Impact of integrated translational research on clinical exome sequencing

Abstract

Purpose

Exome sequencing often identifies pathogenic genetic variants in patients with undiagnosed diseases. Nevertheless, frequent findings of variants of uncertain significance necessitate additional efforts to establish causality before reaching a conclusive diagnosis. To provide comprehensive genomic testing to patients with undiagnosed disease, we established an Individualized Medicine Clinic, which offered clinical exome testing and included a Translational Omics Program (TOP) that provided variant curation, research activities, or research exome sequencing.

Methods

From 2012 to 2018, 1101 unselected patients with undiagnosed diseases received exome testing. Outcomes were reviewed to assess impact of the TOP and patient characteristics on diagnostic rates through descriptive and multivariate analyses.

Results

The overall diagnostic yield was 24.9% (274 of 1101 patients), with 174 (15.8% of 1101) diagnosed on the basis of clinical exome sequencing alone. Four hundred twenty-three patients with nondiagnostic or without access to clinical exome sequencing were evaluated by the TOP, with 100 (9% of 1101) patients receiving a diagnosis, accounting for 36.5% of the diagnostic yield. The identification of a genetic diagnosis was influenced by the age at time of testing and the disease phenotype of the patient.

Conclusion

Integration of translational research activities into clinical practice of a tertiary medical center can significantly increase the diagnostic yield of patients with undiagnosed disease.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Workflow of patients of at the Individualized Medicine Clinic.
Fig. 2: Individualized Medicine Clinic cohort disease phenotype spectrum.
Fig. 3: Translational Omics Program (TOP) research activities and efforts.
Fig. 4: Diagnostic yield by disease category and age, and impact of the Translational Omics Program (TOP).
Fig. 5: Research integration of clinical exome sequencing activities.

References

  1. 1.

    Ashley EA. Towards precision medicine. Nat Rev Genet. 2016;17:507–522.

    CAS  Article  PubMed  Google Scholar 

  2. 2.

    Farwell KD, Shahmirzadi L, El-Khechen D, et al. Enhanced utility of family-centered diagnostic exome sequencing with inheritance model-based analysis: results from 500 unselected families with undiagnosed genetic conditions. Genet Med. 2015;17:578–586.

    CAS  Article  PubMed  Google Scholar 

  3. 3.

    Posey JE, Harel T, Liu P, et al. Resolution of disease phenotypes resulting from multilocus genomic variation. N Engl J Med. 2017;376:21–31.

    CAS  Article  PubMed  Google Scholar 

  4. 4.

    Gahl WA, Wise AL, Ashley EA. The Undiagnosed Diseases Network of the National Institutes of Health: a national extension. JAMA. 2015;314:1797–1798.

    CAS  Article  PubMed  Google Scholar 

  5. 5.

    Gahl WA, Markello TC, Toro C, et al. The National Institutes of Health Undiagnosed Diseases Program: insights into rare diseases. Genet Med. 2012;14:51–59.

    CAS  Article  PubMed  Google Scholar 

  6. 6.

    Taruscio D, Groft SC, Cederroth H, et al. Undiagnosed Diseases Network International (UDNI): white paper for global actions to meet patient needs. Mol Genet Metab. 2015;116:223–225.

    CAS  Article  PubMed  Google Scholar 

  7. 7.

    Li J, Gao K, Yan H, et al. Reanalysis of whole exome sequencing data in patients with epilepsy and intellectual disability/mental retardation. Gene. 2019;700:168–175.

    CAS  Article  PubMed  Google Scholar 

  8. 8.

    Splinter K, Adams DR, Bacino CA, et al. Effect of genetic diagnosis on patients with previously undiagnosed disease. N Engl J Med. 2018;379:2131–2139.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Lazaridis KN, McAllister TM, Babovic-Vuksanovic D, et al. Implementing individualized medicine into the medical practice. Am J Med Genet C Semin Med Genet. 2014;166C:15–23.

    Article  PubMed  Google Scholar 

  10. 10.

    Lazaridis KN, Schahl KA, Cousin MA, et al. Outcome of whole exome sequencing for diagnostic odyssey cases of an individualized medicine clinic: the Mayo Clinic experience. Mayo Clin Proc. 2016;91:297–307.

    Article  PubMed  Google Scholar 

  11. 11.

    Cummings BB, Marshall JL, Tukiainen T, et al. Improving genetic diagnosis in Mendelian disease with transcriptome sequencing. Sci Transl Med. 2017;9:eaal5209.

