Phenotypic variability in Joubert syndrome is partially explained by ciliary pathophysiology

Ann Hum Genet. 2024 Jan;88(1):86-100. doi: 10.1111/ahg.12537. Epub 2023 Nov 3.


Introduction: Joubert syndrome (JS) arises from defects of primary cilia resulting in potential malformations of the brain, kidneys, eyes, liver, and limbs. Several of the 35+ genes associated with JS have recognized genotype/phenotype correlations, but most genes have not had enough reported individuals to draw meaningful conclusions.

Methods: A PubMed literature review identified 688 individuals with JS across 32 genes and 112 publications to bolster known genotype/phenotype relationships and identify new correlations. All included patients had the "molar tooth sign" and a confirmed genetic diagnosis. Individuals were categorized by age, ethnicity, sex and the presence of developmental disability/intellectual disability, hypotonia, abnormal eye movements, ataxia, visual impairment, renal impairment, polydactyly, and liver abnormalities.

Results: Most genes demonstrated unique phenotypic profiles. Grouping proteins based on physiologic interactions established stronger phenotypic relationships that reflect known ciliary pathophysiology. Age-stratified data demonstrated that end-organ disease is progressive in JS. Most genes demonstrated a significant skew towards having variants with either residual protein function or no residual protein function.

Conclusion: This cohort demonstrates that clinically meaningful genotype/phenotype relationships exist within most JS-related genes and can be referenced to allow for more personalized clinical care.

Keywords: Joubert syndrome; agenesis of cerebellar vermis; ciliopathies; genetic association studies; precision medicine.

MeSH terms

  • Abnormalities, Multiple* / genetics
  • Biological Variation, Population
  • Cerebellum / abnormalities
  • Eye Abnormalities* / genetics
  • Humans
  • Kidney Diseases, Cystic* / genetics
  • Proteins / genetics
  • Retina / abnormalities


  • Proteins

Supplementary concepts

  • Agenesis of Cerebellar Vermis