## 4 Olmsted Syndrome  
The genetic basis of various skin diseases (Table 1) has been determined using exome sequencing technology. One example where WES enabled the identification of the underlying causative genes is Olmsted syndrome (OS) [47,48]. OS (OMIM #614594) is a rare disorder characterised by mutilatingpalmoplantar keratoderma and periodici keratosis. Additional clinical features include constriction of the digits, dystrophy of the nails, diffuse alopecia and a predisposition to infection and development of squamous cell carcinoma on keratotic lesions [47]. Different modes of inheritance have been hypothesised [47; 48; 49; 50]. WES was used successfully to identify mutations in the Transient Receptor Potential Cation Channel, Subfamily V, Member 3 (_TRPV3_) gene [47], and the Membrane-Bound Transcription Factor Protease, Site 2 (_MBTPS2_) gene [48] to be associated with OS. [PERSON] _et al._ (2012) performed WES of an OS patient and her unaffected parents and identified a novel _de novo_ heterozygous mutation p.G573S in _TRPV3_[47]. Screening for _TRPV3_ mutations in five other OS patients revealed that three were heterozygous for p.G573S, one heterozygous for p.G573C and one heterozygous for p.W692G [47]. TRPV3 is a member of the TRPV cation channel family, and is known to be expressed in various tissue types including skin and hair follicles [63; 64; 65]. The murine _TRPV3_ mutants p.G573S and p.G573C were discovered in spontaneous hairless rodent strains that develop dermatitis, a trait inherited in an autosomal dominant manner [66]. _Trpv3_ knockout mice display wavy hair, curly whiskers and a defective skin barrier, and it is believed that TRPV3 associates with TGF-\(\omega\)/EGFR in a signalling pathway to modulate keratinocyte differentiation and hair morphogenesis [67]. _In vitro_ functional studies with the three OS-associated TRPV3 mutants indicated that they are gain of function mutants, creating constitutively open channels and causing increased cell death of cells expressing the mutants [47]. Similar results were obtained in _in vitro_ expression studies with the murine TRPV3 mutants p.G573S and p.G573C [68]. It has been hypothesised that _in vivo_ the mutants may cause apoptosis and subsequent keratoderma in patients, and could contribute to their pruritis [47]. A subsequent study using WES revealed the recurrent _TRPV3_ mutation p.G573S in sporadic OS [69]. Screening by Sanger sequencing has also revealed a homozygous mutation in an OS patient, \begin{table}
\begin{tabular}{c c c c} \hline
**Gene** & **Disease** & **Mode of Inheritance** & **Reference** \\ \hline _AGAB_ & Punctate palmoplantar keratoderma Type I & AD & [51; 52] \\ _ADAM10_ & Reticulate acropigmentation of Kitamura & AD & [53] \\ _AQP5_ & Nonepidermolytic palmoplantar keratoderma & AD & [54] \\ _ENPP1_ & Cole disease & AD & [55] \\ _EXPH5_ & Inherited skin fragility & AR & [56] \\ _HOXC13_ & Pure hair and nail ectodermal dysplasia & AR & [57] \\ _KANK2_ & Palmoplantar keratoderma and woolly hair & AR & [58] \\ _MBTPS2_ & Olmsted syndrome & XLR & [48] \\ _POFUT1_ & [PERSON] disease & AD & [59] \\ _POGLUT1_ & [PERSON] disease & AD & [60] \\ _SERPINB7_ & Nagashima-type palmoplantar keratosis & AR & [61] \\ _TRPV3_ & [PERSON] syndrome & AD/AR & [47]/[62] \\ \hline \end{tabular} AD: autosomal dominant; AR: autosomal recessive; XLR: X-linked recessive.  
\end{table} 
Table 1: Examples of genes associated with skin disease discovered using exome sequencing technology. indicating recessive inheritance [62]. Both recessive [70] and sporadic [71]_TRPV3_ mutations have been associated with atypical OS with erythromelalgia. Exome sequencing of two affected males reported previously in a consanguineous pedigree [72] in which OS followed a suggested X-linked recessive inheritance pattern, revealed a novel _MBTPS2_ gene mutation which segregated with disease in the family [48].