Indications for genetic referral: a guide for healthcare providers

Geneticists and genetic counselors are often asked what may be appropriate reasons for referral to a genetics service. The Professional Practice and Guidelines Committee of the American College of Medical Genetics has generated lists of the more common reasons for referral and provide them for use by genetics professionals and other healthcare providers for guidance. The lists are divided into pediatric, prenatal, and adult indications

High Betaine, a Trimethylamine N-Oxide Related Metabolite, Is Prospectively Associated with Low Future Risk of Type 2 Diabetes Mellitus in the PREVEND Study

Background: Gut microbiota-related metabolites, trimethylamine-N-oxide (TMAO), choline, and betaine, have been shown to be associated with cardiovascular disease (CVD) risk. Moreover, lower plasma betaine concentrations have been reported in subjects with type 2 diabetes mellitus (T2DM). However, few studies have explored the association of betaine with incident T2DM, especially in the general population. The goals of this study were to evaluate the performance of a newly developed betaine assay and to prospectively explore the potential clinical associations of betaine and future risk of T2DM in a large population-based cohort. Methods: We developed a high-throughput, nuclear magnetic resonance (NMR) spectroscopy procedure for acquiring spectra that allow for the accurate quantification of plasma/serum betaine and TMAO. Assay performance for betaine quantification was assessed and Cox proportional hazards regression was employed to evaluate the association of betaine with incident T2DM in 4336 participants in the Prevention of Renal and Vascular End-Stage Disease (PREVEND) study. Results: Betaine assay results were linear (y = 1.02X - 3.75) over a wide range of concentrations (26.0-1135 mu M). The limit of blank (LOB), limit of detection (LOD) and limit of quantitation (LOQ) were 6.4, 8.9, and 13.2 mu M, respectively. Coefficients of variation for intra- and inter-assay precision ranged from 1.5-4.3% and 2.5-5.5%, respectively. Deming regression analysis of results produced by NMR and liquid chromatography coupled to tandem mass spectrometry(LC-MS/MS) revealed an R-2 value of 0.94 (Y = 1.08x - 1.89) and a small bias for higher values by NMR. The reference interval, in a cohort of apparently healthy adult participants (n = 501), was determined to be 23.8 to 74.7 mu M (mean of 42.9 +/- 12.6 mu M). In the PREVEND study (n = 4336, excluding subjects with T2DM at baseline), higher betaine was associated with older age and lower body mass index, total cholesterol, triglycerides, and hsCRP. During a median follow-up of 7.3 (interquartile range (IQR), 5.9-7.7) years, 224 new T2DM cases were ascertained. Cox proportional hazards regression models revealed that the highest tertile of betaine was associated with a lower incidence of T2DM. Hazard ratio (HR) for the crude model was 0.61 (95% CI: 0.44-0.85, p = 0.004). The association remained significant even after adjusting for multiple clinical covariates and T2DM risk factors, including fasting glucose. HR for the fully-adjusted model was 0.50 (95% CI: 0.32-0.80, p = 0.003). Conclusions: The newly developed NMR-based betaine assay exhibits performance characteristics that are consistent with usage in the clinical laboratory. Betaine levels may be useful for assessing the risk of future T2DM

Novel B(Ar')2(Ar'') hetero-tri(aryl)boranes: a systematic study of Lewis acidity

A series of homo- and hetero-tri(aryl)boranes incorporating pentafluorophenyl, 3,5-bis(trifluoromethyl)phenyl, and pentachlorophenyl groups, four of which are novel species, have been studied as the acidic component of frustrated Lewis pairs for the heterolytic cleavage of H2. Under mild conditions eight of these will cleave H2; the rate of cleavage depending on both the electrophilicity of the borane and the steric bulk around the boron atom. Electrochemical studies allow comparisons of the electrophilicity with spectroscopic measurements of Lewis acidity for different series of boranes. Discrepancies in the correlation between these two types of measurements, combined with structural characterisation of each borane, reveal that the twist of the aryl rings with respect to the boron-centred trigonal plane is significant from both a steric and electronic perspective, and is an important consideration in the design of tri(aryl)boranes as Lewis acids

Mass-Losing Semiregular Variable Stars in Baade's Windows

By cross-correlating the results of two recent large-scale surveys, the general properties of a well defined sample of semi-regular variable stars have been determined. ISOGAL mid-infrared photometry and MACHO lightcurves are assembled for approximately 300 stars in the Baade's Windows of low extinction towards the Galactic bulge. These stars are mainly giants of late M spectral type, evolving along the asymptotic giant branch (AGB). They are found to possess a wide and continuous distribution of pulsation periods and to obey an approximate log~period -- bolometric magnitude relation or set of such relations. Approximate mass-loss rates in the range of 1e-8 to 5e-7 M_sun per year are derived from ISOGAL mid-infrared photometry and models of stellar spectra adjusted for the presence of optically-thin circumstellar silicate dust. Mass-loss rates depend on luminosity and pulsation period. Some stars lose mass as rapidly as short-period Miras but do not show Mira-like amplitudes. A period of 70 days or longer is a necessary but not a sufficient condition for mass loss to occur. For AGB stars in the mass-loss ranges that we observe, the functional dependence of mass-loss rate on temperature and luminosity is found to be in agreement with recent theoretical predictions. If we include our mass-loss rates with a sample of extreme mass-losing AGB stars in the Large Magellanic Cloud, we get the general result for AGB stars that mass-loss rate is proportional to luminosity^{2.7}, valid for AGB stars with 10^{-8} to 10^{-4} M_sun per year (Abridged).Comment: to appear in The Astrophysical Journal, 51 pages, 9 figures, 3 tables; table 1 will be available in machine-readable format at the electronic Ap

