title: The genetic basis of DOORS syndrome: an exome-sequencing study.
abstract: BACKGROUND
  Deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures (DOORS) syndrome is a rare autosomal recessive disorder of unknown cause. We aimed to identify the genetic basis of this syndrome by sequencing most coding exons in affected individuals.
  
  
  METHODS
  Through a search of available case studies and communication with collaborators, we identified families that included at least one individual with at least three of the five main features of the DOORS syndrome: deafness, onychodystrophy, osteodystrophy, intellectual disability, and seizures. Participants were recruited from 26 centres in 17 countries. Families described in this study were enrolled between Dec 1, 2010, and March 1, 2013. Collaborating physicians enrolling participants obtained clinical information and DNA samples from the affected child and both parents if possible. We did whole-exome sequencing in affected individuals as they were enrolled, until we identified a candidate gene, and Sanger sequencing to confirm mutations. We did expression studies in human fibroblasts from one individual by real-time PCR and western blot analysis, and in mouse tissues by immunohistochemistry and real-time PCR.
  
  
  RESULTS
  26 families were included in the study. We did exome sequencing in the first 17 enrolled families; we screened for TBC1D24 by Sanger sequencing in subsequent families. We identified TBC1D24 mutations in 11 individuals from nine families (by exome sequencing in seven families, and Sanger sequencing in two families). 18 families had individuals with all five main features of DOORS syndrome, and TBC1D24 mutations were identified in half of these families. The seizure types in individuals with TBC1D24 mutations included generalised tonic-clonic, complex partial, focal clonic, and infantile spasms. Of the 18 individuals with DOORS syndrome from 17 families without TBC1D24 mutations, eight did not have seizures and three did not have deafness. In expression studies, some mutations abrogated TBC1D24 mRNA stability. We also detected Tbc1d24 expression in mouse phalangeal chondrocytes and calvaria, which suggests a role of TBC1D24 in skeletogenesis.
  
  
  CONCLUSIONS
  Our findings suggest that mutations in TBC1D24 seem to be an important cause of DOORS syndrome and can cause diverse phenotypes. Thus, individuals with DOORS syndrome without deafness and seizures but with the other features should still be screened for TBC1D24 mutations. More information is needed to understand the cellular roles of TBC1D24 and identify the genes responsible for DOORS phenotypes in individuals who do not have a mutation in TBC1D24.
  
