Exome sequencing as first-tier genetic testing in infantile-onset pharmacoresistant epilepsy: diagnostic yield and
Ponghatai Boonsimma1,2, Chupong Ittiwut1,2, Wuttichart Kamolvisit1,2
1Center of Excellence for Medical Genomics, Medical Genomics Cluster, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok, 10330, Thailand.
Insights
Exome sequencing (ES) is a powerful first-tier genetic test for infantile epilepsy, achieving a 64% diagnostic yield and guiding treatment in 43% of cases. This approach identifies treatable genetic disorders, improving patient outcomes.
Area of Science:
- Genetics
- Neurology
- Pediatrics
Background:
- Infantile-onset pharmacoresistant epilepsy presents significant diagnostic and therapeutic challenges.
- Early and accurate genetic diagnosis is crucial for effective management and treatment of epilepsy in infants.
Purpose of the Study:
- To evaluate the diagnostic yield of exome sequencing (ES) as a first-tier genetic test for infantile-onset pharmacoresistant epilepsy.
- To assess the impact of molecular diagnoses on treatment strategies and patient outcomes.
Main Methods:
- Exome sequencing (ES) was performed on 103 unrelated patients with infantile-onset (≤12 months) pharmacoresistant epilepsy.
- Clinical data and management changes following genetic testing were analyzed.
- Genome sequencing (GS) was used for cases with suspected copy number variations.
Main Results:
- ES achieved a 62% diagnostic yield, identifying 66 pathogenic/likely pathogenic variants in 27 genes, with 19 novel variants.
- The most common causative genes were SCN1A (13%) and KCNQ2 (8%).
- Molecular diagnoses guided gene-specific treatments in 35% of cases, and 8% had treatable disorders leading to seizure freedom, including pyridoxine-dependent epilepsy (6%).
Conclusions:
- Exome sequencing is a highly effective first-tier genetic investigation for infantile-onset pharmacoresistant epilepsy.
- Molecular diagnoses significantly alter clinical management and enable targeted therapies, improving outcomes for affected infants.
- Next-generation sequencing approaches are essential for unraveling the genetic basis of complex early-onset epilepsies.
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.
