PT  - JOURNAL ARTICLE
AU  - Mark A Corbett
AU  - Tracy Dudding-Byth
AU  - Patricia A Crock
AU  - Elena Botta
AU  - Louise M Christie
AU  - Tiziana Nardo
AU  - Giuseppina Caligiuri
AU  - Lynne Hobson
AU  - Jackie Boyle
AU  - Albert Mansour
AU  - Kathryn L Friend
AU  - Jo Crawford
AU  - Graeme Jackson
AU  - Lucianne Vandeleur
AU  - Anna Hackett
AU  - Patrick Tarpey
AU  - Michael R Stratton
AU  - Gillian Turner
AU  - Jozef Gécz
AU  - Michael Field
TI  - A novel X-linked trichothiodystrophy associated with a nonsense mutation in RNF113A
AID  - 10.1136/jmedgenet-2014-102418
DP  - 2015 Apr 01
TA  - Journal of Medical Genetics
PG  - 269--274
VI  - 52
IP  - 4
4099  - http://jmg.bmj.com/content/52/4/269.short
4100  - http://jmg.bmj.com/content/52/4/269.full
SO  - J Med Genet2015 Apr 01; 52
AB  - 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.