Abstract for presentation at 11th International Congress of Human Genetics

Genotype-phenotype correlations in Joubert syndrome

  • Dr Ian Glass, Children's Hospital and University of Washington, Seattle, WA, United States
  • Dr Melissa Parisi, Children's Hospital and University of Washington, Seattle, WA, United States
  • Dr Daniel Doherty, Children's Hospital and University of Washington, Seattle, WA, United States
  • Dr Hamit Ozyurek, Hacettepe University, Ankara, Turkey, Turkey
  • Dr Ozlem Giray, Dokuz Eylul University, Izmir, Turkey, Turkey
  • Dr Abdulrahman Al Swaid, Riyadh Armed Forces Hospital, Riyadh, Saudi Arabia, Saudi Arabia
  • Dr William Dobyns, University of Chicago, Chicago, IL, United States
  • Dr Phillip Chance, Children's Hospital and University of Washington, Seattle, WA, United States

    • Joubert syndrome (JS) is an autosomal recessive condition characterized by hypotonia, ataxia, mental retardation, abnormal breathing pattern, aberrant eye movements, and cerebellar vermis hypoplasia with the "molar tooth sign" (MTS) on MRI. JS is a spectrum of disorders unified by the MTS, with more variable features including polydactyly, retinal dystrophy, colobomas, renal disease (cysts or juvenile nephronophthisis (NPH)), hepatic fibrosis, encephaloceles, and oral hamartomas. Here we summarize our experience with 127 JS pedigrees and describe the clinical features in the probands. Of the 127 families, 76% have a documented MTS, while 100% have hypotonia, mental retardation and some evidence of cerebellar vermis hypoplasia. 52% have oculomotor apraxia, and 62% had neonatal breathing abnormalities. Overall, 19% of the families demonstrate polydactyly, and 3 with mesaxial polydactyly may represent OFD VI. Approximately half of those with retinal dystrophy had renal disease, confirming this association. Of the 8 with liver fibrosis, 5 have colobomas, suggesting an assignment of COACH syndrome. We screened our cohort for mutations in the 2 genes identified so far for JS (NPHP1 and AHI1). Of the 117 patients tested for mutations in NPHP1, 2 families harbored a homozygous NPHP1 deletion, representing ~1% of our cohort. The cohort of 117 JS subjects was screened for AHI1 mutations by haplotype analysis and gene sequencing, which identified 13 subjects with novel mutations (11% of the cohort). The MTS was present in almost all cases. Retinal dystrophy was present in 11/12 families. Two subjects had late-onset renal disease consistent with NPH. None of the subjects exhibited polydactyly, encephaloceles, colobomas, or liver fibrosis. The overall contribution by these two genes appears to be ~15% in our cohort. We note the association of renal impairment in those with NPHP1 deletions and retinal dystrophy with possible NPH in those with AHI1 mutations.

    Conference Organiser - ICMS Pty Ltd