MedicalResearch.com Interview with:
Paul C Marcogliese, Ph.D.
Laboratory of Dr. Hugo Bellen
Department of Molecular and Human Genetics
Baylor College of Medicine
Houston, Texas 77030
Loren D. Pena, MD PhD
Division of Human Genetics
Cincinnati Children’s Hospital Medical Center
Department of Pediatrics
University of Cincinnati
Cincinnati, OH 45229
MedicalResearch.com: What is the background for this study? What are the main findings?
Response: The Undiagnosed Diseases Network (UDN) is a multi-site collaboration across the US that seeks to help diagnose patients with rare disorders that are ill-defined.
Dr. Loren D.M. Pena and Dr. Vandana Shashi at the Duke-Columbia clinical site of the UDN had seen a patient with a severe neurological disorder. While the patient had no symptoms at birth, the patient began falling at about 3 years of age, eventually losing motor coordination and developing seizures. In the interim, the regression has progressed to a severely debilitating state. Re-analysis of the participant’s exome data by our site bioinformatician at Columbia (Nicholas Stong) in Dr. David Goldstein’s laboratory revealed a truncating variant in the single exon gene IRF2BPL that could be the candidate disease-causing gene. The UDN clinicians at Duke then contacted the UDN Model Organism Screening Center (MOSC) led by Dr. Hugo Bellen at Baylor College of Medicine and the Howard Hughes Medical Institute for functional analysis. In parallel, four more patients were found with truncating mutations causing a similar disorder though the UDN and GeneMatcher.org. Additionally, two patients with missense variants in IRF2BPL were identified that displayed seizures and some developmental delay or autism spectrum disorder but no motor regression.
Work in MOSC by Dr. Paul Marcogliese using fruit flies revealed that the IRF2BPL truncating variants are severe loss of function mutations and one of the missense variants was a partial loss of function. Additionally, it was found that the fruit fly IRF2BPL gene, called pits, is expressed in the neurons of the adult fly brain. Lowering the levels of pits by about 50% in fly neurons leads to progressive behavioural abnormalities and neurodegeneration. By combining the human genetics, bioinformatics and model organism data, IRF2BPL was found to be a novel disease-causing gene in humans.
MedicalResearch.com: What should readers take away from your report?
Response: Beyond describing a novel role for IRF2BPL in human disease, this study highlights two important things. Firstly, the study highlights the importance of the UDN in fostering collaboration between clinicians and researchers to push discovery further.
Secondly, this is another study in a growing body of work that exemplifies the ability of model organism like the fruit fly to aid in diagnostics and human genetics. The fly can really be a great platform for validating putative disease-causing variants.
MedicalResearch.com: What recommendations do you have for future research as a result of this study?
Response: Future work will need to uncover the mechanism(s) underlying how variation in IRF2BPL can lead to disease. This will rely on the sophisticated reagents made in flies and also work in mice and human cells. Phenotypes in either of these models could be ideal platforms to test potential therapeutics.
MedicalResearch.com: Is there anything else you would like to add? Any disclosures?
Response: Many families of patients with undiagnosed diseases find relief in finally knowing the cause of their child’s disorder. In this case, we have accomplished the first step but expect that more patients and families with be identified with IRF2BPL-related disorders.
To learn more please visit IRF2BPL.org, the Stand by Eli Foundation and His Beautiful Smiles.
Paul C. Marcogliese et al. IRF2BPL Is Associated with Neurological Phenotypes.The American Journal of Human Genetics, 2018; DOI: 10.1016/j.ajhg.2018.07.006
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