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Genotype–phenotype correlation in CC2D2A-related Joubert syndrome reveals an association with ventriculomegaly and seizures
  1. Ruxandra Bachmann-Gagescu1,
  2. Gisele E Ishak2,
  3. Jennifer C Dempsey1,
  4. Jonathan Adkins1,
  5. Diana O'Day1,
  6. Ian G Phelps1,
  7. Meral Gunay-Aygun3,
  8. Antonie D Kline4,
  9. Krzysztof Szczaluba5,
  10. Loreto Martorell6,
  11. Abdulrahman Alswaid7,
  12. Shatha Alrasheed7,
  13. Shashidhar Pai8,
  14. Louise Izatt9,
  15. Anne Ronan10,
  16. Melissa A Parisi11,
  17. Heather Mefford1,
  18. Ian Glass1,
  19. Dan Doherty1,12
  1. 1Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington, USA
  2. 2Department of Radiology, University of Washington, Seattle Children's Hospital, Seattle, Washington, USA
  3. 3Medical Genetics Branch, National Human Genome Research Institute National Institutes of Health, Bethesda, Maryland, USA
  4. 4Harvey Institute for Human Genetics, Greater Baltimore Medical Center, Baltimore, Maryland, USA
  5. 5Department of Medical Genetics, Institute of Mother and Child, Warsaw, Poland
  6. 6Molecular Genetics Section, Hospital Sant Joan de Deu, Barcelona, Spain
  7. 7Department of Pediatrics, King Abdulaziz Medical City, Riyadh, Saudi Arabia
  8. 8Department of Pediatrics, Medical University of South Carolina, Charleston, South Carolina, USA
  9. 9Clinical Genetics Department, Guy's and St Thomas' NHS Foundation Trust, London, UK
  10. 10Hunter Genetics Unit, Waratah, New South Wales, Australia
  11. 11Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA
  12. 12Division of Developmental Medicine, Department of Pediatrics, University of Washington, Seattle, Washington, USA
  1. Correspondence to Dr Dan Doherty, Associate Professor, Divisions of Genetic Medicine and Developmental Medicine, University of Washington, Box 356320, RR-249, 1959 NE Pacific Street, Seattle, WA 98195-6320, USA; ddoher{at}


Background Joubert syndrome (JS) is a ciliopathy characterised by a distinctive brain malformation (the ‘molar tooth sign’), developmental delay, abnormal eye movements and abnormal breathing pattern. Retinal dystrophy, cystic kidney disease, liver fibrosis and polydactyly are variably present, resulting in significant phenotypic heterogeneity and overlap with other ciliopathies. JS is also genetically heterogeneous, resulting from mutations in 13 genes. These factors render clinical/molecular diagnosis and management challenging. CC2D2A mutations are a relatively common cause of JS and also cause Meckel syndrome. The clinical consequences of CC2D2A mutations in patients with JS have been incompletely reported.

Methods Subjects with JS from 209 families were evaluated to identify mutations in CC2D2A. Clinical and imaging features in subjects with CC2D2A mutations were compared with those in subjects without CC2D2A mutations and reports in the literature.

Results 10 novel CC2D2A mutations in 20 subjects were identified; a summary is provided of all published CC2D2A mutations. Subjects with CC2D2A-related JS were more likely to have ventriculomegaly (p<0.0001) and seizures (p=0.024) than subjects without CC2D2A mutations. No mutation-specific genotype–phenotype correlations could be identified, but the findings confirm the observation that mutations that cause CC2D2A-related JS are predicted to be less deleterious than mutations that cause CC2D2A-related Meckel syndrome. Missense variants in the coiled-coil and C2 domains, as well as the C-terminal region, identify these regions as important for the biological mechanisms underlying JS.

Conclusions CC2D2A testing should be prioritised in patients with JS and ventriculomegaly and/or seizures. Patients with CC2D2A-related JS should be monitored for hydrocephalus and seizures.

  • JS
  • ciliopathy
  • CC2D2A
  • seizures
  • ventriculomegaly
  • clinical genetics
  • cell biology
  • molecular genetics
  • neurology
  • genetics
  • academic medicine
  • epilepsy and seizures

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  • Funding This work was supported by National Institute of Health grants 5KL2RR025015 and R01NS064077 to DD, and K12HD043376 to RB-G, by Basil O'Connor Start Scholar Research Grant No 5-FY09-13 from the March of Dimes Foundation to DD, and by an Arc of Washington Trust Fund grant to DD. We would also like to thank the NHLBI GO Exome Sequencing Project and its ongoing studies which produced and provided exome variant calls for comparison: the Lung GO Sequencing Project (HL-102923), the WHI Sequencing Project (HL-102924), the Broad GO Sequencing Project (HL-102925), the Seattle GO Sequencing Project (HL-102926) and the Heart GO Sequencing Project (HL-103010).

  • Competing interests None.

  • Patient consent Obtained.

  • Ethics approval Ethics approval was provided by University of Washington IRB and Seattle Children's Hospital IRB.

  • Provenance and peer review Not commissioned; externally peer reviewed.