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Early-Life Epilepsies and the Emerging Role of Genetic Testing

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This paper looks at the diagnostic yield of genetic testing when used for children with newly presenting early-life epilepsy. 

In this prospective cohort study of 775 children by Berg et al, diagnostic yields overall were 40%, with epilepsy gene-sequencing panels and whole-exome sequencing having substantially greater diagnostic yields than chromosomal microarray. In the absence of a clinically identified cause, testing yields were greater than 15% and as high as 47% depending on patient subgroups.

The study concludes that Genetic testing, especially with sequencing-based methods, should be incorporated into the routine initial evaluation of early-life epilepsy. 

In a related study Tan et al. investigates the influence of whole-exome sequencing in sequencing-naive children suspected of having a monogenic disorder and evaluates its cost-effectiveness if whole-exome sequencing had been available at different time points in their diagnostic trajectory. This prospective study was part of the Melbourne Genomics Health Alliance demonstration project. At the ambulatory outpatient clinics of the Victorian Clinical Genetics Services at the Royal Children’s Hospital, Melbourne, Australia, children older than 2 years suspected of having a monogenic disorder were prospectively recruited from May 1 through November 30, 2015, by clinical geneticists after referral from general and subspecialist pediatricians. All children had nondiagnostic microarrays and no prior single-gene or panel sequencing.

Singleton whole-exome sequencing identified diagnoses in 23 of 44 children (52%); the diagnoses were unexpected in 8 of 23 children (35%), and clinical management was altered in 6 of 23 children (26%). Whole-exome sequencing was most cost-effective when applied at initial presentation to tertiary care compared with first clinical genetics assessment and the standard diagnostic pathway.

The authors suggest that pediatricians should consider early referral of children with undiagnosed conditions to clinical genetics specialists for whole-exome sequencing to maximize cost-effectiveness.

In an accompanying editorial Johannes R. Lemke, MD writes on High-Throughput Sequencing as First-Tier Diagnostics in Congenital and Early-Onset Disorders. The yield of genetic testing methods has dramatically improved within the past few years, enabling the identification of genetic causes in common as well as rare and unusual phenotypes in an increasing proportion of patients. Thus, genetic testing has become part of the routine diagnostic workup for many disorders. The studies by Tan et al and Berg et al demonstrate the dramatic effect of the diagnostic yield of different genetic testing approaches on cost-effectiveness and the potential design of testing strategies in children with suspected monogenic conditions.


Berg AT, Coryell J, Saneto RP, Grinspan ZM, Alexander JJ, Kekis M et al. (2017) Early-Life Epilepsies and the Emerging Role of Genetic Testing.JAMA Pediatr 171 (9):863-871. DOI: 10.1001/jamapediatrics.2017.1743 PMID: 28759667.

Tan TY, Dillon OJ, Stark Z, Schofield D, Alam K, Shrestha R et al. (2017) Diagnostic Impact and Cost-effectiveness of Whole-Exome Sequencing for Ambulant Children With Suspected Monogenic Conditions.JAMA Pediatr 171 (9):855-862. DOI: 10.1001/jamapediatrics.2017.1755 PMID: 28759686.

Lemke JR (2017) High-Throughput Sequencing as First-Tier Diagnostics in Congenital and Early-Onset Disorders.JAMA Pediatr 171 (9):833-835. DOI: 10.1001/jamapediatrics.2017.1970 PMID: 28759672.

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