Patients or gaurdians of individuals with 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, and care teams obtain answers to these questions by extracting knowledge from omic and associated data using the computational tools and methods we develop and implement. We work with clinicians from many institutions and specialties to provide definitive molecular answers. We help wherever our help is needed and have established collaborations with clinicians and researchers 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.
Image from ME/CFS South Australia
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, Michal Mrug 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.
Charles Daghlian, Public domain, via Wikimedia Commons
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.
Photo by Sincerely Media on Unsplash
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.
Image from the Foundation For Prader-Willi Research
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.
Image by World Duchene Organization
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.
Photo by Bagoes Ilhamy on Unsplash
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 Dr. Pallavi Iyer for the integrative genomic characterization and investigating oncogenic variation in pediatric patients diagnosed with DTC using RNA-Seq and WES.
A.D.A.M. Medical Encyclopedia – Available from: https://medlineplus.gov/ency/imagepages/1205.htm
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.
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD)
These rare neurodegenerative diseases that share genetic risk factors and pathological hallmarks. FTD is a group of disorders that causes progressive damage to the brain’s frontal and temporal lobes. Up to 50% of people with ALS may experience some degree of change in thinking and behavior. We are using genomics and transcriptomics methods to uncover the molecular underpinnings of disease in a number of families at UAB working with Dr. Peter King.
Image from FTDtalk: https://www.ftdtalk.org/what-is-frontotemporal-dementia/neuroimaging/
Featured Image – Photo by National Cancer Institute on Unsplash
