title: Joubert syndrome: a model for untangling recessive disorders with extreme genetic heterogeneity.
abstract: BACKGROUND
  Joubert syndrome (JS) is a recessive neurodevelopmental disorder characterised by hypotonia, ataxia, cognitive impairment, abnormal eye movements, respiratory control disturbances and a distinctive mid-hindbrain malformation. JS demonstrates substantial phenotypic variability and genetic heterogeneity. This study provides a comprehensive view of the current genetic basis, phenotypic range and gene-phenotype associations in JS.
  
  
  METHODS
  We sequenced 27 JS-associated genes in 440 affected individuals (375 families) from a cohort of 532 individuals (440 families) with JS, using molecular inversion probe-based targeted capture and next-generation sequencing. Variant pathogenicity was defined using the Combined Annotation Dependent Depletion algorithm with an optimised score cut-off.
  
  
  RESULTS
  We identified presumed causal variants in 62% of pedigrees, including the first B9D2 mutations associated with JS. 253 different mutations in 23 genes highlight the extreme genetic heterogeneity of JS. Phenotypic analysis revealed that only 34% of individuals have a 'pure JS' phenotype. Retinal disease is present in 30% of individuals, renal disease in 25%, coloboma in 17%, polydactyly in 15%, liver fibrosis in 14% and encephalocele in 8%. Loss of CEP290 function is associated with retinal dystrophy, while loss of TMEM67 function is associated with liver fibrosis and coloboma, but we observe no clear-cut distinction between JS subtypes.
  
  
  CONCLUSIONS
  This work illustrates how combining advanced sequencing techniques with phenotypic data addresses extreme genetic heterogeneity to provide diagnostic and carrier testing, guide medical monitoring for progressive complications, facilitate interpretation of genome-wide sequencing results in individuals with a variety of phenotypes and enable gene-specific treatments in the future.
authors.affiliation: Institute for Molecular Life Sciences and Institute of Medical Genetics, University of Zurich, Zurich, Switzerland.
authors.forename: R
authors.initials: R
authors.lastname: Bachmann-Gagescu
authors.affiliation: Department of Pediatrics, University of Washington, Seattle, Washington, USA.
authors.forename: J C
authors.initials: JC
authors.lastname: Dempsey
authors.affiliation: Department of Pediatrics, University of Washington, Seattle, Washington, USA.
authors.forename: I G
authors.initials: IG
authors.lastname: Phelps
authors.affiliation: Molecular and Medical Genetics, Oregon Health and Science University, Portland, Oregon, USA.
authors.forename: B J
authors.initials: BJ
authors.lastname: O'Roak
authors.affiliation: Department of Oncology, Franciscan Health System, Tacoma, Washington, USA.
authors.forename: D M
authors.initials: DM
authors.lastname: Knutzen
authors.affiliation: Department of Biostatistics, University of Washington, Seattle, Washington, USA.
authors.forename: T C
authors.initials: TC
authors.lastname: Rue
authors.affiliation: Department of Radiology, University of Washington, Seattle Children's Hospital, Seattle, Washington, USA.
authors.forename: G E
authors.initials: GE
authors.lastname: Ishak
authors.affiliation: Department of Pediatrics, University of Washington, Seattle, Washington, USA.
authors.forename: C R
authors.initials: CR
authors.lastname: Isabella
authors.affiliation: Department of Internal Medicine, University of Colorado School of Medicine, Aurora, Colorado, USA.
authors.forename: N
authors.initials: N
authors.lastname: Gorden
authors.affiliation: Division of Integrated Cancer Genomics, Translational Genomics Research Institute, Phoenix, Arizona, USA.
authors.forename: J
authors.initials: J
authors.lastname: Adkins
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington, USA.
authors.forename: E A
authors.initials: EA
authors.lastname: Boyle
authors.affiliation: Department of Psychiatry, University of Washington, Seattle, Washington, USA.
authors.forename: N
authors.initials: N
authors.lastname: de Lacy
authors.affiliation: Department of Pediatrics, University of Washington, Seattle, Washington, USA.
authors.forename: D
authors.initials: D
authors.lastname: O'Day
authors.affiliation: Department of Pediatrics, King Abdulaziz Medical City, Riyadh, Saudi Arabia.
authors.forename: A
authors.initials: A
authors.lastname: Alswaid
authors.affiliation: Rainbow Children's Hospital, Hyderabad, India.
authors.forename: Radha
authors.initials: R
authors.lastname: Ramadevi A
authors.affiliation: Department of Child Neurology, Rainbow Children Hospital, Hyderabad, India.
authors.forename: L
authors.initials: L
authors.lastname: Lingappa
authors.affiliation: Department of Neurosciences and Behavior Neurosciences, School of Medicine of Ribeirão Preto, University of São Paulo, São Paulo, Brazil.
authors.forename: C
authors.initials: C
authors.lastname: Lourenço
authors.affiliation: Department of Genetica Molecular, Hospital Sant Joan de Deu, Barcelona, Spain.
authors.forename: L
authors.initials: L
authors.lastname: Martorell
authors.affiliation: Department of Neurology, Neurometabolic Unit, Hospital Sant Joan de Déu and CIBERER, ISCIII, Barcelona, Spain.
authors.forename: À
authors.initials: À
authors.lastname: Garcia-Cazorla
authors.affiliation: Department of Pediatric Neurology, Faculty of Medicine, Ondokuz Mayis University, Samsun, Turkey.
authors.forename: H
authors.initials: H
authors.lastname: Ozyürek
authors.affiliation: Department of Pediatric Neurology, Hacettepe University Children's Hospital, Ankara, Turkey.
authors.forename: G
authors.initials: G
authors.lastname: Haliloğlu
authors.affiliation: Department of Pediatric Genetics, Cerrahpasa Medical School, Istanbul University, Istanbul, Turkey.
authors.forename: B
authors.initials: B
authors.lastname: Tuysuz
authors.affiliation: Department of Pediatric Neurology, Hacettepe University Children's Hospital, Ankara, Turkey.
authors.forename: M
authors.initials: M
authors.lastname: Topçu
authors.affiliation: Department of Pediatrics, University of Washington, Seattle, Washington, USA.
authors.forename: P
authors.initials: P
authors.lastname: Chance
authors.affiliation: National Institute of Child Health and Human Development, NIH, Bethesda, Maryland, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Parisi
authors.affiliation: Department of Pediatrics, University of Washington, Seattle, Washington, USA Seattle Children's Research Institute, Seattle, Washington, USA.
authors.forename: I A
authors.initials: IA
authors.lastname: Glass
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington, USA.
authors.forename: J
authors.initials: J
authors.lastname: Shendure
authors.affiliation: Department of Pediatrics, University of Washington, Seattle, Washington, USA Seattle Children's Research Institute, Seattle, Washington, USA.
authors.forename: D
authors.initials: D
authors.lastname: Doherty
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics / Q000473:pathology; D002531:Cerebellum / Q000002:abnormalities* / Q000473:pathology; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D005124:Eye Abnormalities / Q000235:genetics / Q000473:pathology; D056726:Genetic Association Studies; D018740:Genetic Heterogeneity; D006801:Humans; D052177:Kidney Diseases, Cystic / Q000235:genetics / Q000473:pathology; D008962:Models, Theoretical; D010375:Pedigree; D012160:Retina / Q000002:abnormalities* / Q000473:pathology; D017422:Sequence Analysis, DNA
keywords: Joubert syndrome; ciliopathy; genetic heterogeneity; genotype-phenotype; next generation sequencing