    Article  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Boczek NJ, Hopp K, Benoit L, et al. Characterization of three ciliopathy pedigrees expands the phenotype associated with biallelic C2CD3 variants. Eur J Hum Genet. 2018;26:1797–1809.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Cousin MA, Conboy E, Wang JS, et al. RINT1 bi-allelic variations cause infantile-onset recurrent acute liver failure and skeletal abnormalities. Am J Hum Genet. 2019;105:108–121.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Oliver GR, Blackburn PR, Ellingson MS, et al. RNA-Seq detects a SAMD12-EXT1 fusion transcript and leads to the discovery of an EXT1 deletion in a child with multiple osteochondromas. Mol Genet Genomic Med. 2019;7:e00560.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Oliver GR, Tang X, Schultz-Rogers LE, et al. A tailored approach to fusion transcript identification increases diagnosis of rare inherited disease. PLoS One. 2019;14:e0223337.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Cousin MA, Smith MJ, Sigafoos AN, et al. Utility of DNA, RNA, protein, and functional approaches to solve cryptic immunodeficiencies. J Clin Immunol. 2018;38:307–319.

    CAS  Article  Google Scholar 

  17. 17.

    Blackburn PR, Tischer A, Zimmermann MT, et al. A novel Kleefstra syndrome-associated variant that affects the conserved TPLX motif within the Ankyrin repeat of EHMT1 leads to abnormal protein folding. J Biol Chem. 2017;292:3866–3876.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Gupta A, Zimmermann MT, Wang H, et al. Molecular characterization of known and novel ACVR1 variants in phenotypes of aberrant ossification. Am J Med Genet A. 2019;179:1764–1777.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Perez Botero J, Chen D, Cousin MA, et al. Clinical characteristics and platelet phenotype in a family with RUNX1 mutated thrombocytopenia. Leuk Lymphoma. 2017;58:1963–1967.

    Article  Google Scholar 

  20. 20.

    Blackburn PR, Xu Z, Tumelty KE, et al. Bi-allelic alterations in AEBP1 lead to defective collagen assembly and connective tissue structure resulting in a variant of Ehlers-Danlos syndrome. Am J Hum Genet. 2018;102:696–705.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Pinto EVF, Kroc SA, Bertsch NL, et al. Biallelic variants in PROZ as a cause of hypercoagulability and livedo racemosa. Thromb Res. 2020;195:187–189.

    Article  CAS  Google Scholar 

  22. 22.

    Gonzalez Santiago TM, Zavialov A, Saarela J, et al. Dermatologic features of ADA2 deficiency in cutaneous polyarteritis nodosa. JAMA Dermatol. 2015;151:1230–1234.

    Article  PubMed  Google Scholar 

  23. 23.

    Kotwal A, Ferrer A, Kumar R, et al. Clinical and biochemical phenotypes in a family with ENPP1 mutations. J Bone Miner Res. 2020;35:662–670.

    CAS  Article  PubMed  Google Scholar 

  24. 24.

    Blackburn PR, Sullivan AE, Gerassimou AG. et al. Functional analysis of the SIM1 variant p.G715V in 2 patients with obesity. J Clin Endocrinol Metab. 2020;105:dgz192.

    Article  PubMed  Google Scholar 

  25. 25.

    Salpietro V, Dixon CL, Guo H, et al. AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders. Nat Commun. 2019;10:3094.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Weyhrauch DL, Ye D, Boczek NJ, et al. Whole exome sequencing and heterologous cellular electrophysiology studies elucidate a novel loss-of-function mutation in the CACNA1A-encoded neuronal P/Q-type calcium channel in a child with congenital hypotonia and developmental delay. Pediatr Neurol. 2016;55:46–51.

    Article  PubMed  Google Scholar 

  27. 27.

    Helbig KL, Lauerer RJ, Bahr JC, et al. De novo pathogenic variants in CACNA1E cause developmental and epileptic encephalopathy with contractures, macrocephaly, and dyskinesias. Am J Hum Genet. 2018;103:666–678.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Lu HC, Tan Q, Rousseaux MW, et al. Disruption of the ATXN1-CIC complex causes a spectrum of neurobehavioral phenotypes in mice and humans. Nat Genet. 2017;49:527–536.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Konrad EDH, Nardini N, Caliebe A, et al. CTCF variants in 39 individuals with a variable neurodevelopmental disorder broaden the mutational and clinical spectrum. Genet Med. 2019;21:2723–2733.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Pant DC, Dorboz I, Schluter A, et al. Loss of the sphingolipid desaturase DEGS1 causes hypomyelinating leukodystrophy. J Clin Invest. 2019;129:1240–1256.

