Heterozygous variants in <em>CTR9</em>, which encodes a major component of the PAF1 complex, are associated with a neurodevelopmental disorder.

Purpose: CTR9 is a subunit of the PAF1 complex (PAF1C) that plays a crucial role in transcription regulation by binding CTR9 to RNA polymerase II. It is involved in transcription-coupled histone modification through promoting H3K4 and H3K36 methylation. We describe the clinical and molecular studies in 13 probands, harboring likely pathogenic CTR9 missense variants, collected through GeneMatcher. Methods: Exome sequencing was performed in all individuals. CTR9 variants were assessed through 3-dimensional modeling of the activated human transcription complex Pol II-DSIF-PAF-SPT6 and the PAF1/CTR9 complex. H3K4/H3K36 methylation analysis, mitophagy assessment based on tetramethylrhodamine ethyl ester perchlorate immunofluorescence, and RNA-sequencing in skin fibroblasts from 4 patients was performed. Results: Common clinical findings were variable degrees of intellectual disability, hypotonia, joint hyperlaxity, speech delay, coordination problems, tremor, and autism spectrum disorder. Mild dysmorphism and cardiac anomalies were less frequent. For 11 CTR9 variants, de novo occurrence was shown. Three-dimensional modeling predicted a likely disruptive effect of the variants on local CTR9 structure and protein interaction. Additional studies in fibroblasts did not unveil the downstream functional consequences of the identified variants. Conclusion: We describe a neurodevelopmental disorder caused by (mainly) de novo variants in CTR9, likely affecting PAF1C function

The FP420 R&D Project : Higgs and New Physics with forward protons at the LHC

We present the FP420 R&D project, which has been studying the key aspects of the development and installation of a silicon tracker and fast-timing detectors in the LHC tunnel at 420 m from the interaction points of the ATLAS and CMS experiments. These detectors would measure precisely very forward protons in conjunction with the corresponding central detectors as a means to study Standard Model (SM) physics, and to search for and characterise New Physics signals. This report includes a detailed description of the physics case for the detector and, in particular, for the measurement of Central Exclusive Production, pp --> p + phi + p, in which the outgoing protons remain intact and the central system phi may be a single particle such as a SM or MSSM Higgs boson. Other physics topics discussed are gamma-gamma and gamma-p interactions, and diffractive processes. The report includes a detailed study of the trigger strategy, acceptance, reconstruction efficiencies, and expected yields for a particular p p --> p H p measurement with Higgs boson decay in the b-bbar mode. The document also describes the detector acceptance as given by the LHC beam optics between the interaction points and the FP420 location, the machine backgrounds, the new proposed connection cryostat and the moving ("Hamburg") beam-pipe at 420 m, and the radio-frequency impact of the design on the LHC. The last part of the document is devoted to a description of the 3D silicon sensors and associated tracking performances, the design of two fast-timing detectors capable of accurate vertex reconstruction for background rejection at high-luminosities, and the detector alignment and calibration strategy.Comment: 178 pages, 128 figures. Updated Timing section. Figures compressed to marginal resolution due to arxiv.org file size requirements. A higher quality document accessible at http://www.fp420.com/papers.htm