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

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.

Assessing personality traits associated with depression: the utility of a tiered model.

BACKGROUND: We sought to develop a refined measure of eight personality traits or constructs observed in those who develop depression. We report the psychometric properties of the derived Temperament and Personality (T and P) questionnaire, as well as a pilot study examining its capacity to differentiate over-represented personality traits in those with depression. METHOD: The factor structure of the T&P measure was examined in a general practice sample of 529 subjects. We imposed a range of factorial solutions to determine how higher-order molar constructs arborized to eight lower-order constructs. Scale scores generated at each derived tier were contrasted for 52 out-patients with major depression and control subjects from the general practice sample to pursue over-represented personality constructs, and to clarify if an optimal number of constructs could be identified. RESULTS: In the factor analysis, some 90% of the items loaded on their a priori construct. The questionnaire showed high internal consistency, test-retest reliability and minimal sensitivity to mood state effects. Analyses rejected the hypothesis that risk to depression might be generally affected by individuals merely scoring high on all 'normal' personality styles, whether higher-order or lower-order traits. CONCLUSIONS: Findings suggest that, while identified constructs linked well with the widely accepted theoretical model of personality (the Five Factor Model) at one tier, such a fixed model may be too inflexible. We therefore detail potential advantages to using a multi-tiered model of personality traits in application studies.