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Exome sequencing as first-tier genetic testing in infantile-onset pharmacoresistant epilepsy: diagnostic yield and treatment impact

Abstract

Pharmacoresistant epilepsy presenting during infancy poses both diagnostic and therapeutic challenges. We aim to identify diagnostic yield and treatment implications of exome sequencing (ES) as first-tier genetic testing for infantile-onset pharmacoresistant epilepsy. From June 2016 to December 2020, we enrolled patients with infantile-onset (age ≤ 12 months) pharmacoresistant epilepsy. 103 unrelated patients underwent ES. Clinical characteristics and changes in management due to the molecular diagnosis were studied. 42% (43/103) had epilepsy onset within the first month of life. After ES as first-tier genetic testing, 62% (64/103) of the cases were solved. Two partially solved cases (2%; 2/103) with heterozygous variants identified in ALDH7A1 known to cause autosomal recessive pyridoxine dependent epilepsy underwent genome sequencing (GS). Two novel large deletions in ALDH7A1 were detected in both cases. ES identified 66 pathogenic and likely pathogenic single nucleotide variants (SNVs) in 27 genes. 19 variants have not been previously reported. GS identified two additional copy number variations (CNVs). The most common disease-causing genes are SCN1A (13%; 13/103) and KCNQ2 (8%; 8/103). Eight percent (8/103) of the patients had treatable disorders and specific treatments were provided resulting in seizure freedom. Pyridoxine dependent epilepsy was the most common treatable epilepsy (6%; 6/103). Furthermore, 35% (36/103) had genetic defects which guided gene-specific treatments. Altogether, the diagnostic yield is 64%. Molecular diagnoses change management in 43% of the cases. This study substantiates the use of next generation sequencing (NGS) as the first-tier genetic investigation in infantile-onset pharmacoresistant epilepsy.

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Fig. 1
Fig. 2: The genetic findings in 103 patients with infantile-onset pharmacoresistant epilepsy.
Fig. 3: Intragenic deletions in the ALDH7A1 gene found in patients with pyridoxine dependent epilepsy.

Data availability

The data sets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

We would like to thank the patients and their families for participating in this study. We also thank Natrujee Wiwattanadittakul M.D., Chinnuwat Sanguansermsri M.D., Kamornwan Katanyuwong M.D., Division of Neurology, Department of Pediatrics, Maharaj Nakorn Chiang Mai Hospital; Somjit Sri-Udomkajorn M.D., Thanin Wechapinan M.D., Sirorat Suwannachote M.D., Chulaluck Kuptanon M.D., Department of Pediatrics, Queen Sirikit National Institute of Child Health, Surachai Likasitwattankul, M.D., Sorawit Viravan, M.D., Mongkon Chanvanichtrakool, M.D. Department of Pediatrics, Siriraj Hospital; Thitiporn Fangsaad, M.D. Department of Pediatrics, Bhumibol Adulyadej Hospital; Vitchayaporn Emarach Saengow, M.D. Department of Pediatrics, Maharat Nakhon Ratchasima Hospital, for their excellent care of the patients.

Funding

The study was supported by Health Systems Research Institute (65-040, 64-125).

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PB, WK, SP and TD collected data. WC, CP, CI, and RI performed DNA sequencing and analysis. PB and CI analyzed the data, drafted and revised the paper. KS and VS revised the draft. KS and VS conceived the study and obtained funding. All authors have read and agreed to the published version of the manuscript.

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Correspondence to Kanya Suphapeetiporn.

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The authors declare no competing interests.

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This study was approved by the Institutional Review Board of Faculty of Medicine, Chulalongkorn University, Thailand (IRB No. 264/62). Written informed consent was obtained from parents or legal guardians of the participants.

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Boonsimma, P., Ittiwut, C., Kamolvisit, W. et al. Exome sequencing as first-tier genetic testing in infantile-onset pharmacoresistant epilepsy: diagnostic yield and treatment impact. Eur J Hum Genet (2022). https://doi.org/10.1038/s41431-022-01202-x

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