No abstract

Dyskeratosis congenita (DC) is a heterogeneous inherited bone marrow failure and cancer predisposition syndrome in which germline mutations in telomere biology genes account for approximately one-half of known families. Hoyeraal Hreidarsson syndrome (HH) is a clinically severe variant of DC in which patients also have cerebellar hypoplasia and may present with severe immunodeficiency and enteropathy. We discovered a germline autosomal recessive mutation in RTEL1, a helicase with critical telomeric functions, in two unrelated families of Ashkenazi Jewish (AJ) ancestry. The affected individuals in these families are homozygous for the same mutation, R1264H, which affects three isoforms of RTEL1. Each parent was a heterozygous carrier of one mutant allele. Patient-derived cell lines revealed evidence of telomere dysfunction, including significantly decreased telomere length, telomere length heterogeneity, and the presence of extra-chromosomal circular telomeric DNA. In addition, RTEL1 mutant cells exhibited enhanced sensitivity to the interstrand cross-linking agent mitomycin C. The molecular data and the patterns of inheritance are consistent with a hypomorphic mutation in RTEL1 as the underlying basis of the clinical and cellular phenotypes. This study further implicates RTEL1 in the etiology of DC/HH and immunodeficiency, and identifies the first known homozygous autosomal recessive disease-associated mutation in RTEL1.

The catechol-o-methyltransferase (COMT) gene on chromosome 22q11 has been considered a strong candidate gene for schizophrenia (SZ) susceptibility. A functional Val/Met polymorphism in exon 4, with potential to affect COMT activity has been implicated in SZ, but the results remain inconclusive. We hypothesized that the association of COMT gene with SZ is not strictly a genetic alteration but could involve DNA methylation, as an epigenetic alteration. Thus, we chose to examine the cytosine DNA methylation profile of the human COMT promoter regions, which partially overlaps with the MB-COMT coding region and covers a total of 56 cytosines. Our analysis of 31 brain regions and 51 individual blood samples suggests that the cytosine methylation in his region is restricted to the CpG dinucleotides only. Also, the methylation pattern is nearly identical in the brain and blood with few exceptions. One cytosine (#27) is partially methylated in 5 brain regions and another cytosine (#23) is partially methylated in 81 of 82 samples studied. The exception being the blood DNA from a single SZ patient with prominent extreme negative symptoms, which was completely methylated. Interestingly, there was no difference in methylation at these sites in the blood DNA from three pairs of monozygotic twins discordant for SZ. The results support the use of blood DNA in methylation studies and rule out S-COMT promoter methylation as a common cause of SZ. The unique observation of a completely methylated cytosine 23 in one patient with SZ may have the potential to affect COMT mRNA transcription and gene activity, but remains to be evaluated.

These review data show CCT results in no clear difference in service use, social functioning or quality of life compared with voluntary care or brief supervised discharge. People receiving CCT were, however, less likely to be victims of violent or non-violent crime. It is unclear whether this benefit is due to the intensity of treatment or its compulsory nature. Short periods of conditional leave may be as effective (or non-effective) as formal compulsory treatment in the community. Evaluation of a wide range of outcomes should be considered when this legislation is introduced. However, conclusions are based on three relatively small trials, with high or unclear risk of blinding bias, and low- to moderate-quality evidence. In addition, clinical trials may not fully reflect the potential benefits of this complex intervention.