RT Journal Article
SR Electronic
T1 A novel X-linked trichothiodystrophy associated with a nonsense mutation in RNF113A
JF Journal of Medical Genetics
JO J Med Genet
FD BMJ Publishing Group Ltd
SP 269
OP 274
DO 10.1136/jmedgenet-2014-102418
VO 52
IS 4
A1 Corbett, Mark A
A1 Dudding-Byth, Tracy
A1 Crock, Patricia A
A1 Botta, Elena
A1 Christie, Louise M
A1 Nardo, Tiziana
A1 Caligiuri, Giuseppina
A1 Hobson, Lynne
A1 Boyle, Jackie
A1 Mansour, Albert
A1 Friend, Kathryn L
A1 Crawford, Jo
A1 Jackson, Graeme
A1 Vandeleur, Lucianne
A1 Hackett, Anna
A1 Tarpey, Patrick
A1 Stratton, Michael R
A1 Turner, Gillian
A1 Gécz, Jozef
A1 Field, Michael
YR 2015
UL http://jmg.bmj.com/content/52/4/269.abstract
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.