Comment
Exome sequencing facilitates personalized treatment in
developmental and epileptic encephalopathy patients:
transforming current clinical practice in Indonesia
Agung Triono,a Kristy Iskandar,b,f,∗ Auliya S. B. Sumpono,c,f Tyas I. Hikmawan,d,f Gunadi,e,f and Elisabeth S. Herinia
a
Department of Child Health, Faculty of Medicine, Public Health, and Nursing, Universitas Gadjah Mada/Dr. Sardjito Hospital,
Yogyakarta, Indonesia
b
Department of Child Health, Faculty of Medicine, Public Health, and Nursing, Universitas Gadjah Mada/UGM Academic Hospital,
Yogyakarta, Indonesia
c
Department of Anatomical Pathology, Faculty of Medicine, Public Health, and Nursing, Universitas Gadjah Mada/Dr. Sardjito
Hospital, Yogyakarta, Indonesia
d
Department of Tropical Biology, Faculty of Biology, Universitas Gadjah Mada, Yogyakarta, Indonesia
e
Pediatric Surgery Division, Department of Surgery, Genetic Working Group/Translational Research Unit, Faculty of Medicine,
Public Health, and Nursing, Universitas Gadjah Mada/Dr. Sardjito Hospital, Yogyakarta, Indonesia
f
Rare Disease Hub, Dr. Sardjito Hospital, Biomedical and Genome Science Initiative (BGSi), Ministry of Health, Indonesia
Developmental epilepsy and encephalopathies (DEEs) This gap is particularly concerning for neuro The Lancet Regional
are among the most severe groups of epilepsies, char metabolic disorders—a treatable subset of DEEs. Health - Southeast
acterized by frequent, often drug-resistant seizures, Indonesia’s national newborn screening program does Asia 2025;39: 100638
distinct epileptiform abnormalities on electroencepha not currently include testing for inherited metabolic Published Online 19 July
lography (EEG), and developmental regression or disorders.6 Biochemical diagnostics, such as plasma 2025
cognitive impairments. In many cases, the underlying amino acid analysis, acylcarnitine profiling, or urine https://doi.org/10.
etiology contributes directly to developmental organic acid testing, are rarely available in routine 1016/j.lansea.2025.
100638
impairment.1–4 clinical settings. As a result, many cases of metabolic
In Indonesia, the selection of antiseizure medica epilepsies go undiagnosed. Other genetic causes—such
tions (ASMs) for DEEs is largely based on an empirical as channelopathies and non-structural epileptic en
approach guided by the apparent seizure type, such as cephalopathies—are similarly under-recognized due to
generalized, focal, or absence seizure. However, this the lack of access to comprehensive genomic
method may not align with the underlying pathogenetic diagnostics.
mechanisms and, in some cases, may exacerbate Our recent study provides compelling evidence
seizure activity. Distinguishing whether seizure wors that exome sequencing is both feasible and clinically
ening is due to inappropriate medication or reflects the valuable in an LMIC setting. Among 57 patients, we
inherent pharmacoresistance of DEEs is often chal identified pathogenic or likely pathogenic variants in
lenging. Furthermore, access to first-line treatments for 17 (29.8%), and variants of uncertain significance
specific DEE remains limited across the Southeast Asia (VUS) in 9 (15.7%), based on the American College
region.5 of Medical Genetics and Genomics guidelines.7 In
Clarifying an etiology-specific diagnosis can signifi total, 26 of 57 patients (45.6%) had a possible genetic
cantly inform treatment decisions in patients with etiology, with ten (17.5%) having diagnoses with
DEEs. Although genetic causes have been implicated in direct therapeutic implications. These included tar
up to 50% of DEE cases—spanning more than 900 geted treatment of underlying biochemical abnor
genes4—most children in low- and middle-income malities (e.g., vitamin or metabolic enzymatic-diet
countries (LMICs) continue to be managed empiri management), rational modification of ASMs based
cally, without molecular diagnosis and often without on molecular diagnosis, surveillance for disease-
access to disease-modifying options. In Indonesia, this related complications, and potential enrollment in
diagnostic gap persisted due to the limited availability gene-specific clinical trials. Notably, four of these ten
and clinical integration of genomic testing. cases were neurometabolic disorders. Beyond clinical
management, these findings offered diagnostic
closure for families navigating complex and pro
longed diagnostic journeys (Fig. 1).8
*Corresponding author. Department of Child Health, Faculty of
Medicine, Public Health, and Nursing, Universitas Gadjah Mada/UGM
While exome sequencing has become a routine part
Academic Hospital, Yogyakarta, Indonesia. of care for DEEs in high-income countries—now
E-mail address: kristy.iskandar@ugm.ac.id (K. Iskandar). moving toward genome sequencing—its use in LMICs
© 2025 The Author(s). Published by Elsevier Ltd. This is an open access remains limited and often questioned. Our finding
article under the CC BY license (http://creativecommons.org/licenses/by/
demonstrates that not only is exome sequencing
4.0/).
www.thelancet.com Vol 39 August, 2025 1
Comment
Fig 1: Workflow strategy and management changes from the genetic testing results.
