A novel X-linked trichothiodystrophy associated with a nonsense mutation in RNF113A

J Med Genet. 2015 Apr;52(4):269-74. doi: 10.1136/jmedgenet-2014-102418.

Mark A Corbett ¹, Tracy Dudding-Byth ², Patricia A Crock ³, Elena Botta ⁴, Louise M Christie ⁵, Tiziana Nardo ⁴, Giuseppina Caligiuri ⁴, Lynne Hobson ⁶, Jackie Boyle ⁵, Albert Mansour ⁷, Kathryn L Friend ⁶, Jo Crawford ¹, Graeme Jackson ⁸, Lucianne Vandeleur ¹, Anna Hackett ⁵, Patrick Tarpey ⁹, Michael R Stratton ⁹, Gillian Turner ⁵, Jozef Gécz ¹⁰, Michael Field ⁵

Affiliations

1 Neurogenetics Research Program, School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide, Australia.
2 Genetics of Learning Disability Service, Hunter Genetics, Waratah, Australia University of Newcastle, Newcastle, Australia.
3 Department of Paediatric Endocrinology and Diabetes, John Hunter Children's Hospital, University of Newcastle, Newcastle, Australia.
4 Istituto di Genetica Molecolare CNR, Pavia, Italy.
5 Genetics of Learning Disability Service, Hunter Genetics, Waratah, Australia.
6 Molecular Genetics, Department of Genetic Medicine, SA Pathology at Women's and Children's Hospital, North Adelaide, Australia.
7 The Children's Hospital at Westmead, Westmead, Australia.
8 Brain Research Institute, Florey Neurosciences Institutes, West Heidelberg, Australia.
9 The Wellcome Trust Sanger Institute, Hinxton, UK.
10 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.

PMID: 25612912 DOI: 10.1136/jmedgenet-2014-102418

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.

Keywords

Dermatology; Endocrinology; Genetics; Intellectual disability; Trichothiodystrophy.

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