A state-based approach to genomics for rare disease and population screening



The Alabama Genomic Health Initiative (AGHI) is a state-funded effort to provide genomic testing. AGHI engages two distinct cohorts across the state of Alabama. One cohort includes children and adults with undiagnosed rare disease; a second includes an unselected adult population. Here we describe findings from the first 176 rare disease and 5369 population cohort AGHI participants.


AGHI participants enroll in one of two arms of a research protocol that provides access to genomic testing results and biobank participation. Rare disease cohort participants receive genome sequencing to identify primary and secondary findings. Population cohort participants receive genotyping to identify pathogenic and likely pathogenic variants for actionable conditions.


Within the rare disease cohort, genome sequencing identified likely pathogenic or pathogenic variation in 20% of affected individuals. Within the population cohort, 1.5% of individuals received a positive genotyping result. The rate of genotyping results corroborated by reported personal or family history varied by gene.


AGHI demonstrates the ability to provide useful health information in two contexts: rare undiagnosed disease and population screening. This utility should motivate continued exploration of ways in which emerging genomic technologies might benefit broad populations.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Data availability

The data that support the findings of this study are available from the corresponding author (K.M.E.). Global screening array identified and Sanger confirmed P/LP variants have been submitted to ClinVar (searchable by study IDs: AGHI_GT and AGHI_WGS).


  1. 1.

    Deciphering Developmental Disorders Study. Large-scale discovery of novel genetic causes of developmental disorders. Nature 519, 223–228 (2015).

    Article  Google Scholar 

  2. 2.

    Ramoni, R. B. et al. The Undiagnosed Diseases Network: Accelerating Discovery about Health and Disease. Am. J. Hum. Genet. 100, 185–192 (2017).

    CAS  Article  Google Scholar 

  3. 3.

    All of Us Research Program Investigators, Denny, J. C. et al. The “All of Us” Research Program. N. Engl. J. Med. 381, 668–676, https://doi.org/10.1056/NEJMsr1809937 (2019).

    Article  Google Scholar 

  4. 4.

    Wiesner, G. L. et al. Returning Results in the Genomic Era: Initial Experiences of the eMERGE Network. J. Pers. Med. 10, 30 (2020).

    Article  Google Scholar 

  5. 5.

    Richards, S. et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet. Med. 17, 405–424. (2015).

    Article  Google Scholar 

  6. 6.

    Amendola, L. M. et al. Actionable exomic incidental findings in 6503 participants: challenges of variant classification. Genome. Res. 25, 305–315 (2015).

    CAS  Article  Google Scholar 

  7. 7.

    Natarajan, P. et al. Aggregate penetrance of genomic variants for actionable disorders in European and African Americans. Sci. Transl. Med. 8, 364ra151 (2016).

    Article  Google Scholar 

  8. 8.

    Kalia, S. S. et al. Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2016 update (ACMG SF v2.0): a policy statement of the American College of Medical Genetics and Genomics. Genet. Med. 19, 249–255 (2017).

    Article  Google Scholar 

  9. 9.

    ACMG Board of Directors. The use of ACMG secondary findings recommendations for general population screening: a policy statement of the American College of Medical Genetics and Genomics (ACMG). Genet. Med. 21, 1467–1468 (2019).

    Article  Google Scholar 

  10. 10.

    Zoltick, E. S. et al. Predispositional genome sequencing in healthy adults: design, participant characteristics, and early outcomes of the PeopleSeq Consortium. Genome. Med. 11, 10 (2019).

    Article  Google Scholar 

  11. 11.

    Spratt, D. E. et al. Racial/Ethnic Disparities in Genomic Sequencing. JAMA Oncol. 2, 1070–1074 (2016).

    Article  Google Scholar 

  12. 12.

    May, T. et al. Recruiting diversity where it exists: The Alabama Genomic Health Initiative. J Genet Couns 29, 471–478 (2020).

    Article  Google Scholar 

  13. 13.

    Adam M. P., et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020. https://www.ncbi.nlm.nih.gov/books/NBK1116/.

