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PURPOSE. We determined the fraction of families in a wellcharacterized cohort with a provisional diagnosis of autosomal dominant retinitis pigmentosa (adRP) that have disease-causing mutations in the X-linked retinitis pigmentosa GTPase regulator (RPGR) gene or the retinitis pigmentosa 2 (RP2) gene. METHODS.Families with a provisional clinical diagnosis of adRP, and a pedigree consistent with adRP but no male-to-male transmission were selected from a cohort of 258 families, and tested for mutations in the RPGR and RP2 genes with di-deoxy sequencing. To facilitate testing of RPGR in ''adRP'' families that had no male members available for testing, the repetitive and purine-rich ORF15 of RPGR was subcloned and sequenced in heterozygous female subjects from 16 unrelated families.RESULTS. Direct sequencing of RPGR and RP2 allowed for identification of a disease-causing mutation in 21 families. Of these ''adRP'' families 19 had RPGR mutations, and two had RP2 mutations. Subcloning and sequencing of ORF15 of RPGR in female subjects identified one additional RPGR mutation. Of the 22 mutations identified, 15 have been reported previously.CONCLUSIONS. These data show that 8.5% (22 in 258) of families thought to have adRP truly have X-linked retinitis pigmentosa (XLRP). These results have substantive implications for calculation of recurrence risk, genetic counseling, and potential treatment options, and illustrate the importance of screening families with a provisional diagnosis of autosomal inheritance and no male-to-male transmission for mutations in X-linked genes. Mutations in RPGR are one of the most common causes of all forms of retinitis pigmentosa. (Invest Ophthalmol Vis Sci.

BACKGROUND:The transcription factor TCF21 is involved in mesenchymal-to-epithelial differentiation and was shown to be aberrantly hypermethylated in lung and head and neck cancers. Because of its reported high frequency of hypermethylation in lung cancer, further characterization of the stages and types of nonsmall cell lung cancer (NSCLC) that are hypermethylated and the frequency of hypermethylation and associated ''second hits'' were assessed. METHODS: TCF21 promoter hypermethylation in 105 NSCLC including various stages and histologies in smokers and nonsmokers was determined. In addition, TCF21 loss of heterozygosity and mutational status were examined. Twentytwo cancer cell lines from varied tissue origins were also assayed. The NSCLC results were validated and expanded by examining TCF21 immunohistochemical expression on a tissue microarray containing 300 NSCLC cases. RESULTS: Overall, 81% of NSCLC samples showed TCF21 promoter hypermethylation, and 84% showed decreased TCF21 protein expression. Multivariate analysis showed that TCF21 expression, although below normal in both histologies, was lower in adenocarcinoma than in squamous cell carcinoma and was not independently correlated with sex, smoking, and EGFR mutation status or with clinical outcome. Cell lines from other cancer types also showed frequent TCF21 promoter hypermethylation. CONCLUSIONS: Hypermethylation and decreased expression of TCF21 were tumor specific and very frequent in all NSCLCs, even early-stage disease, thus making TCF21 a potential candidate methylation biomarker for early-stage NSCLC screening. TCF21 hypermethylation in a variety of tumor cell lines suggests it may also be a valuable methylation biomarker in other tumor types. Cancer 2011;117:606-17.

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