Whole-exome sequencing in clinical application – experience of the Clinical Hospital Center Split
DOI:
https://doi.org/10.13112/pc.1049Keywords:
NEURODEVELOPMENTAL DISORDERS; CONGENITAL ABNORMALITIES; EXOME SEQUENCING; HIGH-THROUGHPUT NUCLEOTIDE SEQUENCINGAbstract
Objective: To report on the effectiveness of whole-exome sequencing (WES) in patients at the University Hospital of Split from January 2021 to December 2024.
Methods: WES analysis was performed in 64 patients with neurodevelopmental disorders, 20 patients with malformations, and 53 patients with disorders primarily affecting one organ system.
Results: WES analysis led to a diagnosis in 34.38 % of patients with neurodevelopmental disorders, variants in genes potentially associated with the phenotype were found in 32.81 %, and in 32.81 % no significant variants were found. In the case of malformations, a diagnosis was established after WES analysis in 40 % of patients, variants in genes potentially associated with the phenotype were found in 35 %, and no significant variants were found in 25 %. Among disorders that primarily affect one organ system, WES analysis was most successful in the case of neuromuscular disorders (diagnosis established in 45.45 % of cases), and the least successful in patients with epilepsy (diagnosis established in 16.67 %).
Conclusion: WES is an effective genetic test for patients with neurodevelopmental disorders and malformations and should be used early in the diagnostic workup because it can lead to the establishment of a diagnosis in a large number of cases. As for disorders that primarily affect one organ system, WES analysis is effective for neuromuscular disorders, while for other disorders, targeted gene panels or clinical exome sequencing should be primarily used.
References
1. Collins FS, Green ED, Guttmacher AE, Guyer MS. A vision for the future of genomics research. Nature. 2003;422(6934):835–47. doi:10.1038/nature01626
2. Smith ED, Blanco K, Sajan SA, Hunter JM, Shinde DN, Wayburn B, et al. A retrospective review of multiple findings in diagnostic exome sequencing: half are distinct and half are overlapping diagnoses. Genet Med. 2019;21(10):2199–207. doi:10.1038/s41436-019-0477-2
3. Seaby EG, Pengelly RJ, Ennis S. Exome sequencing explained: a practical guide to its clinical application. Brief Funct Genomics. 2015;15(5):374–84. doi:10.1093/bfgp/elv054
4. Sawyer SL, Hartley T, Dyment DA, Beaulieu CL, Schwartzentruber J, Smith A, et al. Utility of whole-exome sequencing for those near the end of the diagnostic odyssey: time to address gaps in care. Clin Genet. 2015;89(3):275–84. doi:10.1111/cge.12654
5. Marinakis NM, Svingou M, Veltra D, Kekou K, Sofocleous C, Tilemis F, et al. Phenotype‐driven variant filtration strategy in exome sequencing toward a high diagnostic yield and identification of 85 novel variants in 400 patients with rare Mendelian disorders. Am J Med Genet A. 2021;185(8):2561–71. doi:10.1002/ajmg.a.62338
6. Yang Y, Muzny DM, Xia F, Niu Z, Person R, Ding Y, et al. Molecular findings among patients referred for clinical whole-exome sequencing. JAMA. 2014;312(18):1870–9. doi:10.1001/jama.2014.14601
7. Lee H, Deignan JL, Dorrani N, Strom SP, Kantarci S, Quintero-Rivera F, et al. Clinical exome sequencing for genetic identification of rare Mendelian disorders. JAMA. 2014;312(18):1880. doi:10.1001/jama.2014.14604
