SUFU – Joubert Syndrome

The SUFU gene encodes a key negative regulator of the Sonic Hedgehog (SHH) pathway, essential for cerebellar and limb development. Joubert syndrome is a recessively inherited ciliopathy characterized by congenital ataxia, cerebellar vermis hypoplasia, elongated superior cerebellar peduncles, cranio-facial dysmorphism, and postaxial polydactyly. The association between SUFU and Joubert syndrome is supported by genetic and functional evidence demonstrating biallelic hypomorphic variants that impair SHH repression.

The clinical validity of SUFU in Joubert syndrome is classified as Moderate based on identification of four probands from two unrelated families with a consistent autosomal recessive inheritance pattern and concordant functional data (PMID:28965847).

Genetic evidence shows that whole-exome sequencing in four affected children from two unrelated pedigrees revealed homozygous missense and truncating SUFU variants. All probands presented with congenital ataxia, cerebellar vermis hypoplasia, elongated superior cerebellar peduncles, hypertelorism, frontal bossing, and postaxial polydactyly. Representative variants include c.1274C>T (p.Ala425Val) and c.895C>T (p.Arg299Ter) (PMID:28965847). The autosomal recessive inheritance is supported by absence of disease in heterozygous carriers.

Functional studies in cellular models and patient fibroblasts demonstrated that SUFU hypomorphic variants significantly reduce protein stability and binding to GLI3, impairing its processing into the repressor form GLI3R. Molecular dynamics simulations predicted altered conformational movements at the GLI3 binding site. This leads to derepression of SHH target genes, consistent with the observed developmental defects (PMID:28965847).

No conflicting evidence has been reported to date for SUFU’s role in Joubert syndrome. The loss-of-function mechanism via impaired GLI3 repression is concordant across genetic and functional assays.

Integration of genetic and experimental findings supports that germline hypomorphic SUFU variants cause a distinct form of autosomal recessive Joubert syndrome. Additional evidence from larger cohorts and long-term follow-up could strengthen this association. Key take-home: SUFU should be included in diagnostic gene panels for Joubert syndrome to inform genetic counseling, prognosis, and potential pathway-targeted therapies.

References

• American Journal of Human Genetics • 2017 • Hypomorphic Recessive Variants in SUFU Impair the Sonic Hedgehog Pathway and Cause Joubert Syndrome with Cranio-facial and Skeletal Defects. PMID:28965847

Evidence Based Scoring (AI generated)