title: A novel X-linked trichothiodystrophy associated with a nonsense mutation in RNF113A.
abstract: BACKGROUND
  Trichothiodystrophy (TTD) is a group of rare autosomal recessive disorders that variably affect a wide range of organs derived from the neuroectoderm. The key diagnostic feature is sparse, brittle, sulfur deficient hair that has a 'tiger-tail' banding pattern under polarising light microscopy.
  
  
  METHODS
  We describe two male cousins affected by TTD associated with microcephaly, profound intellectual disability, sparse brittle hair, aged appearance, short stature, facial dysmorphism, seizures, an immunoglobulin deficiency, multiple endocrine abnormalities, cerebellar hypoplasia and partial absence of the corpus callosum, in the absence of cellular photosensitivity and ichthyosis. Obligate female carriers showed 100% skewed X-chromosome inactivation. Linkage analysis and Sanger sequencing of 737 X-chromosome exons and whole exome sequencing was used to find the responsible gene and mutation.
  
  
  RESULTS
  Linkage analysis localised the disease allele to a 7.75 Mb interval from Xq23-q25. We identified a nonsense mutation in the highly conserved RNF113A gene (c.901 C>T, p.Q301*). The mutation segregated with the disease in the family and was not observed in over 100,000 control X chromosomes. The mutation markedly reduced RNF113A protein expression in extracts from lymphoblastoid cell lines derived from the affected individuals.
  
  
  CONCLUSIONS
  The association of RNF113A mutation with non-photosensitive TTD identifies a new locus for these disorders on the X chromosome. The extended phenotype within this family includes panhypopituitarism, cutis marmorata and congenital short oesophagus.
authors.affiliation: Neurogenetics Research Program, School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide, Australia.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Corbett
authors.affiliation: Genetics of Learning Disability Service, Hunter Genetics, Waratah, Australia University of Newcastle, Newcastle, Australia.
authors.forename: Tracy
authors.initials: T
authors.lastname: Dudding-Byth
authors.affiliation: Department of Paediatric Endocrinology and Diabetes, John Hunter Children's Hospital, University of Newcastle, Newcastle, Australia.
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Crock
authors.affiliation: Istituto di Genetica Molecolare CNR, Pavia, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Botta
authors.affiliation: Genetics of Learning Disability Service, Hunter Genetics, Waratah, Australia.
authors.forename: Louise M
authors.initials: LM
authors.lastname: Christie
authors.affiliation: Istituto di Genetica Molecolare CNR, Pavia, Italy.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Nardo
authors.affiliation: Istituto di Genetica Molecolare CNR, Pavia, Italy.
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Caligiuri
authors.affiliation: Molecular Genetics, Department of Genetic Medicine, SA Pathology at Women's and Children's Hospital, North Adelaide, Australia.
authors.forename: Lynne
authors.initials: L
authors.lastname: Hobson
authors.affiliation: Genetics of Learning Disability Service, Hunter Genetics, Waratah, Australia.
authors.forename: Jackie
authors.initials: J
authors.lastname: Boyle
authors.affiliation: The Children's Hospital at Westmead, Westmead, Australia.
authors.forename: Albert
authors.initials: A
authors.lastname: Mansour
authors.affiliation: Molecular Genetics, Department of Genetic Medicine, SA Pathology at Women's and Children's Hospital, North Adelaide, Australia.
authors.forename: Kathryn L
authors.initials: KL
authors.lastname: Friend
authors.affiliation: Neurogenetics Research Program, School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide, Australia.
authors.forename: Jo
authors.initials: J
authors.lastname: Crawford
authors.affiliation: Brain Research Institute, Florey Neurosciences Institutes, West Heidelberg, Australia.
authors.forename: Graeme
authors.initials: G
authors.lastname: Jackson
authors.affiliation: Neurogenetics Research Program, School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide, Australia.
authors.forename: Lucianne
authors.initials: L
authors.lastname: Vandeleur
authors.affiliation: Genetics of Learning Disability Service, Hunter Genetics, Waratah, Australia.
authors.forename: Anna
authors.initials: A
authors.lastname: Hackett
authors.affiliation: The Wellcome Trust Sanger Institute, Hinxton, UK.
authors.forename: Patrick
authors.initials: P
authors.lastname: Tarpey
authors.affiliation: The Wellcome Trust Sanger Institute, Hinxton, UK.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Stratton
authors.affiliation: Genetics of Learning Disability Service, Hunter Genetics, Waratah, Australia.
authors.forename: Gillian
authors.initials: G
authors.lastname: Turner
authors.affiliation: Neurogenetics Research Program, School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide, Australia School of Molecular and Biomedical Science, The University of Adelaide, Adelaide, Australia Robinson Research Institute, The University of Adelaide, Adelaide, Australia.
authors.forename: Jozef
authors.initials: J
authors.lastname: Gécz
authors.affiliation: Genetics of Learning Disability Service, Hunter Genetics, Waratah, Australia.
authors.forename: Michael
authors.initials: M
authors.lastname: Field
mesh_terms: D000293:Adolescent; D000595:Amino Acid Sequence; D018389:Codon, Nonsense; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics*; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D010375:Pedigree; D054463:Trichothiodystrophy Syndromes / Q000235:genetics*
chemical_list: D018389:Codon, Nonsense; D004268:DNA-Binding Proteins; C107097:RNF113A protein, human
keywords: Dermatology; Endocrinology; Genetics; Intellectual disability; Trichothiodystrophy