8. Nguengang Wakap S, Lambert DM, Olry A, Rodwell C, Gueydan C, Lanneau V, et al. Estimating cumulative point prevalence of rare diseases: analysis of the Orphanet database. Eur J Hum Genet. 2019;28(1):165–73. doi:10.1038/s41431-019-0508-0
9. Philippakis AA, Azzariti DR, Beltran S, Brookes AJ, Brownstein CA, Brudno M, et al. The Matchmaker Exchange: a platform for rare disease gene discovery. Hum Mutat. 2015;36(10):915–21. doi:10.1002/humu.22858
10. Manickam K, McClain MR, Demmer LA, Biswas S, Kearney HM, Malinowski J, 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(11):2029–37. doi:10.1038/s41436-021-01242-6
11. Srivastava S, Love-Nichols JA, Dies KA, Ledbetter DH, Martin CL, Chung WK, et al. Meta-analysis and multidisciplinary consensus statement: exome sequencing is a first-tier clinical diagnostic test for individuals with neurodevelopmental disorders. Genet Med. 2019;21(11):2413–21. doi:10.1038/s41436-019-0554-6
12. Biesecker LG, Green RC. Diagnostic clinical genome and exome sequencing. N Engl J Med. 2014;370(25):2418–25. doi:10.1056/NEJMra1312543
13. Stark Z, Schofield D, Alam K, Wilson W, Mupfeki N, Macciocca I, et al. Prospective comparison of the cost-effectiveness of clinical whole-exome sequencing with that of usual care overwhelmingly supports early use and reimbursement. Genet Med. 2017;19(8):867–74. doi:10.1038/gim.2016.221
14. Soden SE, Saunders CJ, Willig LK, Farrow EG, Smith LD, Petrikin JE, et al. Effectiveness of exome and genome sequencing guided by acuity of illness for diagnosis of neurodevelopmental disorders. Sci Transl Med. 2014;6(265):265ra168. doi:10.1126/scitranslmed.3010076
15. Need AC, Shashi V, Hitomi Y, Schoch K, Shianna KV, McDonald MT, et al. Clinical application of exome sequencing in undiagnosed genetic conditions. J Med Genet. 2012;49(6):353–61. doi:10.1136/jmedgenet-2012-100819
16. de Ligt J, Willemsen MH, van Bon BWM, Kleefstra T, Yntema HG, Kroes T, et al. Diagnostic exome sequencing in persons with severe intellectual disability. N Engl J Med. 2012;367(20):1921–9. doi:10.1056/NEJMoa1206524
17. Schuurs-Hoeijmakers JHM, Vulto-van Silfhout AT, Vissers LELM, van de Vondervoort IIGM, van Bon BWM, de Ligt J, et al. Identification of pathogenic gene variants in small families with intellectually disabled siblings by exome sequencing. J Med Genet. 2013;50(12):802–11. doi:10.1136/jmedgenet-2013-101644
18. Willemsen MH, Kleefstra T. Making headway with genetic diagnostics of intellectual disabilities. Clin Genet. 2013;85(2):101–10. doi:10.1111/cge.12244
19. Monroe GR, Frederix GW, Savelberg SMC, de Vries TI, Duran KJ, van der Smagt JJ, et al. Effectiveness of whole-exome sequencing and costs of the traditional diagnostic trajectory in children with intellectual disability. Genet Med. 2016;18(9):949–56. doi:10.1038/gim.2015.200
20. Vissers LELM, van Nimwegen KJM, Schieving JH, Kamsteeg EJ, Kleefstra T, Yntema HG, et al. A clinical utility study of exome sequencing versus conventional genetic testing in pediatric neurology. Genet Med. 2017;19(9):1055–63. doi:10.1038/gim.2017.1
21. Thevenon J, Duffourd Y, Masurel-Paulet A, Lefebvre M, Feillet F, El Chehadeh-Djebbar S, et al. Diagnostic odyssey in severe neurodevelopmental disorders: toward clinical whole-exome sequencing as a first-line diagnostic test. Clin Genet. 2016;89(6):700–7. doi:10.1111/cge.12732
22. Rauch A, Wieczorek D, Graf E, Wieland T, Endele S, Schwarzmayr T, et al. Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study. Lancet. 2012;380(9854):1674–82. doi:10.1016/S0140-6736(12)61480-9
