Purpose We describe the clinical implementation of genome-wide DNA methylation analysis in rare disorders across the EpiSign diagnostic laboratory network and the assessment of results and clinical impact in the first subjects tested. Methods We outline the logistics and data flow between an integrated network of clinical diagnostics laboratories in Europe, the United States, and Canada. We describe the clinical validation of EpiSign using 211 specimens and assess the test performance and diagnostic yield in the first 207 subjects tested involving two patient subgroups: the targeted cohort (subjects with previous ambiguous/inconclusive genetic findings including genetic variants of unknown clinical significance) and the screening cohort (subjects with clinical findings consistent with hereditary neurodevelopmental syndromes and no previous conclusive genetic findings). Results Among the 207 subjects tested, 57 (27.6%) were positive for a diagnostic episignature including 48/136 (35.3%) in the targeted cohort and 8/71 (11.3%) in the screening cohort, with 4/207 (1.9%) remaining inconclusive after EpiSign analysis. Conclusion This study describes the implementation of diagnostic clinical genomic DNA methylation testing in patients with rare disorders. It provides strong evidence of clinical utility of EpiSign analysis, including the ability to provide conclusive findings in the majority of subjects tested.

Summary Overlapping clinical phenotypes and an expanding breadth and complexity of genomic associations are a growing challenge in the diagnosis and clinical management of Mendelian disorders. The functional consequences and clinical impacts of genomic variation may involve unique, disorder-specific, genomic DNA methylation episignatures. In this study, we describe 19 novel episignature disorders and compare the findings alongside 38 previously established episignatures for a total of 57 episignatures associated with 65 genetic syndromes. We demonstrate increasing resolution and specificity ranging from protein complex, gene, sub-gene, protein domain, and even single nucleotide-level Mendelian episignatures. We show the power of multiclass modeling to develop highly accurate and disease-specific diagnostic classifiers. This study significantly expands the number and spectrum of disorders with detectable DNA methylation episignatures, improves the clinical diagnostic capabilities through the resolution of unsolved cases and the reclassification of variants of unknown clinical significance, and provides further insight into the molecular etiology of Mendelian conditions.

The adsorption of CO 2 on zeolite Li-Rho (unit cell composition Li 9.8 Al 9.8 Si 38.2 O 96 ) has been investigated by the measurement of adsorption isotherms (273 -300 K), breakthrough curves with a CO 2 /CH 4 /He mixture (308 K) and in situ synchrotron X-ray powder diffraction in CO 2 (298 K). The Rho framework distorts when in the Li-form to give a shape selective adsorbent for CO 2 over CH 4 , although breakthrough curves reveal diffusional limitations. In situ synchrotron powder XRD follows the expansion of the Li-Rho unit cell upon adsorption, which remains single phase to a CO 2 pressure of ca. 0.6 bar. Partial cation exchange of Li-2 Rho by Na + or Cs + gives two series of M,Li-Rho zeolites (M = Na, Cs). Where the occupancy of window sites (8R, D8R) between lta cages is less than 50%, hysteresis is not observed in CO 2 isotherms at 298 K. For Cs 1.8 Li 8 -Rho, which has a larger unit cell and a wider window than zeolite Li-Rho due to the presence of large Cs + cations in double 8-ring sites, breakthrough curves indicate faster CO 2 diffusion without significant loss of selectivity. We propose this control of adsorption kinetics of the flexible zeolite Rho via modification of cation content as a mechanism for cation controlled molecular sieving.

No abstract

No abstract

An expanding range of genetic syndromes are characterized by genome‐wide disruptions in DNA methylation profiles referred to as episignatures. Episignatures are distinct, highly sensitive, and specific biomarkers that have recently been applied in clinical diagnosis of genetic syndromes. Episignatures are contained within the broader disorder‐specific genome‐wide DNA methylation changes, which can share significant overlap among different conditions. In this study, we performed functional genomic assessment and comparison of disorder‐specific and overlapping genome‐wide DNA methylation changes related to 65 genetic syndromes with previously described episignatures. We demonstrate evidence of disorder‐specific and recurring genome‐wide differentially methylated probes (DMPs) and regions (DMRs). The overall distribution of DMPs and DMRs across the majority of the neurodevelopmental genetic syndromes analyzed showed substantial enrichment in gene promoters and CpG islands, and under‐representation of the more variable intergenic regions. Analysis showed significant enrichment of the DMPs and DMRs in gene pathways and processes related to neurodevelopment, including neurogenesis, synaptic signaling and synaptic transmission. This study expands beyond the diagnostic utility of DNA methylation episignatures by demonstrating correlation between the function of the mutated genes and the consequent genomic DNA methylation profiles as a key functional element in the molecular etiology of genetic neurodevelopmental disorders.

No abstract

The theory of "pore blocking" is often used, particularly in combination with percolation theory, to develop methods of analysis for gas sorption data for the structural characterization of porous media. However, the evidence for the existence of the pore-blocking effect is conflicting and equivocal. In the work described here mercury porosimetry experiments were integrated with gas sorption to detect the existence of poreblocking effects during the desorption of nitrogen from a mesoporous sol-gel silica material at 77 K.