Exome & General Genetics
Since its introduction in 2011, diagnostic whole exome sequencing (DES) has proven instrumental in providing a molecular diagnosis for many patients with a broad spectrum of undiagnosed genetic disorders, particularly severe early-onset epilepsies. In our current study, we assess the utility of DES and characterize the positive findings in an unselected laboratory cohort of patients with epilepsy.
We assessed data from 596 consecutive patients undergoing DES over a five-year period, expanding the findings of our previously reported cohort of 314 patients. In most patients, triobased exome sequencing was performed. Novel genetic etiologies were assessed by standardized assessment criteria taking into account microdeletion/duplication syndromes, gene function and expression profiles, co-localization and interaction with genes known to cause similar phenotypes, animal models, and gene family and pathway information.
We confirm a diagnostic rate of 32.4% (193/596) through DES; novel genetic etiologies were identified in 8.6% (29/337) of patients. Approximately 70% of positive findings were due to de novo mutations. Autosomal recessive inheritance accounted for 20% of positive findings. Most positive findings (68%) were in genes only identified in single patients. MECP2, STXBP1, CACNA1A, and KCNQ2 were the most common genes and the only genes identified at an approximate frequency of 1%. We observed a low frequency of patients with SCN1A mutations, indicating that patients with SCN1A-positive Dravet syndrome may primarily be identified through methods other than DES.
Assessing the data of the longest ongoing diagnostic exome series, we confirm the highly heterogeneous genetic nature of the epilepsies with only a limited number of genes present in ≥1% of patients. The most common genes identified in our study have an unexpectedly broad phenotypic spectrum, including MECP2, STXBP1, and CACNA1A. DES may help identify recurrent genes with atypical presentations and capture underrepresented aspects of the genetic architecture of the epilepsies.