23. Shaheen R, Patel N, Shamseldin H, Alzahrani F, Al-Yamany R, Al Moisheer A, et al. Accelerating matchmaking of novel dysmorphology syndromes through clinical and genomic characterization of a large cohort. Genet Med. 2015;18(7):686–95. doi:10.1038/gim.2015.147
24. Anazi S, Maddirevula S, Faqeih E, Alsedairy H, Alzahrani F, Shamseldin HE, et al. Clinical genomics expands the morbid genome of intellectual disability and offers a high diagnostic yield. Mol Psychiatry. 2016;22(4):615–24. doi:10.1038/mp.2016.113
25. Gilissen C, Hehir-Kwa JY, Thung DT, van de Vorst M, van Bon BWM, Willemsen MH, et al. Genome sequencing identifies major causes of severe intellectual disability. Nature. 2014;511(7509):344–7. doi:10.1038/nature13394
26. Zahir FR, Mwenifumbo JC, Chun HJE, Lim EL, Van Karnebeek CDM, Couse M, et al. Comprehensive whole genome sequence analyses yield novel genetic and structural insights for intellectual disability. BMC Genomics. 2017;18(1). doi:10.1186/s12864-017-3671-0
27. Petrovski S, Aggarwal V, Giordano JL, Stosic M, Wou K, Bier L, et al. Whole-exome sequencing in the evaluation of fetal structural anomalies: a prospective cohort study. Lancet. 2019;393(10173):758–67. doi:10.1016/S0140-6736(18)32042-7
28. Fu F, Li R, Li Y, Nie ZQ, Lei T, Wang D, et al. Whole exome sequencing as a diagnostic adjunct to clinical testing in fetuses with structural abnormalities. Ultrasound Obstet Gynecol. 2018;51(4):493–502. doi:10.1002/uog.18915
29. Guo W, Lai Y, Yan Z, Wang Y, Nie Y, Guan S, et al. Trio-whole-exome sequencing and preimplantation genetic diagnosis for unexplained recurrent fetal malformations. Hum Mutat. 2019;41(2):432–48. doi:10.1002/humu.23935
30. Pauta M, Martinez‐Portilla RJ, Borrell A. Diagnostic yield of exome sequencing in fetuses with multisystem malformations: systematic review and meta-analysis. Ultrasound Obstet Gynecol. 2022;59(6):715–22. doi:10.1002/uog.24862
31. Slavotinek A, Rego S, Sahin-Hodoglugil N, Kvale M, Lianoglou B, Yip T, et al. Diagnostic yield of pediatric and prenatal exome sequencing in a diverse population. NPJ Genom Med. 2023;8(1). doi:10.1038/s41525-023-00353-0
32. Piñeros-Fernández MC, Morte B, García-Giménez JL. Utility of exome sequencing for the diagnosis of pediatric-onset neuromuscular diseases beyond diagnostic yield: a narrative review. Neurol Sci. 2024;45(4):1455–64. doi:10.1007/s10072-023-07210-z
33. Perucca P, Scheffer IE, Harvey AS, James PA, Lunke S, Thorne N, et al. Real-world utility of whole exome sequencing with targeted gene analysis for focal epilepsy. Epilepsy Res. 2017;131:1–8. doi:10.1016/j.eplepsyres.2017.02.001
34. Chengyan L, Chupeng X, You W, Yinhui C, Binglong H, Dang A, et al. Identification of genetic causes in children with unexplained epilepsy based on trio-whole-exome sequencing. Clin Genet. 2024;106(2):140–9. doi:10.1111/cge.14519
Downloads
Published
Issue
Section
License
Copyright (c) 2025 Bernarda Lozić, Marin Ogorevc, Tomislav Smoljo, Dora Knezović

This work is licensed under a Creative Commons Attribution 4.0 International License.
By publishing in Paediatria Croatica, authors retain the copyright to their work and grant others the right to use, reproduce, and share their research articles in accordance with the Creative Commons Attribution License (CC BY 4.0), which allows others to distribute and build upon the work as long as they credit the author for the original creation.