Patients or guardians of individuals with genetic disorders have many questions they would like answers to. These include:
- What is the diagnosis?
- How did it happen?
- Who else is at risk?
- What can be done?
- What can we expect?
Within CGDS, we work to help patients, their families, care teams, and other researchers obtain answers to these questions by extracting knowledge from omic and associated data using the computational tools and methods we develop and/or implement. We work with clinicians, researchers, and patient organizations from many institutions and specialties through established collaborations spanning many rare or not-so-rare diseases.
Myalgic encephalomyelitis /chronic fatigue syndrome (ME/CFS)
ME/CFS is a complex disorder leading to exertional intolerance, chronic fatigue not helped by rest, pain syndromes, as well as a multitude of other multi-system symptoms. Working with Dr. Jarred Younger’s group at UAB, we are analyzing patient medical histories, as well as WGS and RNA-seq data to identify molecular variation associated with onset or symptoms of ME/CFS. And working to identify potential treatments for patients based on the molecular findings we are uncovering.
Ciliopathies
Ciliopathies are human disorders that arise from the dysfunction of motile and/or non-motile cilia. At least 35 different ciliopathies collectively affect nearly all organ systems, with prevalent phenotypes including polycystic kidney disease, retinal degeneration, obesity, skeletal malformations, and brain anomalies. We are working with Drs. Brad Yoder, John Parant, Chenbei Chang, Courtney Haycraft and others at UAB to understand the molecular underpinnings of these diseases and to prioritize variants of uncertain significance for functional confirmation in a variety of animal models.
Cystic Fibrosis (CF)
Cystic Fibrosis is a rare disease that displays heterogeneous symptoms and a non-responder rate of 30%. Patients within the same family with the same molecular cause of CF can have very different symptoms, progression, and outcomes. CGDS works with Dr. Phil Farrell and Dr. HuiChuan Lai at UW-Madison and other members of the CF-FIRST consortia to identify genetic modifiers in patients with CF that are related to their symptoms and response to therapeutics making use of candidate variant and polygenic risk analyses.
Prader-Willi Syndrome (PWS)
Molecular variation in the genetic imprinting region on Chr 15 cause PWS, which presents with a wide variety of symptoms, including behavioral problems, intellectual disability, and short stature. There is a wide range of symptoms and severity in individual patients, and they are not always tied to the molecular variation present in the individual. We are collaborating with Dr. Theresa Strong of the Foundation for Prader Willi research to generate a comprehensive data repository to unravel these complex genotype-phenotype associations.
Muscular Dystrophies (MD)
Several distinct forms of muscular dystrophy exist. In all, molecular variation leads to muscle degeneration, and most individuals with this condition will eventually need a wheelchair. Other symptoms include trouble breathing or swallowing. Some patients also experience neurologic symptoms, including autism-like behaviors. Working in collaboration with UAB’s Drs. Matt Alexander and Mike Lopez and their collaborator Dr. Luca Bello, we are undertaking studies to identify causal variation in patients where existing tests were not diagnostic, as well as studies aimed at identifying modifier variation.
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Multiple Chorangioma Syndrome
Chorangiomas, benign placental capillary lesions occur with a frequency of about 1% of births, usually presenting as a solitary nodule or, less frequently, as multiple nodules. They can be associated with significant alteration in the hemodynamics of the placenta when large or numerous. In such cases, adverse outcomes to both mother and child may be seen including heart failure, hydrops fetalis and sudden intrauterine fetal death. It has been hypothesized that chronic environmental hypoxia and/or genetic changes may lead to aberrant angiogenesis and chorangioma formation in the development of these lesions, but definitive findings remain to be shown. In collaboration with UAB’s Dr. Virginia Duncan we are undertaking studies to identify molecular mechanisms underlying chorangioma formation and progression.
Pediatric Differentiated Thyroid Cancer (DTC)
Thyroid cancer is the second most common cancer diagnosed in adolescents and young females in the USA and occurs when there is an abnormal, invasive growth of mutated thyroid cells in the thyroid gland. Depending upon which cells are mutated, thyroid cancer can be of various types. One of them is differentiated thyroid cancer (DTC), which has the two most common histological types: papillary thyroid carcinoma (PTC) and follicular thyroid carcinoma (FTC), accounting for 70-80% and 10-15% of thyroid cancers. They are more aggressive in the pediatric population than in the adults and occurs due to mutations in a number of genes leading to dysregulation of MAPK and PI3K signaling pathways. We are working with Drs. Pallavi Iyer and Shuko Harada for the integrative genomic characterization and investigating oncogenic variation in pediatric patients diagnosed with DTC using RNA-Seq and WES.
Pulmonary Arterial Hypertension (PAH)
Pulmonary arterial hypertension (PAH) is a rare, progressive disease characterized by elevated pressure in the pulmonary arteries, leading to occlusive vascular lesions. It affects 15-20 individuals per million annually and presents with significant variability in symptoms and age of onset. A notable subset of PAH, heritable PAH (HPAH), comprises 15% of cases and is often caused by BMPR2 mutations. Despite identifying these genetic factors, the overall understanding of PAH’s pathobiology remains limited, which hinders diagnosis and treatment options. Working in collaboration with Vanderbilt’s Dr. Rizwan Hamid and Dr. Eric D. Austin, we are undertaking studies identifying genetic modifiers through integrative omics analysis. We are also exploring drug repositioning strategies to discover and validate candidate drug targets to improve treatment options for PAH.
Juxtaglomerular tumors, Glomus tumors, and Myopericytomas
Juxtaglomerular tumors, Glomus tumors, and Myopericytomas
Juxtaglomerular cell tumors (JGCT) are rare, often difficult-to-diagnose neoplasms originating from the juxtaglomerular apparatus of the kidney. These tumors can present with a wide range of clinical features—including hypertension driven by excess renin production—and vary significantly in their age of onset and progression. While certain genetic factors have been implicated in JGCT pathogenesis, our overall understanding of the molecular and cellular mechanisms underlying these tumors remains limited. This knowledge gap significantly hinders both early diagnosis and the development of effective, targeted therapies.
Working with Drs. Cristina Magi-Galluzi and Shuko Harada, we are pursuing omic approaches to uncover genetic variation and biomarkers in a multi-institutional cohort of JGCTs, Glomus tumors, and Myopericytomas diagnosed by experienced genitourinary pathologists, evaluating clinical presentation and outcome, morphologic diversity, and, importantly, the molecular features.
Neurofibromatosis
Neurofibromatosis tumors
Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic disorder caused by mutations in the NF1 gene. It is characterized by the development of benign tumors along nerves (neurofibromas), distinctive skin changes such as café-au-lait spots, and a range of potential complications including learning disabilities and skeletal abnormalities.
Working with Drs. Deeann Wallis and Robert Kesterson, we are pursuing multi-omic approaches to uncover NF1-associated Breast Cancer molecular signatures and pathways and identify repurposable drugs using in a rat model of Neurofibromatosis.
Long COVID
Molecular components of long COVID
Long COVID, also known as post-acute sequelae of SARS-CoV-2 infection (PASC), refers to the persistence of symptoms well beyond the initial COVID-19 infection. It is characterized by a range of chronic issues, including fatigue, shortness of breath, and cognitive difficulties, that can significantly impact daily functioning and quality of life. there is significant overlap with ME/CFS.
Working with clinicians and researchers at UAB and directly with patients and their families we are analyzing patient medical histories, as well as WGS and RNA-seq data to identify molecular variation associated with onset or symptoms of Long COVID. And working to identify potential treatments for patients based on the molecular findings we are uncovering.
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