The Baylor College of Medicine (BCM) Undiagnosed Diseases Network (UDN) Clinical Site (CS) has successfully advanced the objectives of phase I UDN. We established a high throughput integrated pipeline for patients with undiagnosed diseases (UDD) to access a state of the art diagnostic, clinical, and molecular evaluation. We led extramural UDN clinical sites in number of patient acceptances and in person evaluations, while being one of two extramural sites to achieve 100% for these two key milestones. We developed innovative approaches including trio RNA sequencing that led us to achieve a diagnostic rate for solved and strong candidate genes in 45% of cases completed to date. Finally, we engaged the UDN and the broader scientific/lay community in sharing best practices, collaborative discovery, and education. This was achieved by leveraging the integrated genetic and genomic program that is the Department of Molecular and Human Genetics (DMHG) at BCM. The Department is a combination of basic science, clinical, and molecular pathology departments. Because these are consumed under one organizational unit, we have rapidly translated discovery to practice, and served as a nexus for the research community at BCM, the Texas Medical Center, and nationally. The leadership of the DMHG in genetic and genomic medicine at BCM has ensured the integration of the partnering Departments of Pediatrics, Internal Medicine, and Neurology into phase I of the BCM UDN CS. In phase II we propose to apply this integrated approach to achieve the new and ongoing objectives of the UDN. The BCM UDN CS leadership includes established clinical investigators in Genetics, Pediatrics, Medicine, and Neurology who will lead a primary team while drawing from consultants in partner Departments institution-wide. Clinical delineation and subsequent DNA molecular diagnosis will leverage both established (Human Genome Sequencing Center, Baylor Genetics laboratory, and NIH Center for Mendelian Genomics) and BCM UDN CS-specific bioinformatics pipelines. The interpretation and ultimate functional study of genomic data will flow to specialized organ-based research centers including the Center for Skeletal Medicine and Biology (led by Dr. Brendan Lee), the Neurological Research Institute (led by Dr. Huda Zoghbi), the Center for Human Immunology (led by Dr. Jordan Orange), and the NIH UDN Model Organism Screening Center and Knockout Mouse Phenotyping programs. For sustainability, BCM will 1) establish and financially support a Center for Undiagnosed Diseases, 2) leverage a newly developed DMHG virtual platform for medical genetics care delivery platform (Consultagene.org) to increase efficiency, decrease cost, and expand access for patient and provider engagement, 3) translate research tools to the clinical diagnostic arena, i.e., Baylor Genetics laboratory, 4) complete ongoing health economic studies to improve payor coverage for these tools, and 5) widely disseminate patient variants to stimulate collaboration with basic scientists for functional studies.

Public Health Relevance

This proposal describes the renewal of an Undiagnosed Diseases Network (UDN) Clinical Site at Baylor College of Medicine in Houston Texas as a regional and national referral site for clinical evaluation of undiagnosed disease in the southwest US and the Gulf Coast. It builds on a successful phase I of the UDN and leverages a long standing tradition of clinical discovery and translational research housed within the uniquely integrated activities of the Department of Molecular and Human Genetics (DMHG). In so doing, we will accelerate discovery in undiagnosed rare diseases thereby facilitating the study of disease mechanisms which will lead to their improved recognition, diagnosis, and treatment.

Agency
National Institute of Health (NIH)
Institute
National Human Genome Research Institute (NHGRI)
Type
Research Project--Cooperative Agreements (U01)
Project #
2U01HG007709-05
Application #
9594644
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Wise, Anastasia Leigh
Project Start
2014-07-01
Project End
2022-06-30
Budget Start
2018-09-21
Budget End
2019-06-30
Support Year
5
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Baylor College of Medicine
Department
Genetics
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Splinter, Kimberly; Adams, David R; Bacino, Carlos A et al. (2018) Effect of Genetic Diagnosis on Patients with Previously Undiagnosed Disease. N Engl J Med 379:2131-2139
Johnston, Jennifer J; van der Smagt, Jasper J; Rosenfeld, Jill A et al. (2018) Autosomal recessive Noonan syndrome associated with biallelic LZTR1 variants. Genet Med 20:1175-1185
Poli, M Cecilia; Ebstein, Frédéric; Nicholas, Sarah K et al. (2018) Heterozygous Truncating Variants in POMP Escape Nonsense-Mediated Decay and Cause a Unique Immune Dysregulatory Syndrome. Am J Hum Genet 102:1126-1142
Wang, Xia; Posey, Jennifer E; Rosenfeld, Jill A et al. (2018) Phenotypic expansion in DDX3X - a common cause of intellectual disability in females. Ann Clin Transl Neurol 5:1277-1285
Lalani, Seema R (2017) Current Genetic Testing Tools in Neonatal Medicine. Pediatr Neonatol 58:111-121
Zhang, Jing; Gambin, Tomasz; Yuan, Bo et al. (2017) Haploinsufficiency of the E3 ubiquitin-protein ligase gene TRIP12 causes intellectual disability with or without autism spectrum disorders, speech delay, and dysmorphic features. Hum Genet 136:377-386
Bostwick, Bret L; McLean, Scott; Posey, Jennifer E et al. (2017) Phenotypic and molecular characterisation of CDK13-related congenital heart defects, dysmorphic facial features and intellectual developmental disorders. Genome Med 9:73
Spillmann, Rebecca C; McConkie-Rosell, Allyn; Pena, Loren et al. (2017) A window into living with an undiagnosed disease: illness narratives from the Undiagnosed Diseases Network. Orphanet J Rare Dis 12:71
Wang, Xia; Charng, Wu-Lin; Chen, Chun-An et al. (2017) Germline mutations in ABL1 cause an autosomal dominant syndrome characterized by congenital heart defects and skeletal malformations. Nat Genet 49:613-617
Chao, Hsiao-Tuan; Davids, Mariska; Burke, Elizabeth et al. (2017) A Syndromic Neurodevelopmental Disorder Caused by De Novo Variants in EBF3. Am J Hum Genet 100:128-137

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