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 Mark A Corbett
A1 Tracy Dudding-Byth
A1 Patricia A Crock
A1 Elena Botta
A1 Louise M Christie
A1 Tiziana Nardo
A1 Giuseppina Caligiuri
A1 Lynne Hobson
A1 Jackie Boyle
A1 Albert Mansour
A1 Kathryn L Friend
A1 Jo Crawford
A1 Graeme Jackson
A1 Lucianne Vandeleur
A1 Anna Hackett
A1 Patrick Tarpey
A1 Michael R Stratton
A1 Gillian Turner
A1 Jozef Gécz
A1 Michael Field
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.