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A novel X-linked trichothiodystrophy associated with a nonsense mutation in RNF113A
  1. Mark A Corbett1,
  2. Tracy Dudding-Byth2,3,
  3. Patricia A Crock4,
  4. Elena Botta5,
  5. Louise M Christie2,
  6. Tiziana Nardo5,
  7. Giuseppina Caligiuri5,
  8. Lynne Hobson6,
  9. Jackie Boyle2,
  10. Albert Mansour7,
  11. Kathryn L Friend6,
  12. Jo Crawford1,
  13. Graeme Jackson8,
  14. Lucianne Vandeleur1,
  15. Anna Hackett2,
  16. Patrick Tarpey9,
  17. Michael R Stratton9,
  18. Gillian Turner2,
  19. Jozef Gécz1,10,11,
  20. Michael Field2
  1. 1Neurogenetics Research Program, School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide, Australia
  2. 2Genetics of Learning Disability Service, Hunter Genetics, Waratah, Australia
  3. 3University of Newcastle, Newcastle, Australia
  4. 4Department of Paediatric Endocrinology and Diabetes, John Hunter Children's Hospital, University of Newcastle, Newcastle, Australia
  5. 5Istituto di Genetica Molecolare CNR, Pavia, Italy
  6. 6Molecular Genetics, Department of Genetic Medicine, SA Pathology at Women's and Children's Hospital, North Adelaide, Australia
  7. 7The Children's Hospital at Westmead, Westmead, Australia
  8. 8Brain Research Institute, Florey Neurosciences Institutes, West Heidelberg, Australia
  9. 9The Wellcome Trust Sanger Institute, Hinxton, UK
  10. 10School of Molecular and Biomedical Science, The University of Adelaide, Adelaide, Australia
  11. 11Robinson Research Institute, The University of Adelaide, Adelaide, Australia
  1. Correspondence to Dr Michael Field, The GOLD service Hunter Genetics, University of Newcastle, NSW 2308, Australia; mike.field{at}health.nsw.gov.au Prof Jozef Gécz, Neurogenetics Research Program, School of Paediatrics and Reproductive Health, University of Adelaide (at Women's and Children's Hospital), WCH-940, 72 King William Rd, North Adelaide, 5006, Australia; jozef.gecz@adelaide.edu.au

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.

Patients and 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.

  • Genetics
  • Endocrinology
  • Dermatology
  • Trichothiodystrophy
  • Intellectual disability

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