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

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


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.

Keywords: environmental exposures; epidemiology; genetics; questionnaire; undiagnosed disease.

Publication types

  • Multicenter Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adolescent
  • Adult
  • Child
  • Environment
  • Environmental Exposure* / adverse effects
  • Female
  • Gene-Environment Interaction*
  • Genetic Predisposition to Disease*
  • Genetic Testing
  • Humans
  • Male
  • Rare Diseases / diagnosis
  • Rare Diseases / epidemiology*
  • Rare Diseases / etiology*
  • Risk Factors
  • Surveys and Questionnaires
  • Undiagnosed Diseases / diagnosis
  • Undiagnosed Diseases / epidemiology*
  • Undiagnosed Diseases / etiology*
  • Whole Genome Sequencing
  • Young Adult