Joint, multifaceted genomic analysis enables diagnosis of diverse, ultra-rare monogenic presentations.

Genomics for rare disease diagnosis has advanced at a rapid pace due to our ability to perform "N-of-1" analyses on individual patients. The increasing sizes of ultra-rare, "N-of-1" disease cohorts internationally newly enables cohort-wide analyses for new discoveries, but well-calibrated statistical genetics approaches for jointly analyzing these patients are still under development.1,2 The Undiagnosed Diseases Network (UDN) brings multiple clinical, research and experimental centers under the same umbrella across the United States to facilitate and scale N-of-1 analyses. Here, we present the first joint analysis of whole genome sequencing data of UDN patients across the network. We apply existing and introduce new, well-calibrated statistical methods for prioritizing disease genes with de novo recurrence and compound heterozygosity. We also detect pathways enriched with candidate and known diagnostic genes. Our computational analysis, coupled with a systematic clinical review, recapitulated known diagnoses and revealed new disease associations. We make our gene-level findings and variant-level information across the cohort available in a public-facing browser (https://dbmi-bgm.github.io/udn-browser/). These results show that N-of-1 efforts should be supplemented by a joint genomic analysis across cohorts.

The 4D Nucleome Data Portal as a resource for searching and visualizing curated nucleomics data.

The 4D Nucleome (4DN) Network aims to elucidate the complex structure and organization of chromosomes in the nucleus and the impact of their disruption in disease biology. We present the 4DN Data Portal ( https://data.4dnucleome.org/ ), a repository for datasets generated in the 4DN network and relevant external datasets. Datasets were generated with a wide range of experiments, including chromosome conformation capture assays such as Hi-C and other innovative sequencing and microscopy-based assays probing chromosome architecture. All together, the 4DN data portal hosts more than 1800 experiment sets and 36000 files. Results of sequencing-based assays from different laboratories are uniformly processed and quality-controlled. The portal interface allows easy browsing, filtering, and bulk downloads, and the integrated HiGlass genome browser allows interactive visualization and comparison of multiple datasets. The 4DN data portal represents a primary resource for chromosome contact and other nuclear architecture data for the scientific community.