  
  BACKGROUND
  US National Institutes of Health, the CIHR (Canada), the NIHR (UK), the Wellcome Trust, the Henry Smith Charity, and Action Medical Research.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
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authors.lastname: Campeau
authors.affiliation: Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London, UK.
authors.forename: Dalia
authors.initials: D
authors.lastname: Kasperaviciute
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA; Department of Structural and Computational Biology and Molecular Biophysics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: James T
authors.initials: JT
authors.lastname: Lu
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
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authors.affiliation: Department of Pharmacology, Baylor College of Medicine, Houston, TX, USA.
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authors.affiliation: Department of Pediatrics, Toyohashi Municipal Hospital, Toyohashi, Aichi, Japan.
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authors.affiliation: Genetics Service, Belfast City Hospital, Belfast, Ireland.
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authors.affiliation: Medical Genetics Service, Clinical Hospital of Porto Alegre, Porto Alegre, Brazil.
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authors.affiliation: Department of Medical Genetics, University Hospital Antwerp, 2650 Antwerp, Belgium.
authors.forename: Jenneke
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authors.affiliation: Department of Medical Genetics, Poznañ University of Medical Sciences, Poznañ, Poland.
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authors.affiliation: Medical Genetics Department, Istanbul Medical Faculty, Istanbul University, Turkey.
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authors.affiliation: Department of Genetics, University of Groningen, Groningen, Netherlands.
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authors.affiliation: Department of Pediatric Genetics, Amrita Institute of Medical Sciences and Research Centre, Kerala, India.
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authors.affiliation: Pediatric Neurology, Braunschweig Hospital, Braunschweig, Germany.
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authors.affiliation: Department of Pediatrics, Saveetha Medical College and Hospital, Saveetha University, Chennai, Tamil Nadu, 600077, India.
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authors.affiliation: Division of Genetics, Children's Mercy Hospitals and Clinics and the University of Missouri-Kansas City School of Medicine, Kansas City, MO, USA.
authors.forename: Michael L
authors.initials: ML
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authors.affiliation: Department of Medical Genetics, Montreal Children's Hospital, McGill University Health Center, Quebec, Canada.
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authors.affiliation: Department of Pediatrics, NKP Salve Institute of Medical Sciences and Lata Mangeshkar Hospital, Maharashtra, India.
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authors.affiliation: University of Washington Medical Center, Seattle, WA, USA.
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authors.affiliation: Center for Human Genetics, Facultad de Medicina, Clínica Alemana-Universidad del Desarrollo, Santiago, Chile.
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authors.lastname: Repetto
authors.affiliation: Department of Pediatrics, University of California San Francisco, San Francisco, CA, USA.
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authors.affiliation: Department of Clinical Genetics, Churchill Hospital, Oxford, UK.
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authors.affiliation: Clinical Genetics Department, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.
authors.forename: Alison
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authors.affiliation: Centre Référence Anomalie Développement et Syndromes Malformatifs, Centre Hospitalier Universitaire de Nice, France.
authors.forename: Fabienne
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authors.affiliation: Kariminejad-Najmabadi Pathology and Genetics Center, Tehran, Iran.
authors.forename: Ariana
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authors.affiliation: Manchester Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK; Manchester Centre for Genomic Centre for Genetic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK; St Mary's Hospital, Manchester Academic Health Science Centre, Manchester, UK.
authors.forename: William G
authors.initials: WG
authors.lastname: Newman
authors.affiliation: Manchester Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK; Manchester Centre for Genomic Centre for Genetic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK; St Mary's Hospital, Manchester Academic Health Science Centre, Manchester, UK.
authors.forename: Sanjeev S
authors.initials: SS
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authors.affiliation: Manchester Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK; Manchester Centre for Genomic Centre for Genetic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK; St Mary's Hospital, Manchester Academic Health Science Centre, Manchester, UK.
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: Dickerson
authors.affiliation: Manchester Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK; Manchester Centre for Genomic Centre for Genetic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK; St Mary's Hospital, Manchester Academic Health Science Centre, Manchester, UK.
authors.forename: Bronwyn
authors.initials: B
authors.lastname: Kerr
authors.affiliation: Manchester Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK; Manchester Centre for Genomic Centre for Genetic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK; St Mary's Hospital, Manchester Academic Health Science Centre, Manchester, UK.
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authors.initials: JC
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authors.initials: D
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authors.affiliation: Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London, UK.
authors.forename: Anna
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authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Joanna
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authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
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authors.affiliation: Department of Pediatrics and Translational Genetics, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands.
authors.forename: Raoul C
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authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Richard A
authors.initials: RA
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authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Howard Hughes Medical Institutes, Houston, TX, USA. Electronic address: blee@bcm.edu.
authors.forename: Brendan H
authors.initials: BH
authors.lastname: Lee
authors.affiliation: Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London, UK; Epilepsy Society, Buckinghamshire, UK. Electronic address: s.sisodiya@ucl.ac.uk.
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mesh_terms: D000293:Adolescent; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D019465:Craniofacial Abnormalities / Q000175:diagnosis / Q000235:genetics*; D059472:Exome / Q000235:genetics*; D005260:Female; D020690:GTPase-Activating Proteins; D006228:Hand Deformities, Congenital / Q000175:diagnosis / Q000235:genetics*; D006319:Hearing Loss, Sensorineural / Q000175:diagnosis / Q000235:genetics*; D006801:Humans; D007223:Infant; D008607:Intellectual Disability / Q000175:diagnosis / Q000235:genetics*; D038622:Internationality; D008297:Male; D008565:Membrane Proteins; D009264:Nails, Malformed / Q000175:diagnosis / Q000235:genetics*; D009419:Nerve Tissue Proteins; D010641:Phenotype; D017422:Sequence Analysis, DNA / Q000379:methods*; D055815:Young Adult
chemical_list: D002352:Carrier Proteins; D020690:GTPase-Activating Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C552551:TBC1D24 protein, human