Abstract
Early-onset epileptic encephalopathy (EE) and combined developmental and epileptic encephalopathies (DEE) are clinically and genetically heterogeneous severely devastating conditions. Recent studies emphasized de novo variants as major underlying cause suggesting a generally low-recurrence risk. In order to better understand the full genetic landscape of EE and DEE, we performed high-resolution chromosomal microarray analysis in combination with whole-exome sequencing in 63 deeply phenotyped independent patients. After bioinformatic filtering for rare variants, diagnostic yield was improved for recessive disorders by manual data curation as well as molecular modeling of missense variants and untargeted plasma-metabolomics in selected patients. In total, we yielded a diagnosis in ∼42% of cases with causative copy number variants in 6 patients (∼10%) and causative sequence variants in 16 established disease genes in 20 patients (∼32%), including compound heterozygosity for causative sequence and copy number variants in one patient. In total, 38% of diagnosed cases were caused by recessive genes, of which two cases escaped automatic calling due to one allele occurring de novo. Notably, we found the recessive gene SPATA5 causative in as much as 3% of our cohort, indicating that it may have been underdiagnosed in previous studies. We further support candidacy for neurodevelopmental disorders of four previously described genes (PIK3AP1, GTF3C3, UFC1, and WRAP53), three of which also followed a recessive inheritance pattern. Our results therefore confirm the importance of de novo causative gene variants in EE/DEE, but additionally illustrate the major role of mostly compound heterozygous or hemizygous recessive inheritance and consequently high-recurrence risk.
Highlights
The term epileptic encephalopathy (EE) denotes a rare group of severe, early-onset epilepsies that tend to beThe role of recessive inheritance in early-onset epileptic encephalopathies: a combined whole-exome. . .abundant epileptiform activity interferes with development resulting in cognitive slowing and often regression” and “developmental and epileptic encephalopathy” (DEE) where there is additional developmental impairment independent of the epileptic activity [3].Despite the growing number of known EE/DEE disease genes, the majority of patients still remain without etiological diagnosis
Applying high-resolution chromosomal copy number profiling and whole-exome sequencing in 63 index cases with EE/DEE and the majority of their healthy parents established a diagnosis in ∼42% of patients
De novo copy number variants (CNVs) accounted for ∼10% of the diagnostic yield, which is higher than the 3–5% reported in most of previous studies [4,5,6,7], but is in line with a recent report on copy number profiling from exome sequencing data [8] and may be explained by the higher genome-wide resolution for CNV detection of our high-resolution chromosomal microarray analysis in comparison with the lower-resolution microarrays and exome sequencing data previously used
Summary
The term epileptic encephalopathy (EE) denotes a rare group of severe, early-onset epilepsies that tend to beThe role of recessive inheritance in early-onset epileptic encephalopathies: a combined whole-exome. . .abundant epileptiform activity interferes with development resulting in cognitive slowing and often regression” and “developmental and epileptic encephalopathy” (DEE) where there is additional developmental impairment independent of the epileptic activity [3].Despite the growing number of known EE/DEE disease genes, the majority of patients still remain without etiological diagnosis. The role of recessive inheritance in early-onset epileptic encephalopathies: a combined whole-exome. In patients with a clinically unrecognized etiology (likely) causative de novo copy number variants (CNVs) accounted for about 3– 10% of patients in several studies [4,5,6,7,8]. A large wholeexome sequencing study in “epileptic encephalopathy” patients established de novo variants, as disease cause in 12% [9]. In order to further evaluate the etiology and the role of recessive inheritance in EE/DEE, we performed a comprehensive single-center study to unravel the underlying etiology in 63 deeply phenotyped patients with early-onset EE or DEE of clinically unrecognized etiology by combining wholeexome sequencing and high-resolution chromosomal CNV studies
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