title: Molecular genetic findings and clinical correlations in 100 patients with Joubert syndrome and related disorders prospectively evaluated at a single center.
abstract: Joubert syndrome (JS) is a genetically and clinically heterogeneous ciliopathy characterized by distinct cerebellar and brainstem malformations resulting in the diagnostic "molar tooth sign" on brain imaging. To date, more than 30 JS genes have been identified, but these do not account for all patients.
  
  
  
  In our cohort of 100 patients with JS from 86 families, we prospectively performed extensive clinical evaluation and provided molecular diagnosis using a targeted 27-gene Molecular Inversion Probes panel followed by whole-exome sequencing (WES).
  
  
  
  We identified the causative gene in 94% of the families; 126 (27 novel) unique potentially pathogenic variants were found in 20 genes, including KIAA0753 and CELSR2, which had not previously been associated with JS. Genotype-phenotype correlation revealed the absence of retinal degeneration in patients with TMEM67, C5orf52, or KIAA0586 variants. Chorioretinal coloboma was associated with a decreased risk for retinal degeneration and increased risk for liver disease. TMEM67 was frequently associated with kidney disease.
  
  
  
  In JS, WES significantly increases the yield for molecular diagnosis, which is essential for reproductive counseling and the option of preimplantation and prenatal diagnosis as well as medical management and prognostic counseling for the age-dependent and progressive organ-specific manifestations, including retinal, liver, and kidney disease.Genet Med advance online publication 26 January 2017.
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.|Inova Translational Medicine Institute, Falls Church, Virginia, USA.
authors.forename: Thierry
authors.initials: T
authors.lastname: Vilboux
authors.affiliation: Department of Pediatrics, University of Washington, Seattle, Washington, USA.|Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, Washington, USA.
authors.forename: Daniel A
authors.identifier: 0000-0001-9377-028X
authors.initials: DA
authors.lastname: Doherty
authors.affiliation: Department of Pediatrics, University of Washington, Seattle, Washington, USA.|Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, Washington, USA.
authors.forename: Ian A
authors.initials: IA
authors.lastname: Glass
authors.affiliation: Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Melissa A
authors.identifier: 0000-0001-6707-1004
authors.initials: MA
authors.lastname: Parisi
authors.affiliation: Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, Washington, USA.
authors.forename: Ian G
authors.initials: IG
authors.lastname: Phelps
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.|Department of Anatomy, Howard University College of Medicine, Washington DC, USA.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Cullinane
authors.affiliation: Ophthalmic Genetics &Visual Function Branch, National Eye Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Wadih
authors.initials: W
authors.lastname: Zein
authors.affiliation: Ophthalmic Genetics &Visual Function Branch, National Eye Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Brian P
authors.identifier: 0000-0002-3771-6120
authors.initials: BP
authors.lastname: Brooks
authors.affiliation: Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, USA.
authors.forename: Theo
authors.initials: T
authors.lastname: Heller
authors.affiliation: NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Ariane
authors.identifier: 0000-0003-3570-5230
authors.initials: A
authors.lastname: Soldatos
authors.affiliation: The EMMES Corporation, Rockville, Maryland, USA.
authors.forename: Neal L
authors.initials: NL
authors.lastname: Oden
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Deniz
authors.initials: D
authors.lastname: Yildirimli
authors.affiliation: NIH Intramural Sequencing Center, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Meghana
authors.initials: M
authors.lastname: Vemulapalli
authors.affiliation: NIH Intramural Sequencing Center, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: James C
authors.initials: JC
authors.lastname: Mullikin
authors.affiliation: NIH Intramural Sequencing Center, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.lastname: Nisc Comparative Sequencing Program
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.|NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: May Christine V
authors.identifier: 0000-0003-0825-3750
authors.initials: MCV
authors.lastname: Malicdan
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.|NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, Maryland, USA.|Office of the Clinical Director, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: William A
authors.initials: WA
authors.lastname: Gahl
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.|Office of the Clinical Director, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.|Department of Pediatrics and McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Meral
authors.initials: M
authors.lastname: Gunay-Aygun
mesh_terms: D000015:Abnormalities, Multiple / Q000175:diagnosis* / Q000235:genetics* / Q000503:physiopathology; D000293:Adolescent; D000328:Adult; D002531:Cerebellum / Q000002:abnormalities* / Q000503:physiopathology; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D003103:Coloboma / Q000175:diagnosis / Q000235:genetics; D005124:Eye Abnormalities / Q000175:diagnosis* / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D006801:Humans; D007223:Infant; D007674:Kidney Diseases / Q000175:diagnosis / Q000235:genetics; D052177:Kidney Diseases, Cystic / Q000175:diagnosis* / Q000235:genetics* / Q000503:physiopathology; D008107:Liver Diseases / Q000175:diagnosis / Q000235:genetics; D008297:Male; D025202:Molecular Diagnostic Techniques; D015335:Molecular Probes; D011446:Prospective Studies; D012160:Retina / Q000002:abnormalities* / Q000503:physiopathology; D012162:Retinal Degeneration / Q000175:diagnosis / Q000235:genetics; D000073336:Whole Genome Sequencing; D055815:Young Adult
chemical_list: D015335:Molecular Probes