An integrated clinical program and crowdsourcing strategy for genomic sequencing and Mendelian disease gene discovery.

Despite major progress in defining the genetic basis of Mendelian disorders, the molecular etiology of many cases remains unknown. Patients with these undiagnosed disorders often have complex presentations and require treatment by multiple health care specialists. Here, we describe an integrated clinical diagnostic and research program using whole-exome and whole-genome sequencing (WES/WGS) for Mendelian disease gene discovery. This program employs specific case ascertainment parameters, a WES/WGS computational analysis pipeline that is optimized for Mendelian disease gene discovery with variant callers tuned to specific inheritance modes, an interdisciplinary crowdsourcing strategy for genomic sequence analysis, matchmaking for additional cases, and integration of the findings regarding gene causality with the clinical management plan. The interdisciplinary gene discovery team includes clinical, computational, and experimental biomedical specialists who interact to identify the genetic etiology of the disease, and when so warranted, to devise improved or novel treatments for affected patients. This program effectively integrates the clinical and research missions of an academic medical center and affords both diagnostic and therapeutic options for patients suffering from genetic disease. It may therefore be germane to other academic medical institutions engaged in implementing genomic medicine programs

The Forward Physics Facility: Sites, Experiments, and Physics Potential

The Forward Physics Facility (FPF) is a proposal to create a cavern with thespace and infrastructure to support a suite of far-forward experiments at theLarge Hadron Collider during the High Luminosity era. Located along the beamcollision axis and shielded from the interaction point by at least 100 m ofconcrete and rock, the FPF will house experiments that will detect particlesoutside the acceptance of the existing large LHC experiments and will observerare and exotic processes in an extremely low-background environment. In thiswork, we summarize the current status of plans for the FPF, including recentprogress in civil engineering in identifying promising sites for the FPF andthe experiments currently envisioned to realize the FPF's physics potential. Wethen review the many Standard Model and new physics topics that will beadvanced by the FPF, including searches for long-lived particles, probes ofdark matter and dark sectors, high-statistics studies of TeV neutrinos of allthree flavors, aspects of perturbative and non-perturbative QCD, andhigh-energy astroparticle physics.<br