Prospective Evaluation of Kidney Disease in Joubert Syndrome

Clin J Am Soc Nephrol. 2017 Dec 7;12(12):1962-1973. doi: 10.2215/CJN.05660517. Epub 2017 Nov 16.


Background and objectives: Joubert syndrome is a genetically heterogeneous ciliopathy associated with >30 genes. The characteristics of kidney disease and genotype-phenotype correlations have not been evaluated in a large cohort at a single center.

Design, setting, participants, & measurements: We evaluated 97 individuals with Joubert syndrome at the National Institutes of Health Clinical Center using abdominal ultrasonography, blood and urine chemistries, and DNA sequencing.

Results: Patients were ages 0.6-36 years old (mean of 9.0±7.6 years old); 41 were female. Mutations were identified in 19 genes in 92 patients; two thirds of the mutations resided in six genes: TMEM67, C5orf42, CC2D2A, CEP290, AHI1, and KIAA0586. Kidney disease was detected in 30%, most commonly in association with the following genes: CEP290 (six of six), TMEM67 (11 of 22), and AHI1 (three of six). No kidney disease was identified in patients with mutations in C5orf42 (zero of 15) or KIAA0586 (zero of six). Prenatal ultrasonography of kidneys was normal in 72% of patients with kidney disease. Specific types of kidney disease included nephronophthisis (31%), an overlap phenotype of autosomal recessive polycystic kidney disease/nephronophthisis (35%), unilateral multicystic dysplastic kidney (10%), and indeterminate-type cystic kidney disease (24%). Early-onset hypertension occurred in 24% of patients with kidney disease. Age at ESRD (n=13) ranged from 6 to 24 years old (mean of 11.3±4.8 years old).

Conclusions: Kidney disease occurs in up to one third of patients with Joubert syndrome, most commonly in those with mutations in CEP290, TMEM67, and AHI1. Patients with mutations in C5orf42 or KIAA0586 are less likely to develop kidney disease. Prenatal ultrasonography is a poor predictor of kidney involvement in Joubert syndrome. Unilateral multicystic dysplastic kidney and autosomal recessive polycystic kidney disease-like enlarged kidneys with early-onset hypertension can be part of the Joubert syndrome kidney phenotype.

Keywords: Abnormalities, Multiple; Cerebellum; Ciliopathies; Eye Abnormalities; Genetic Association Studies; Joubert syndrome 1; Kidney Diseases, Cystic; Kidney Failure, Chronic; Multicystic Dysplastic Kidney; Mutation; Phenotype; Polycystic Kidney, Autosomal Recessive; Pregnancy; Prospective Studies; Retina; Sequence Analysis, DNA; Ultrasonography, Prenatal; ciliopathy; cystic kidney; genetic renal disease; hypertension; kidney; nephronophthisis; polycystic kidney disease.

MeSH terms

  • Abnormalities, Multiple / diagnostic imaging
  • Abnormalities, Multiple / genetics*
  • Abnormalities, Multiple / metabolism*
  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Vesicular Transport
  • Adolescent
  • Adult
  • Age of Onset
  • Antigens, Neoplasm / genetics
  • Cell Cycle Proteins / genetics
  • Cerebellum / abnormalities*
  • Cerebellum / diagnostic imaging
  • Cerebellum / metabolism
  • Child
  • Child, Preschool
  • Cytoskeletal Proteins
  • Eye Abnormalities / complications
  • Eye Abnormalities / diagnostic imaging
  • Eye Abnormalities / genetics*
  • Eye Abnormalities / metabolism*
  • Female
  • Genotype
  • Humans
  • Infant
  • Kidney Diseases, Cystic / complications
  • Kidney Diseases, Cystic / congenital*
  • Kidney Diseases, Cystic / diagnostic imaging
  • Kidney Diseases, Cystic / genetics
  • Kidney Diseases, Cystic / metabolism
  • Kidney Failure, Chronic / etiology
  • Kidney Failure, Chronic / genetics*
  • Magnetic Resonance Imaging
  • Male
  • Membrane Proteins / genetics
  • Multicystic Dysplastic Kidney / complications
  • Multicystic Dysplastic Kidney / diagnostic imaging
  • Multicystic Dysplastic Kidney / genetics
  • Mutation
  • Neoplasm Proteins / genetics
  • Phenotype
  • Polycystic Kidney, Autosomal Recessive / complications
  • Polycystic Kidney, Autosomal Recessive / diagnostic imaging
  • Polycystic Kidney, Autosomal Recessive / genetics
  • Prospective Studies
  • Proteins / genetics
  • Retina / abnormalities*
  • Retina / diagnostic imaging
  • Retina / metabolism
  • Ultrasonography, Prenatal
  • Young Adult


  • AHI1 protein, human
  • Adaptor Proteins, Signal Transducing
  • Adaptor Proteins, Vesicular Transport
  • Antigens, Neoplasm
  • CC2D2A protein, human
  • CPLANE1 protein, human
  • Cell Cycle Proteins
  • Cep290 protein, human
  • Cytoskeletal Proteins
  • KIAA0586 protein, human
  • Membrane Proteins
  • Neoplasm Proteins
  • Proteins
  • TMEM67 protein, human

Supplementary concepts

  • Agenesis of Cerebellar Vermis
  • Nephronophthisis, familial juvenile