    Article  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Zimmermann MT, Urrutia R, Cousin MA, et al. Assessing human genetic variations in glucose transporter SLC2A10 and their role in altering structural and functional properties. Front Genet. 2018;9:276.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Kaiwar C, Zimmermann MT, Ferber MJ, et al. Novel NR2F1 variants likely disrupt DNA binding: molecular modeling in two cases, review of published cases, genotype-phenotype correlation, and phenotypic expansion of the Bosch-Boonstra-Schaaf optic atrophy syndrome. Cold Spring Harb Mol Case Stud. 2017;3:a002162.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Blackburn PR, Barnett SS, Zimmermann MT, et al. Novel de novo variant in EBF3 is likely to impact DNA binding in a patient with a neurodevelopmental disorder and expanded phenotypes: patient report, in silico functional assessment, and review of published cases. Cold Spring Harb Mol Case Stud. 2017;3:a001743.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Wiltrout K, Ferrer A, van de Laar I, et al. Variants in DOCK3 cause developmental delay and hypotonia. Eur J Hum Genet. 2019;27:1225–1234.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Gupta A, Dsouza NR, Zarate YA, et al. Genetic variants in DGAT1 cause diverse clinical presentations of malnutrition through a specific molecular mechanism. Eur J Med Genet. 2020;63:103817.

    Article  Google Scholar 

  36. 36.

    Masnada S, Hedrich UBS, Gardella E, et al. Clinical spectrum and genotype-phenotype associations of KCNA2-related encephalopathies. Brain. 2017;140:2337–2354.

    Article  Google Scholar 

  37. 37.

    Nambot S, Faivre L, Mirzaa G, et al. De novo TBR1 variants cause a neurocognitive phenotype with ID and autistic traits: report of 25 new individuals and review of the literature. Eur J Hum Genet. 2020;28:770–782.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Ferrer A, Schultz-Rogers L, Kaiwar C. et al. Three rare disease diagnoses in one patient through exome sequencing. Cold Spring Harb Mol Case Stud. 2019;5:a004390.

    Article  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Posey JE, Rosenfeld JA, James RA, et al. Molecular diagnostic experience of whole-exome sequencing in adult patients. Genet Med. 2016;18:678–685.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  40. 40.

    Retterer K, Juusola J, Cho MT, et al. Clinical application of whole-exome sequencing across clinical indications. Genet Med. 2016;18:696–704.

    CAS  Article  PubMed  Google Scholar 

  41. 41.

    Cherot E, Keren B, Dubourg C, et al. Using medical exome sequencing to identify the causes of neurodevelopmental disorders: experience of 2 clinical units and 216 patients. Clin Genet. 2018;93:567–576.

    CAS  Article  PubMed  Google Scholar 

  42. 42.

    Tumiene B, Maver A, Writzl K, et al. Diagnostic exome sequencing of syndromic epilepsy patients in clinical practice. Clin Genet. 2018;93:1057–1062.

    CAS  Article  PubMed  Google Scholar 

  43. 43.

    Serra EG, Schwerd T, Moutsianas L, et al. Somatic mosaicism and common genetic variation contribute to the risk of very-early-onset inflammatory bowel disease. Nat Commun. 2020;11:995.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Ji J, Shen L, Bootwalla M, et al. A semiautomated whole-exome sequencing workflow leads to increased diagnostic yield and identification of novel candidate variants. Cold Spring Harb Mol Case Stud. 2019;5:a003756.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. 45.

    Sobreira N, Schiettecatte F, Valle D, Hamosh A. GeneMatcher: a matching tool for connecting investigators with an interest in the same gene. Hum Mutat. 2015;36:928–930.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This research did not receive support from any funding agency in the public, commercial, or not-for-profit sectors.

Author information

Affiliations

Authors

Corresponding authors

Correspondence to Eric W. Klee PhD or Konstantinos N. Lazaridis MD.

Ethics declarations

Disclosure

The authors declare no conflicts of interest.

Additional information

Publisher’s note Springer Nature remains neutral with regard to 1jurisdictional 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

Klee, E.W., Cousin, M.A., Pinto e Vairo, F. et al. Impact of integrated translational research on clinical exome sequencing. Genet Med (2020). https://doi.org/10.1038/s41436-020-01005-9

Download citation

Keywords

  • diagnostic odyssey
  • undiagnosed disease
  • variants of uncertain significance
  • clinical practice
  • genomics

Search