title: Exome sequencing identifies DYNC2H1 mutations as a common cause of asphyxiating thoracic dystrophy (Jeune syndrome) without major polydactyly, renal or retinal involvement.
abstract: BACKGROUND
  Jeune asphyxiating thoracic dystrophy (JATD) is a rare, often lethal, recessively inherited chondrodysplasia characterised by shortened ribs and long bones, sometimes accompanied by polydactyly, and renal, liver and retinal disease. Mutations in intraflagellar transport (IFT) genes cause JATD, including the IFT dynein-2 motor subunit gene DYNC2H1. Genetic heterogeneity and the large DYNC2H1 gene size have hindered JATD genetic diagnosis.
  
  
  OBJECTIVE
  To determine the contribution to JATD we screened DYNC2H1 in 71 JATD patients JATD patients combining SNP mapping, Sanger sequencing and exome sequencing.
  
  
  CONCLUSIONS
  We detected 34 DYNC2H1 mutations in 29/71 (41%) patients from 19/57 families (33%), showing it as a major cause of JATD especially in Northern European patients. This included 13 early protein termination mutations (nonsense/frameshift, deletion, splice site) but no patients carried these in combination, suggesting the human phenotype is at least partly hypomorphic. In addition, 21 missense mutations were distributed across DYNC2H1 and these showed some clustering to functional domains, especially the ATP motor domain. DYNC2H1 patients largely lacked significant extra-skeletal involvement, demonstrating an important genotype-phenotype correlation in JATD. Significant variability exists in the course and severity of the thoracic phenotype, both between affected siblings with identical DYNC2H1 alleles and among individuals with different alleles, which suggests the DYNC2H1 phenotype might be subject to modifier alleles, non-genetic or epigenetic factors. Assessment of fibroblasts from patients showed accumulation of anterograde IFT proteins in the ciliary tips, confirming defects similar to patients with other retrograde IFT machinery mutations, which may be of undervalued potential for diagnostic purposes.
authors: Molecular Medicine Unit, Birth Defects Research Centre, University College London UCL Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK.
authors: Miriam
authors: M
authors: Schmidts
authors: Heleen H
authors: HH
authors: Arts
authors: Ernie M H F
authors: EM
authors: Bongers
authors: Zhimin
authors: Z
authors: Yap
authors: Machteld M
authors: MM
authors: Oud
authors: Dinu
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authors: Antony
authors: Lonneke
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authors: Duijkers
authors: Richard D
authors: RD
authors: Emes
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authors: Stalker
authors: Jan-Bart L
authors: JB
authors: Yntema
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authors: Plagnol
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authors: Hoischen
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authors: Gilissen
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authors: Forsythe
authors: Ekkehart
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authors: Lausch
authors: Joris A
authors: JA
authors: Veltman
authors: Nel
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authors: Roeleveld
authors: Andrea
authors: A
authors: Superti-Furga
authors: Anna
authors: A
authors: Kutkowska-Kazmierczak
authors: Erik-Jan
authors: EJ
authors: Kamsteeg
authors: Nursel
authors: N
authors: Elçioğlu
authors: Merel C
authors: MC
authors: van Maarle
authors: Luitgard M
authors: LM
authors: Graul-Neumann
authors: Koenraad
authors: K
authors: Devriendt
authors: Sarah F
authors: SF
authors: Smithson
authors: Diana
authors: D
authors: Wellesley
authors: Nienke E
authors: NE
authors: Verbeek
authors: Raoul C M
authors: RC
authors: Hennekam
authors: Hulya
authors: H
authors: Kayserili
authors: Peter J
authors: PJ
authors: Scambler
authors: Philip L
authors: PL
authors: Beales
authors: Nine Vam
authors: NV
authors: Knoers
authors: Ronald
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authors: Roepman
authors: Hannah M
authors: HM
authors: Mitchison
mesh_terms: D001483:Base Sequence; D056445:Cytoplasmic Dyneins / Q000737:chemistry / Q000235:genetics*; D004613:Ellis-Van Creveld Syndrome / Q000235:genetics*; D059472:Exome / Q000235:genetics*; D040461:Gene Components; D006801:Humans; D008856:Microscopy, Fluorescence; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011487:Protein Conformation; D017422:Sequence Analysis, DNA
chemical_list: C099883:DYNC2H1 protein, human; D056445:Cytoplasmic Dyneins