMID:33004012). Family segregation analyses, although limited in size (0 additional affected relatives reported beyond probands), further cement the reproducibility of the genotype–phenotype relationship.

Genetic evidence reveals a diverse variant spectrum including missense, frameshift, and truncating mutations. A representative variant is reported as c.1508A>G (p.Tyr503Cys), which aligns with autosomal recessive inheritance and has been identified in a patient with compound heterozygous mutations (PMID:30858804; PMID:33004012). These findings support the use of PIBF1 genetic testing in patients with Joubert syndrome phenotypes.

Functional studies provide additional support for the pathogenic role of PIBF1 variants. In particular, experiments in the Xenopus model demonstrated that knockdown of pibf1 leads to defective ciliary function and that patient-specific alleles, including p.Tyr503Cys, show an attenuated rescue of the phenotype (PMID:30858804). These results are consonant with a mechanism involving disrupted cilia biogenesis, a known contributor to Joubert syndrome pathology.

Integration of genetic and experimental data consolidates the clinical utility of PIBF1 testing. The convergence of multiple lines of evidence—including several case reports, segregation in autosomal recessive families, and corroborative functional analyses—strongly supports the role of PIBF1 in Joubert syndrome. This association informs diagnostic decisions and highlights the potential for incorporating PIBF1 in targeted gene panels.

Key take‑home message: PIBF1 is a robust diagnostic marker for Joubert syndrome, with both genetic and functional evidence underscoring its pathogenic impact; its testing should be integrated into clinical workflows to enhance accurate diagnosis and personalized care.

References

• Journal of human genetics • 2018 • A biallelic 36-bp insertion in PIBF1 is associated with Joubert syndrome PMID:29695797
• Frontiers in physiology • 2019 • The Frog Xenopus as a Model to Study Joubert Syndrome: The Case of a Human Patient With Compound Heterozygous Variants in PIBF1 PMID:30858804
• BMC medical genetics • 2020 • Identification of two novel pathogenic variants of PIBF1 by whole exome sequencing in a 2-year-old boy with Joubert syndrome PMID:33004012
• Journal of movement disorders • 2021 • Clinical and Imaging Profile of Patients with Joubert Syndrome PMID:34592808

Evidence Based Scoring (AI generated)