Abstract
In severe early-onset epilepsy, precise clinical and molecular genetic diagnosis is complex, as many metabolic and electro-physiological processes have been implicated in disease causation. The clinical phenotypes share many features such as complex seizure types and developmental delay. Molecular diagnosis has historically been confined to sequential testing of candidate genes known to be associated with specific sub-phenotypes, but the diagnostic yield of this approach can be low. We conducted whole-genome sequencing (WGS) on six patients with severe early-onset epilepsy who had previously been refractory to molecular diagnosis, and their parents. Four of these patients had a clinical diagnosis of Ohtahara Syndrome (OS) and two patients had severe non-syndromic early-onset epilepsy (NSEOE). In two OS cases, we found de novo non-synonymous mutations in the genes KCNQ2 and SCN2A. In a third OS case, WGS revealed paternal isodisomy for chromosome 9, leading to identification of the causal homozygous missense variant in KCNT1, which produced a substantial increase in potassium channel current. The fourth OS patient had a recessive mutation in PIGQ that led to exon skipping and defective glycophosphatidyl inositol biosynthesis. The two patients with NSEOE had likely pathogenic de novo mutations in CBL and CSNK1G1, respectively. Mutations in these genes were not found among 500 additional individuals with epilepsy. This work reveals two novel genes for OS, KCNT1 and PIGQ. It also uncovers unexpected genetic mechanisms and emphasizes the power of WGS as a clinical tool for making molecular diagnoses, particularly for highly heterogeneous disorders.
Highlights
Many recent studies have successfully used whole-exome or whole-genome sequencing (WES, WGS) to uncover the genetic basis of rare disorders, primarily in a research context
These reports provide strong supporting evidence that these de novo mutations, which have not been previously reported in any epilepsy patients, are responsible for Ohtahara Syndrome (OS) in these children
As part of a wide-ranging program to evaluate the clinical utility of WGS (WGS500), we sequenced six patients with severe early-onset epilepsy who had evaded molecular diagnosis by conventional single-gene clinical screening
Summary
Many recent studies have successfully used whole-exome or whole-genome sequencing (WES, WGS) to uncover the genetic basis of rare disorders (reviewed by 1,2), primarily in a research context. In order to assess the possible clinical utility of WGS, we have sequenced the genomes of 500 individuals with a variety of medical conditions, including cancer, immunological disease and rare, putatively monogenic syndromes (3 –5). As part of this ‘WGS500 project’, we sequenced six patients with severe early-onset epilepsy who had been previously refractory to molecular diagnosis. It is increasingly being recognized that a given gene can cause multiple phenotypes [6], and that more comprehensive genetic testing may improve molecular diagnostic yield [7] This is useful clinically because it can help make or confirm a diagnosis, and because it may allow counseling on recurrence risk and prenatal testing
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