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Am J Med Genet A. 2019 Jun;179(6):958-965. doi: 10.1002/ajmg.a.61132. Epub 2019 Mar 23.

Reported environmental exposures are inversely associated with obtaining a genetic diagnosis in the Undiagnosed Diseases Network.

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Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
Department of Medicine, Harvard Medical School, Boston, Massachusetts.
Institute for Society and Genetics, University of California at Los Angeles, Los Angeles, California.
Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
Division of Genomic Medicine, National Human Genome Research Institute, Bethesda, Maryland.
Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.


The Undiagnosed Diseases Network (UDN) aims to achieve a unifying etiologic diagnosis for patients with mysterious conditions. Although the UDN has focused on the identification of genetic determinants, environmental etiologies may be causative or modifying agents that interact with predisposing genes. We developed and implemented a screening questionnaire to assess environmental exposures in UDN patients. We hypothesized that patients with potentially adverse environmental exposures would be less likely to have a genetic basis for their undiagnosed disease. Among seven postnatal environmental exposure categories assessed in 269 UDN participants, patients with a confirmed or strong candidate genetic diagnosis were significantly less likely to report exposures to metals, dust, or chemicals (p < 0.05). A composite variable of the seven exposure categories was substantially more common (40%) in patients without a genetic diagnosis than in those with a genetic diagnosis (18.4%) (p = 0.004). In multivariable analysis adjusting for age and sex, the composite variable of any positive environmental exposure was associated with a reduced odds of finding a genetic diagnosis (OR 0.41, 95% CI 0.18-0.96, p = 0.04). These results were generally robust to exclusion of patients with early life disease onset. Our results suggest a possible approach to increase the yield of genetic etiologies for adult undiagnosed diseases by first focusing on patients without significant environmental exposures. Still, there is ample reason to expect cases in which specific environmental exposures impact the risk of clinically evident genetic disease. Our findings emphasize the importance of systematic investigations of potential environmental risk factors for undiagnosed diseases.


environmental exposures; epidemiology; genetics; questionnaire; undiagnosed disease


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