Genome-Wide DNA Methylation Maps in Follicular Lymphoma Cells Determined by Methylation-Enriched Bisulfite Sequencing

BACKGROUND: Follicular lymphoma (FL) is a form of non-Hodgkin's lymphoma (NHL) that arises from germinal center (GC) B-cells. Despite the significant advances in immunotherapy, FL is still not curable. Beyond transcriptional profiling and genomics datasets, there currently is no epigenome-scale dataset or integrative biology approach that can adequately model this disease and therefore identify novel mechanisms and targets for successful prevention and treatment of FL. METHODOLOGY/PRINCIPAL FINDINGS: We performed methylation-enriched genome-wide bisulfite sequencing of FL cells and normal CD19(+) B-cells using 454 sequencing technology. The methylated DNA fragments were enriched with methyl-binding proteins, treated with bisulfite, and sequenced using the Roche-454 GS FLX sequencer. The total number of bases covered in the human genome was 18.2 and 49.3 million including 726,003 and 1.3 million CpGs in FL and CD19(+) B-cells, respectively. 11,971 and 7,882 methylated regions of interest (MRIs) were identified respectively. The genome-wide distribution of these MRIs displayed significant differences between FL and normal B-cells. A reverse trend in the distribution of MRIs between the promoter and the gene body was observed in FL and CD19(+) B-cells. The MRIs identified in FL cells also correlated well with transcriptomic data and ChIP-on-Chip analyses of genome-wide histone modifications such as tri-methyl-H3K27, and tri-methyl-H3K4, indicating a concerted epigenetic alteration in FL cells. CONCLUSIONS/SIGNIFICANCE: This study is the first to provide a large scale and comprehensive analysis of the DNA methylation sequence composition and distribution in the FL epigenome. These integrated approaches have led to the discovery of novel and frequent targets of aberrant epigenetic alterations. The genome-wide bisulfite sequencing approach developed here can be a useful tool for profiling DNA methylation in clinical samples

Rare loss of function variants in candidate genes and risk of colorectal cancer

Although ~ 25% of colorectal cancer or polyp (CRC/P) cases show familial aggregation, current germline genetic testing identifies a causal genotype in the 16 major genes associated with high penetrance CRC/P in only 20% of these cases. As there are likely other genes underlying heritable CRC/P, we evaluated the association of variation at novel loci with CRC/P. We evaluated 158 a priori selected candidate genes by comparing the number of rare potentially disruptive variants (PDVs) found in 84 CRC/P cases without an identified CRC/P risk-associated variant and 2440 controls. We repeated this analysis using an additional 73 CRC/P cases. We also compared the frequency of PDVs in select genes among CRC/P cases with two publicly available data sets. We found a significant enrichment of PDVs in cases vs. controls: 20% of cases vs. 11.5% of controls with ≥ 1 PDV (OR = 1.9, p = 0.01) in the original set of cases. Among the second cohort of CRC/P cases, 18% had a PDV, significantly different from 11.5% (p = 0.02). Logistic regression, adjusting for ancestry and multiple testing, indicated association between CRC/P and PDVs in NTHL1 (p = 0.0001), BRCA2 (p = 0.01) and BRIP1 (p = 0.04). However, there was no significant difference in the frequency of PDVs at each of these genes between all 157 CRC/P cases and two publicly available data sets. These results suggest an increased presence of PDVs in CRC/P cases and support further investigation of the association of NTHL1, BRCA2 and BRIP1 variation with CRC/P

Prime Focus Spectrograph - Subaru's future -

The Prime Focus Spectrograph (PFS) of the Subaru Measurement of Images and Redshifts (SuMIRe) project has been endorsed by Japanese community as one of the main future instruments of the Subaru 8.2-meter telescope at Mauna Kea, Hawaii. This optical/near-infrared multi-fiber spectrograph targets cosmology with galaxy surveys, Galactic archaeology, and studies of galaxy/AGN evolution. Taking advantage of Subaru's wide field of view, which is further extended with the recently completed Wide Field Corrector, PFS will enable us to carry out multi-fiber spectroscopy of 2400 targets within 1.3 degree diameter. A microlens is attached at each fiber entrance for F-ratio transformation into a larger one so that difficulties of spectrograph design are eased. Fibers are accurately placed onto target positions by positioners, each of which consists of two stages of piezo-electric rotary motors, through iterations by using back-illuminated fiber position measurements with a wide-field metrology camera. Fibers then carry light to a set of four identical fast-Schmidt spectrographs with three color arms each: the wavelength ranges from 0.38 {\mu}m to 1.3 {\mu}m will be simultaneously observed with an average resolving power of 3000. Before and during the era of extremely large telescopes, PFS will provide the unique capability of obtaining spectra of 2400 cosmological/astrophysical targets simultaneously with an 8-10 meter class telescope. The PFS collaboration, led by IPMU, consists of USP/LNA in Brazil, Caltech/JPL, Princeton, & JHU in USA, LAM in France, ASIAA in Taiwan, and NAOJ/Subaru.Comment: 13 pages, 11 figures, submitted to "Ground-based and Airborne Instrumentation for Astronomy IV, Ian S. McLean, Suzanne K. Ramsay, Hideki Takami, Editors, Proc. SPIE 8446 (2012)