Genotype-Phenotype Analysis of Children with Epilepsy Referred for Whole-Exome Sequencing at a Tertiary Care
Fahad A Bashiri1,2, Rawan AlSheikh3, Muddathir H Hamad2
1Department of Pediatrics, College of Medicine, King Saud University, Riyadh 11461, Saudi Arabia.
Insights
Genetic testing identified numerous mutations in Saudi children with epilepsy, many new to the region. This study underscores the importance of genetic analysis for diagnosing childhood epilepsy and understanding its varied presentations.
Area of Science:
- Pediatric Neurology
- Clinical Genetics
- Epilepsy Research
Background:
- Limited data exists on genetic epilepsy in Saudi Arabia, despite high consanguinity rates.
- Characterizing genetic mutations and their phenotypic presentations is crucial for understanding epilepsy in this population.
Purpose of the Study:
- To identify and characterize genetic mutations associated with epilepsy in pediatric patients in Saudi Arabia.
- To describe the phenotypic presentations of epilepsy linked to identified genetic mutations.
Main Methods:
- Retrospective chart review of pediatric epilepsy patients from 2015-2018 at a single Saudi Arabian center.
- Inclusion criteria required patients to have undergone whole-exome sequencing (WES) genetic testing.
Main Results:
- Positive WES identified 37 mutations in 45 patients; six mutations (SCN1A, DENND5A, KCNQ2, ACY1, SCN2A, PCDH19) were recurrent.
- Phenotypic presentations were heterogeneous, even among patients with the same mutation. Common features included developmental and cognitive delays, language delay, behavioral issues, and microcephaly.
- Consanguinity (31.8%) and family history (33.3%) were frequent. Many mutations were reported for the first time in Saudi Arabia. Seizure control varied with antiseizure medications (ASMs).
Conclusions:
- Multiple, often novel, epilepsy-associated mutations were identified in Saudi children, emphasizing the genetic heterogeneity.
- The study highlights the critical role of genetic testing in the comprehensive evaluation of childhood epilepsy in Saudi Arabia.
- Understanding these genetic underpinnings can inform diagnosis, management, and genetic counseling.
Background:
Despite the high consanguinity rates, data on genetic epilepsy in Saudi Arabia is limited. The objective of the current study was to characterize genetic mutations associated with epilepsy in pediatric patients and describe their phenotypic presentations.
Methods:
A retrospective chart review was conducted among children presented with epilepsy in one center in Saudi Arabia between 2015 and 2018. Only those who had undergone genetic testing were included.
Results:
A total of 45 patients had positive whole-exome sequencing (WES) genetic testing with 37 mutations. Six mutations (SCN1A, DENND5A, KCNQ2, ACY1, SCN2A, and PCDH19) were repeated in 15 patients, with largely heterogeneous phenotypic presentations in patients with the same mutation. Several mutations are reported for the first time in Saudi Arabia. The median age at epilepsy onset was four months. Consanguineous parents and family history of epilepsy were frequent (31.8% and 33.3%, respectively). Developmental delay (44.4%), cognitive delay (42.2%), language delay (40.0%), behavioral features (28.9%), and microcephaly (20.0%) were frequent presentations. At initial diagnosis, 68.9% of EEG and 48.9% of brain MRI were abnormal. The most currently used antiseizure medications (ASMs) were levetiracetam (48.9%), topiramate (28.9%), and valproic acid (20.0%). Approximately 60% of the patients were controlled with (47.6%) or without (11.9%) ASMs, and three (7.1%) patients died.
Conclusions:
Multiple mutations among children with epilepsy are reported in one hospital in Saudi Arabia, with the majority reported for the first time. The current findings highlight the importance of doing genetic testing for the evaluation of childhood epilepsy.
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