  14. 14.

    National Comprehensive Cancer Network. Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic (Version 1.2020). https://www.nccn.org/professionals/physician_gls/pdf/genetics_bop.pdf. Accessed May, 2020.

  15. 15.

    National Comprehensive Cancer Network. Genetic/Familial High-Risk Assessment: Colorectal (Version 1.2020). https://www.nccn.org/professionals/physician_gls/pdf/genetics_colon.pdf. Accessed May, 2020.

  16. 16.

    Bick, A. G. et al. Burden of rare sarcomere gene variants in the Framingham and Jackson Heart Study cohorts. Am J Hum Genet 91, 513–519 (2012).

    CAS  Article  Google Scholar 

  17. 17.

    Peloso, G. M. et al. Phenotypic extremes in rare variant study designs. Eur J Hum Genet 24, 924–930 (2016).

    Article  Google Scholar 

  18. 18.

    US Preventive Services Task Force, Owens, D. K. et al. Risk Assessment, Genetic Counseling, and Genetic Testing for BRCA-Related Cancer: US Preventive Services Task Force Recommendation Statement [published correction appears in JAMA. 2019 Nov 12;322(18):1830]. JAMA 322, 652–665 (2019).

    Article  Google Scholar 

  19. 19.

    Murray M. F., Evans J. P., Khoury M. J. DNA-Based Population Screening: Potential Suitability and Important Knowledge Gaps [published online ahead of print, 2019 Dec 6]. JAMA. 2019. https://doi.org/10.1001/jama.2019.18640.

  20. 20.

    Manickam, K. et al. Exome Sequencing-Based Screening for BRCA1/2 Expected Pathogenic Variants Among Adult Biobank Participants. JAMA Netw Open. 1, e182140 (2018). Published 2018 Sep 7.

    Article  Google Scholar 

Download references


We thank the AGHI participants for their contributions to this study. This study was supported by funding from the State of Alabama. This study was also supported by the UAB Center for Clinical and Translational Science, funded by a National Institutes of Health (NIH) Clinical and Translational Science Award (CTSA) grant (UL1TR003096).

Author information





Conceptualization: K.M.E., W.V.K., A.C., T.M., G.M.C., M.M., G.S.B., B.R.K.; Data curation: K.M.E., W.V.K., A.C., M.E.C., I.P.M., K.M.B., M.L.T., R.D.J.; Formal Analysis: K.M.E, W.V.K., A.C., M.E.C, I.P.M., K.M.B., M.L.T., R.D.J.; Funding acquisition: I.P.M., G.M.C., M.M., G.S.B., B.R.K.; Investigation: W.V.K., M.E.C., I.P.M., A.C.E.H., K.M.B., M.L.T., E.M.B.; Methodology: K.M.E., W.V.K., A.C., I.P.M., T.M., M.N.O., S.O.S., J.C.E., J.J.C., M.F., W.A.C., A.C.E.H., G.M.C., M.M., G.S.B., B.R.K.; Project Administration: I.P.M., Supervision: G.M.C., M.M., G.S.B., B.R.K.; Writing – original draft: K.M.E., W.V.K., A.C., M.E.C.; Writing– review & editing: K.M.E, W.V.K., A.C., M.E.C, I.P.M, T.M., M.N.O., S.O.S., J.C.E., J.J.C, M.F., W.A.C., A.C.E.H., K.M.B., M.L.T., E.M.B., R.D.J., G.M.C, M.M., G.S.B., B.R.K.

Corresponding author

Correspondence to Kelly M. East MS.

Ethics declarations

Competing interests

The authors declare no conflicts of interest.

Ethics declaration

The Alabama Genomic Health Initiative was reviewed and approved by the UAB Institutional Review Board (protocol number F170303004). Informed consent was obtained from all participants.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

East, K.M., Kelley, W.V., Cannon, A. et al. A state-based approach to genomics for rare disease and population screening. Genet Med (2020). https://doi.org/10.1038/s41436-020-01034-4

Download citation


Quick links