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

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...

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Bibliographic Details
Published in:European journal of human genetics : EJHG 2023-02, Vol.31 (2), p.179-187
Main Authors: Boonsimma, Ponghatai, Ittiwut, Chupong, Kamolvisit, Wuttichart, Ittiwut, Rungnapa, Chetruengchai, Wanna, Phokaew, Chureerat, Srichonthong, Chalurmpon, Poonmaksatit, Sathida, Desudchit, Tayard, Suphapeetiporn, Kanya, Shotelersuk, Vorasuk
Format: Article
Language:English
Subjects:
Copy number
DNA Copy Number Variations
Epilepsy
Epilepsy - genetics
Exome Sequencing
Genetic screening
Genetic testing
Genetic Testing - methods
Genomes
Humans
Infant
KCNQ2 protein
Next-generation sequencing
Patients
Potassium channels (voltage-gated)
Pyridoxine
Seizures
Sodium channels (voltage-gated)
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Summary: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.
ISSN:1018-4813
1476-5438
DOI:10.1038/s41431-022-01202-x