Genotype-phenotype correlates in Joubert syndrome: A review

Am J Med Genet C Semin Med Genet. 2022 Mar;190(1):72-88. doi: 10.1002/ajmg.c.31963. Epub 2022 Mar 3.


Joubert syndrome (JS) is a genetically heterogeneous primary ciliopathy characterized by a pathognomonic cerebellar and brainstem malformation, the "molar tooth sign," and variable organ involvement. Over 40 causative genes have been identified to date, explaining up to 94% of cases. To date, gene-phenotype correlates have been delineated only for a handful of genes, directly translating into improved counseling and clinical care. For instance, JS individuals harboring pathogenic variants in TMEM67 have a significantly higher risk of liver fibrosis, while pathogenic variants in NPHP1, RPGRIP1L, and TMEM237 are frequently associated to JS with renal involvement, requiring a closer monitoring of liver parameters, or renal functioning. On the other hand, individuals with causal variants in the CEP290 or AHI1 need a closer surveillance for retinal dystrophy and, in case of CEP290, also for chronic kidney disease. These examples highlight how an accurate description of the range of clinical symptoms associated with defects in each causative gene, including the rare ones, would better address prognosis and help guiding a personalized management. This review proposes to address this issue by assessing the available literature, to confirm known, as well as to propose rare gene-phenotype correlates in JS.

Keywords: Joubert syndrome; ciliopathies; genotype-phenotype correlations; pleiotropy; primary cilia.

Publication types

  • Review
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abnormalities, Multiple* / diagnosis
  • Antigens, Neoplasm / genetics
  • Cell Cycle Proteins / genetics
  • Cerebellum / abnormalities
  • Cytoskeletal Proteins / genetics
  • Eye Abnormalities* / pathology
  • Female
  • Genotype
  • Humans
  • Kidney Diseases, Cystic* / genetics
  • Male
  • Phenotype
  • Retina / abnormalities
  • Retina / pathology


  • Antigens, Neoplasm
  • Cell Cycle Proteins
  • Cep290 protein, human
  • Cytoskeletal Proteins

Supplementary concepts

  • Agenesis of Cerebellar Vermis