TY - JOUR
T1 - Prospective evaluation of kidney disease in joubert syndrome
AU - Fleming, Leah R.
AU - Doherty, Daniel A.
AU - Parisi, Melissa A.
AU - Glass, Ian A.
AU - Bryant, Joy
AU - Fischer, Roxanne
AU - Turkbey, Baris
AU - Choyke, Peter
AU - Daryanani, Kailash
AU - Vemulapalli, Meghana
AU - Mullikin, James C.
AU - Malicdan, May Christine
AU - Vilboux, Thierry
AU - Sayer, John A.
AU - Gahl, William A.
AU - Gunay-Aygun, Meral
N1 - Funding Information:
The authors thank the Joubert Syndrome and Related Disorders Foundation for their extensive support and the individuals with Joubert syndrome and their families who generously participated in this investigation. D.A.D. was supported by grant R01NS064077, the University of Washington Intellectual and Developmental Disabilities Research Center, grant U54HD083091 Genetics Core 6845 and subproject 6849, and private donations from families of children with Joubert syndrome. This research was supported by the Intramural Research Program of the National Human Genome Research Institute and the National Institutes of Health (NIH) Clinical Center, NIH.
Funding Information:
D.A.D. was supported by grant R01NS064077, the University of Washington Intellectual and Developmental Disabilities Research Center, grant U54HD083091 Genetics Core 6845 and subproject 6849, and private donations from families of children with Joubert syndrome. This research was supported by the Intramural Research Program of the National Human Genome Research Institute and the National Institutes of Health (NIH) Clinical Center, NIH.
Publisher Copyright:
© 2017 by the American Society of Nephrology.
PY - 2017/12/7
Y1 - 2017/12/7
N2 - 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, andAHI1. 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.
AB - 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, andAHI1. 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.
KW - Abnormalities, multiple
KW - Cerebellum
KW - Ciliopathies
KW - Ciliopathy
KW - Cystic kidney
KW - Eye abnormalities
KW - Genetic association studies
KW - Genetic renal disease
KW - Hypertension
KW - Joubert syndrome 1
KW - Kidney
KW - Kidney diseases, cystic
KW - Kidney failure, chronic
KW - Multicystic dysplastic kidney
KW - Mutation
KW - Nephronophthisis
KW - Phenotype
KW - Polycystic kidney disease
KW - Polycystic kidney, autosomal recessive
KW - Pregnancy
KW - Prospective studies
KW - Retina
KW - Sequence analysis, DNA
KW - Ultrasonography, prenatal
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U2 - 10.2215/CJN.05660517
DO - 10.2215/CJN.05660517
M3 - Article
C2 - 29146704
AN - SCOPUS:85037720337
SN - 1555-9041
VL - 12
SP - 1962
EP - 1973
JO - Clinical Journal of the American Society of Nephrology
JF - Clinical Journal of the American Society of Nephrology
IS - 12
ER -