Mount Sinai Center for Undiagnosed Diseases

We propose an Undiagnosed Diseases Network (UDN) Diagnostic Center of Excellence (DCoE) at the Mount Sinai Health System (MSHS) and the Icahn School of Medicine at Mount Sinai (ISMMS). The MSHS, a large health system in New York City, serves highly diverse populations. Our investigators are leaders in community-engaged genomic research with equitably diverse enrollment.

Mount Sinai's DCoE will build upon our Undiagnosed Disease Program (UDP), modeled on the UDN approach, that has a strong track record of applying state-of-the-art genomic approaches, including using artificial intelligence (AI)-based variant prioritization and long-read genome sequencing.

We routinely pursue functional genomic studies for high- quality candidate variants, through our Drosophila-based modeling core and collaboratively. Adapting to and complying with the UDN standardized approach will be our deep commitment. We will be active contributors to UDN governance. For Aim 1, we will incorporate Mount Sinai's UDP as a DCoE within the collaborative UDN ecosystem.

Enrolled Tier 2-4 pediatric and adult patients (35–50/year) with rare, undiagnosed disorders will be assessed in the ISMMS Clinical Research Unit by a team of physicians with broad expertise in Genetics, Pediatrics, Medicine, and Neurology, among others.

Our DCoE central group includes the persons who have driven the success of our existing UDP, which routinely screens referrals and analyzes exome, genome, and RNAseq data for unsolved cases.

To enhance diverse UDP referrals from the NYC area, we will expand our existing outreach to the > 7,000 physicians in the MSHS as well as those with our community partner, the Institute for Family Health, and draw from unsolved cases within our clinical genetics services.

We will seek to advance sustainability through a multi-prong approach including establishing clinical utility and conversations with payers, and by continued philanthropic donor engagement.

For Aim 2, we will deploy the clinical and research benefits of our UDN DCoE equitably for New York City's highly diverse population.

We will leverage the fact that the MSHS resides in one of the most ancestrally diverse places on earth, providing the potential for equitable inclusion.

We will rely on our site's expertise with community-engaged participatory research, specifically for genomic medicine, in order to fashion strategies to make UDN participation accessible and attractive. The Mount Sinai DCoE will apply this proven approach to improve the diversity of UDN referrals. For Aim 3, we will undertake in-depth, research-based characterization of UDN patients with immunological disorders.

We will perform extensive immune profiling of participants prioritized as more likely to have single- gene disorders of the immune system in order to drive understanding of trait pathogenesis.

For adult patients likely to have traits with somatic gene variants, we will undertake deep sequencing to detect mosaicism.

In summary, we are proposing a Mount Sinai DCoE that will draw upon a diverse urban population, experience with our own UDP, and expertise in community-engaged research to contribute to the UDNs Phase III goals.