Rational approach to modern genetic diagnostics
DOI:
https://doi.org/10.13112/pc.1045Keywords:
GENETICS, GENETIC TESTING, HIGH-THROUGHPUT NUCLEOTIDE SEQUENCING, PRECISION MEDICINE, GENETIC COUNSELINGAbstract
Thanks to the accelerated advancement of technologies, increased knowledge, and falling prices, the potential of genetic testing has never been greater. The expansion of knowledge and possibilities has dramatically altered our diagnostic methods, including who we test, when we test, the methods used, and how we interpret the obtained results. This influences the criteria for conducting tests, the selection of diagnostic testing methods, and the potential for evaluating genetic risk factors for common complex conditions, ultimately resulting in tailored care for each individual patient. New methods have become the preferred approach for diagnosing genetic conditions, yet it's essential to remember that traditional techniques remain a highly effective option when used appropriately. The geneticist plays a vital role in the diagnostic process, from formulating a working diagnosis based on the patient's medical history, current condition, disease progression, and previous treatment outcomes, to recommending appropriate genetic testing, understanding its benefits and drawbacks, and accurately interpreting relevant findings that impact the patient's and their family's future.
References
1. Horton RH, Lucassen AM. Recent developments in genetic/genomic medicine. Clin Sci (Lond). 2019;133:697-708.
2. Lalonde E, Rentas S, Lin F, Dulik MC, Skraban CM, Spinner NB. Genomic diagnosis for pediatric disorders: revolution and evolution. Front Pediatr. 2020;8:373.
3. Narayanan DL, Girisha KM. Genomic testing for diagnosis of genetic disorders in children: chromosomal microarray and next-generation sequencing. Indian Pediatr. 2020;57(6):549-54.
4. Manning M, Hudgins L; Professional Practice and Guidelines Committee. Array-based technology and recommendations for utilization in medical genetics practice for detection of chromosomal abnormalities. Genet Med. 2010;12:742-5.
5. Miller DT, Adam MP, Aradhya S, et al. Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. Am J Hum Genet. 2010;86:749-64.
6. Manickam K, McClain MR, Demmer LA, et al. Exome and genome sequencing for pediatric patients with congenital anomalies or intellectual disability: an evidence-based clinical guideline of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2021;23:2029-37.
7. South ST, Lee C, Lamb AN, Higgins AW, Kearney HM; Working Group for the American College of Medical Genetics and Genomics Laboratory Quality Assurance Committee. ACMG standards and guidelines for constitutional cytogenomic microarray analysis, including postnatal and prenatal applications: revision 2013. Genet Med. 2013;15(11):901-9.
8. Eren K, Taktakoğlu N, Pirim I. DNA sequencing methods: from past to present. Eurasian J Med. 2022;54(Suppl1):47-56.
9. Bagger FO, Borgwardt L, Jespersen AS, et al. Whole genome sequencing in clinical practice. BMC Med Genomics. 2024;17(1):39.
10. Nurchis MC, Altamura G, Riccardi MT, et al. Whole genome sequencing diagnostic yield for pediatric patients with suspected genetic disorders: systematic review, meta-analysis, and GRADE assessment. Arch Public Health. 2023;81:93.
11. Richards S, Aziz N, Bale S, et al. ACMG Laboratory Quality Assurance Committee. 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. 2015;17:405-24.
12. Walsh N, Cooper A, Dockery A, O'Byrne JJ. Variant reclassification and clinical implications. J Med Genet. 2024;61(3):207-11.
13. Westphal DS, Burkard T, Moscu-Gregor A, Gebauer R, Hessling G, Wolf CM. Reclassification of genetic variants in children with long QT syndrome. Mol Genet Genomic Med. 2020;8(9):e1300.
14. Davies B, Bartels K, Hathaway J,et al. Variant reinterpretation in survivors of cardiac arrest with preserved ejection fraction (the Cardiac Arrest Survivors With Preserved Ejection Fraction Registry) by clinicians and clinical commercial laboratories. Circ Genom Precis Med. 2021;14(3):e003235.
15. Fellner A, Goldberg Y, Basel-Salmon L. Ordering genetic testing by neurologists: points to consider. J Neurol. 2023;270:3714-22.
16. Kothur K, Holman K, Farnsworth E, et al. Diagnostic yield of targeted massively parallel sequencing in children with epileptic encephalopathy. Seizure. 2018;59:132-40.
17. Clark MM, Stark Z, Farnaes L, et al. Meta-analysis of the diagnostic and clinical utility of genome and exome sequencing and chromosomal microarray in children with suspected genetic diseases. NPJ Genom Med. 2018;3:16.
18. Mattick JS, Dinger M, Schonrock N, Cowley M. Whole genome sequencing provides better diagnostic yield and future value than whole exome sequencing. Med J Aust. 2018;209(5):197-9.
19. Lionel AC, Costain G, Monfared N, et al. Improved diagnostic yield compared with targeted gene sequencing panels suggests a role for whole-genome sequencing as a first-tier genetic test. Genet Med. 2018;20:435-43.
20. Miller DT, Lee K, Gordon AS, et al.; ACMG Secondary Findings Working Group. Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2021 update: a policy statement of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2021;23(8):1391-8.
21. Schobers G, Schieving JH, Yntema HG, et al. Reanalysis of exome negative patients with rare disease: a pragmatic workflow for diagnostic applications. Genome Med. 2022;14(1):66.
22. Wortmann SB, Oud MM, Alders M, et al. How to proceed after "negative" exome: A review on genetic diagnostics, limitations, challenges, and emerging new multiomics techniques. J Inherit Metab Dis. 2022;45(4):663-81.
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