Exome sequencing for patients with developmental and epileptic encephalopathies in clinical practice. (14th June 2022)

• Record Type: Journal Article
• Authors: Scheffer, Ingrid E.; Bennett, Caitlin A.; Gill, Deepak; de Silva, Michelle G.; Boggs, Kirsten; Marum, Justine; Baker, Naomi; Palmer, Elizabeth E.; Howell, Katherine B.
• Other Names: Andrews Ian investigator.; Antony Jayne investigator.; Ardern‐Holmes Simone investigator.; Bye Ann M investigator.; Cardamone Michael investigator.; Chelakkadan Shabeed investigator.; Clark Damian investigator.; Curnow Sarah R investigator.; Dabscheck Gabriel investigator.; Fahey Michael C investigator.; Freeman Jeremy L investigator.; Gupta Sachin investigator.; Harvey A Simon investigator.; Hildebrand Michael S investigator.; Inder Marie investigator.; Kanhangad Manoj investigator.; Kornberg Andrew J investigator.; Kothur Kavitha investigator.; Lawson John A investigator.; Leventer Richard J investigator.; Malone Stephen investigator.; Menezes Manoj P investigator.; Mohammad Shekeeb investigator.; Nagarajan Lakshmi investigator.; Pillai Sekhar investigator.; Pridmore Clair investigator.; Procopis Peter G investigator.; Sampaio Hugo investigator.; Silberstein Jonathon investigator.; Sinclair Adriane investigator.; Smith Nicholas investigator.; Subramanian Gopinath investigator.; Troedson Christopher investigator.; Ware Tyson investigator.; White Susan M investigator.;
• Is Part Of: Developmental medicine & child neurology. Volume 65:Number 1(2023)
• Page Start: 50
• Page End: 57
• Publication Date: 2022-06-14
• Subjects: Child development -- Periodicals; Pediatric neurology -- Periodicals; 616.8
• DOI: 10.1111/dmcn.15308
• Languages: English
• ISSNs: 0012-1622

Abstract

Abstract: 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. What this paper adds: The cause was identified in 35% of patients with developmental and epileptic encephalopathies. KCNQ2, CDKL5, SCN1A, and STXBP1 were the most frequently identified genes. Reanalysis of genomic data found the cause in an additional six patients. Genetic aetiology was identified in 41% of children with seizure onset under 2 years, compared to 18% with older onset. Finding the molecular cause led to management changes in 36% of patients with DEEs. What this paper adds: The cause was identified in 35% of patients with developmental and epileptic encephalopathies. KCNQ2, CDKL5, SCN1A, and STXBP1 were the most frequently identified genes. Reanalysis of genomic data found the cause in an additional six patients. Genetic aetiology was identified in 41% of children with seizure onset under 2 years, compared to 18% with older onset. Finding the molecular cause led to management changes in 36% of patients with DEEs.