Novel PIBF1 Pathogenic Variant in Three Siblings with Joubert Syndrome Type 33

BACKGROUND: Joubert syndrome type 33 (JBTS33) is a rare autosomal recessive disorder characterized by developmental delay, severe renal disease, hypotonia/ataxia, cerebellar vermian hypoplasia/aplasia, optic nerve atrophy, renal atrophy, and the “molar tooth sign” on imaging. Nearly 40 genes associated with Joubert syndrome have been identified, including CEP290, TMEM216, TMEM67, AHI1, and CC2D2A. METHODS: We report a consanguineous family with JBTS33 diagnosed through whole-exome sequencing. A novel biallelic homozygous nonsense mutation (ENST00000326291.11: c.1231C>T; p.Arg411Ter) in progesterone-induced blocking factor 1 (PIBF1) was identified. RESULTS: Our study included 3 patients with the same homozygous mutation in PIBF1, which contributed to clinical features such as psychomotor issues, dysmorphic features, hypotonia/ataxia, kidney failure, and possibly seizures. All 3 patient seizures have been eliminated after phenobarbital administration. This mutation has not been reported in public databases. CONCLUSION: This study confirmed PIBF1 as a disease-causing gene for JBTS33, expanding the molecular and clinical spectrum of JBTS. Our findings underscore the importance of identifying the genetic underpinnings and phenotypic expansions of PIBF1 mutations. Enhanced diagnostic awareness can facilitate early intervention and management. Further research is required to elucidate the relationship between PIBF1 mutations and associated clinical manifestations.