Exome sequencing for patients with developmental and epileptic encephalopathies in clinical practice

Aim To assess the clinical utility of exome sequencing for patients with developmental and epileptic encephalopathies (DEEs). Method Over 2 years, patients with DEEs were recruited for singleton exome sequencing. Parental segregation was performed where indicated. Results Of the 103 patients recruited (54 males, 49 females; aged 2 weeks-17 years), the genetic aetiology was identified in 36 out of 103 (35%) with management implications in 13 out of 36. Exome sequencing revealed pathogenic or likely pathogenic variants in 30 out of 103 (29%) patients, variants of unknown significance in 39 out of 103 (38%), and 34 out of 103 (33%) were negative on exome analysis. After the description of new genetic diseases, a molecular diagnosis was subsequently made for six patients or through newly available high-density chromosomal microarray testing. Interpretation We demonstrate the utility of exome sequencing in routine clinical care of children with DEEs. We highlight that molecular diagnosis often leads to changes in management and informs accurate prognostic and reproductive counselling. Our findings reinforce the need for ongoing analysis of genomic data to identify the aetiology in patients in whom the cause is unknown. The implementation of genomic testing in the care of children with DEEs should become routine in clinical practice.

Automated summary

Exome sequencing has been demonstrated to have clinical utility in the management of patients with DEEs, providing molecular diagnosis, guiding treatment, and informing accurate prognosis and reproductive counseling. Ongoing analysis of genomic data is necessary to identify the cause in patients with unknown etiology. The routine implementation of genomic testing in the care of children with DEEs should be considered in clinical practice.