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Joubert syndrome: a model for untangling recessive disorders with extreme genetic heterogeneity.
J Med Genet. 2015 Aug; 52(8):514-22.JM

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+Show Affiliations

Institute for Molecular Life Sciences and Institute of Medical Genetics, University of Zurich, Zurich, Switzerland.Department of Pediatrics, University of Washington, Seattle, Washington, USA.Department of Pediatrics, University of Washington, Seattle, Washington, USA.Molecular and Medical Genetics, Oregon Health and Science University, Portland, Oregon, USA.Department of Oncology, Franciscan Health System, Tacoma, Washington, USA.Department of Biostatistics, University of Washington, Seattle, Washington, USA.Department of Radiology, University of Washington, Seattle Children's Hospital, Seattle, Washington, USA.Department of Pediatrics, University of Washington, Seattle, Washington, USA.Department of Internal Medicine, University of Colorado School of Medicine, Aurora, Colorado, USA.Division of Integrated Cancer Genomics, Translational Genomics Research Institute, Phoenix, Arizona, USA.Department of Genome Sciences, University of Washington, Seattle, Washington, USA.Department of Psychiatry, University of Washington, Seattle, Washington, USA.Department of Pediatrics, University of Washington, Seattle, Washington, USA.Department of Pediatrics, King Abdulaziz Medical City, Riyadh, Saudi Arabia.Rainbow Children's Hospital, Hyderabad, India.Department of Child Neurology, Rainbow Children Hospital, Hyderabad, India.Department of Neurosciences and Behavior Neurosciences, School of Medicine of Ribeirão Preto, University of São Paulo, São Paulo, Brazil.Department of Genetica Molecular, Hospital Sant Joan de Deu, Barcelona, Spain.Department of Neurology, Neurometabolic Unit, Hospital Sant Joan de Déu and CIBERER, ISCIII, Barcelona, Spain.Department of Pediatric Neurology, Faculty of Medicine, Ondokuz Mayis University, Samsun, Turkey.Department of Pediatric Neurology, Hacettepe University Children's Hospital, Ankara, Turkey.Department of Pediatric Genetics, Cerrahpasa Medical School, Istanbul University, Istanbul, Turkey.Department of Pediatric Neurology, Hacettepe University Children's Hospital, Ankara, Turkey.No affiliation info availableDepartment of Pediatrics, University of Washington, Seattle, Washington, USA.National Institute of Child Health and Human Development, NIH, Bethesda, Maryland, USA.Department of Pediatrics, University of Washington, Seattle, Washington, USA Seattle Children's Research Institute, Seattle, Washington, USA.Department of Genome Sciences, University of Washington, Seattle, Washington, USA.Department of Pediatrics, University of Washington, Seattle, Washington, USA Seattle Children's Research Institute, Seattle, Washington, USA.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.

Language

eng

PubMed ID

26092869

Citation

Bachmann-Gagescu, R, et al. "Joubert Syndrome: a Model for Untangling Recessive Disorders With Extreme Genetic Heterogeneity." Journal of Medical Genetics, vol. 52, no. 8, 2015, pp. 514-22.
Bachmann-Gagescu R, Dempsey JC, Phelps IG, et al. Joubert syndrome: a model for untangling recessive disorders with extreme genetic heterogeneity. J Med Genet. 2015;52(8):514-22.
Bachmann-Gagescu, R., Dempsey, J. C., Phelps, I. G., O'Roak, B. J., Knutzen, D. M., Rue, T. C., Ishak, G. E., Isabella, C. R., Gorden, N., Adkins, J., Boyle, E. A., de Lacy, N., O'Day, D., Alswaid, A., Ramadevi A, R., Lingappa, L., Lourenço, C., Martorell, L., Garcia-Cazorla, À., ... Doherty, D. (2015). Joubert syndrome: a model for untangling recessive disorders with extreme genetic heterogeneity. Journal of Medical Genetics, 52(8), 514-22. https://doi.org/10.1136/jmedgenet-2015-103087
Bachmann-Gagescu R, et al. Joubert Syndrome: a Model for Untangling Recessive Disorders With Extreme Genetic Heterogeneity. J Med Genet. 2015;52(8):514-22. PubMed PMID: 26092869.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Joubert syndrome: a model for untangling recessive disorders with extreme genetic heterogeneity. AU - Bachmann-Gagescu,R, AU - Dempsey,J C, AU - Phelps,I G, AU - O'Roak,B J, AU - Knutzen,D M, AU - Rue,T C, AU - Ishak,G E, AU - Isabella,C R, AU - Gorden,N, AU - Adkins,J, AU - Boyle,E A, AU - de Lacy,N, AU - O'Day,D, AU - Alswaid,A, AU - Ramadevi A,Radha, AU - Lingappa,L, AU - Lourenço,C, AU - Martorell,L, AU - Garcia-Cazorla,À, AU - Ozyürek,H, AU - Haliloğlu,G, AU - Tuysuz,B, AU - Topçu,M, AU - ,, AU - Chance,P, AU - Parisi,M A, AU - Glass,I A, AU - Shendure,J, AU - Doherty,D, Y1 - 2015/06/19/ PY - 2015/02/23/received PY - 2015/06/01/accepted PY - 2015/6/21/entrez PY - 2015/6/21/pubmed PY - 2016/5/6/medline KW - Joubert syndrome KW - ciliopathy KW - genetic heterogeneity KW - genotype-phenotype KW - next generation sequencing SP - 514 EP - 22 JF - Journal of medical genetics JO - J. Med. Genet. VL - 52 IS - 8 N2 - 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. SN - 1468-6244 UR - https://www.unboundmedicine.com/medline/citation/26092869/Joubert_syndrome:_a_model_for_untangling_recessive_disorders_with_extreme_genetic_heterogeneity_ L2 - http://jmg.bmj.com/cgi/pmidlookup?view=long&pmid=26092869 DB - PRIME DP - Unbound Medicine ER -