feasible in such settings, but its implementation can eight-year diagnostic odyssey and the cumulative
also be transformative. It delivers definitive diagnoses, burden of untreated disease. Moreover, non-stepwise
refines clinical decision-making, informs prognosis, diagnostic approaches may be more economical in the
and enables genetic counselling. long term.9,10
Despite real challenges—cost, infrastructure, and It is time to redefine essential care. Exome
workforce limitations—these barriers are not insur sequencing should be considered a first-line investiga
mountable. With strategic national investments, tion for infants with unexplained, treatment-resistant
community-supported funding, collaborative efforts epilepsy. Early molecular diagnosis not only improves
across academic and clinical institutions, and selective therapeutic decision-making but also opens access to
out-of-pocket funding, exome sequencing can be emerging gene-based treatments and international
implemented selectively for high-yield indications such trials as precision medicine evolves.
as early-onset epilepsies of unknown cause. Compared Indonesia’s experience demonstrates that genomic
to other genetic modalities such as metabolic panels, medicine is not a distant ideal-it is a practical and
chromosomal microarray, or targeted panels, exome impactful tool. For children with DEEs, a timely and
sequencing offers broader coverage and may be more accurate diagnosis can mean the difference between
cost-effective.9 lifelong disability and meaningful intervention. This
Our study, supported by national research funding evidence should catalyze a shift in health policy:
and multidisciplinary collaboration, illustrates a scal exome sequencing must be recognized not as a
able model. At approximately USD 350 per test, the cost luxury, but as a standard of care in pediatric
of exome sequencing is modest compared to the typical neurology.11
2 www.thelancet.com Vol 39 August, 2025
Comment
Contributors 2 Zuberi SM, Wirrell E, Yozawitz E, et al. ILAE classification and
Agung Triono-literature search, study design, data collection, data definition of epilepsy syndromes with onset in neonates and in
analysis, data interpretation. fants: position statement by the ILAE Task Force on Nosology and
Kristy Iskandar-literature search, study design, data collection, data Definitions. Epilepsia. 2022;63(6):1349–1397.
3 Scheffer IE, Zuberi S, Mefford HC, Guerrini R, McTague A.
analysis, data interpretation and writing.
Developmental and epileptic encephalopathies. Nat Rev Dis Prim.
Auliya SB Sumpono-data collection, data analysis, data interpreta 2024;10(1). Available from: https://doi.org/10.1038/s41572-024-
tion and writing. 00546-6.
Tyas I Hikmawan-data analysis, data interpretation, bioinformatics. 4 Scheffer IE, French J, Valente KD, Auvin S, Cross JH, Specchio N.
Gunadi-data analysis, data interpretation and writing. Operational definition of developmental and epileptic encepha
Elisabeth Siti Herini-data analysis, data interpretation and writing. lopathies to underpin the design of therapeutic trials. Epilepsia.
2025;66:1014–1023.
Declaration of interests 5 Lim KS, Chia ZJ, Myint MZ, et al. Epilepsy in southeast asia, how
None declared. much have we closed the management gap in past two decades?
Neurol Asia. 2020;25(4):425–438.
Acknowledgements 6 Octavius GS, Daleni VA, Sagala YDS. An insight into Indonesia’s
The authors acknowledge the support and guidance provided by the progress for newborn screening program: what is currently going
on. Heliyon. 2024;10(13):e33479. Available from: https://doi.org/
Genomics and Science Dojo and the Genomics and Science Workshop
10.1016/j.heliyon.2024.e33479.
and facilitators during the manuscript preparation. The Genomics and 7 Richards S, Aziz N, Bale S, et al. Standards and guidelines for the
Science Dojo and Workshop was supported by the British Embassy in interpretation of sequence variants: a joint consensus recommen
Jakarta (FCDO Project Name: Indonesia Digital Health, FCDO Project dation of the American College of medical genetics and genomics
Number: PCA IDJ 000001). and the association for molecular pathology. Genet Med. 2015;17
Funding: The study was supported by grants from the Ministry of (5):405–424.
Education, Culture, Research, and Technology/National Research and 8 Triono A, Herini ES, Gunadi. Hubungan Genotip dan Fenotip
Innovation Agency of the Republic of Indonesia to KI under contract Developmental and Epileptic Encephalopathy pada Anak dengan
Metode Pemeriksaan Next-Generation Sequencing. [Thesis]
number 2137/UN1/DITLIT/Dit-Lit/PT.01.03/2023. The funders of the
[Bahasa]. Yogyakarta [Indonesia]: Universitas Gadjah Mada;
study had no role in the design. Data analysis, data interpretation, or writing 2025.
of the article. The corresponding authors had full access to all the data, and 9 Kanmaz S, Tekgul H, Kayilioglu H, et al. Therapeutic implications
had final responsibility for the decision to submit the study for publication. of etiology-specific diagnosis of early-onset developmental and
epileptic encephalopathies (EO-DEEs): a nationwide Turkish
Appendix A. Supplementary data cohort study. Seizure. 2024;123:17–25.
Supplementary data related to this article can be found at https://doi. 10 Joshi C, Kolbe DL, Mansilla MA, Mason SO, Smith RJH,
org/10.1016/j.lansea.2025.100638. Campbell CA. Reducing the cost of the diagnostic odyssey in
early onset epileptic encephalopathies. BioMed Res Int.
2016;2016.
References 11 Triono A, Iskandar K, Hadiyanto ML, et al. Identification of the
1 Scheffer IE, Berkovic S, Capovilla G, et al. ILAE classification of the genetic basis of pediatric neurogenetic disorders at a tertiary
epilepsies: position paper of the ILAE commission for classifica referral hospital in Indonesia: contribution of whole exome
tion and terminology. Epilepsia. 2017;58(4):512–521. sequencing. PLoS One. 2023;18(10):e0293113-3.
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