Clinical whole-genome sequencing in severe early-onset epilepsy reveals new genes and improves molecular diagnosis

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.

Diagnostic exome sequencing provides a molecular diagnosis for a significant proportion of patients with epilepsy

“…8,9,23 Data from small cohorts of patients with severe epilepsies also highlight the utility of DES for improving molecular diagnoses. [24][25][26] However, these studies rely on data from small, highly selected patient cohorts and may not reflect the diagnostic yield in an unselected sample of patients with epilepsy.…”

Recent developments in the genetics of childhood epileptic encephalopathies: impact in clinical practice

“…Recently, genes encoding ion channels have also been associated with OS. One of them is the gene encoding the voltage-gated potassium channel Kv7.2 (KCNQ2), in which de novo missense mutations were found in patients with OS and neonatal epileptic encephalopathies resembling OS 18 . Another ion channel associated with OS is the voltage-gated sodium channel Nav1.2 (SCN2A), in which de novo missense mutations were also identified 18 .…”

“…One of them is the gene encoding the voltage-gated potassium channel Kv7.2 (KCNQ2), in which de novo missense mutations were found in patients with OS and neonatal epileptic encephalopathies resembling OS 18 . Another ion channel associated with OS is the voltage-gated sodium channel Nav1.2 (SCN2A), in which de novo missense mutations were also identified 18 . Mutations in both KCNQ2 and SCN2A are involved in a wide clinical spectrum of EOEEs, which overlap each other including benign phenotypes such as benign familial neonatal seizures, but also severe forms of CEEs.…”

“…Mutations in both KCNQ2 and SCN2A are involved in a wide clinical spectrum of EOEEs, which overlap each other including benign phenotypes such as benign familial neonatal seizures, but also severe forms of CEEs. Recently, a WGS study also revealed two novel genes for OS: KCNT1, which encodes the potassium channel KCa4.1, and PIGQ, encoding a subunit of an N-acetylglucosaminyltransferase involved in the glycosylphosphatidyl inositol (GPI) biosynthesis 18 .…”

Cerebral visual impairment and intellectual disability caused by PGAP1 variants

“…15 Several genes known to be involved in the GPI anchor biosynthesis (PIGA, PIGL, PIGN, PIGT, PIGV, PIGO, PIGW and PIGQ) and modeling (PGAP2 and PGAP3) are implicated in X-linked and autosomal recessive intellectual disability disorders. [16][17][18][19][20][21][22][23][24][25][26] Additional features such as seizures, congenital abnormalities and facial dysmorphisms are commonly present. Moreover, CVI has been reported in individuals with PIGA, PIGN and PIGT variants, suggesting that the GPI anchor biosynthesis is important in the development of the visual areas of the brain.…”