Early Infantile Epileptic Encephalopathy Panel

Early Infantile Epileptic Encephalopathy (EIEE) is a clinically heterogeneous neurodevelopmental disorder. It is characterized by frequent and/or severe seizures within the first weeks of life (Noh et al. 2012. PubMed ID: 22342633). These seizures are often associated with febrile events and may be refractory to treatment with anti-epileptic drugs (AEDs). Patients with EIEE may also present with an abnormal EEG pattern, such as the characteristic burst-suppression pattern seen in Ohtahara syndrome (Khan and Al Baradie 2012. PubMed ID: 23213494). Intellectual disability and psychomotor delay are common features of many severe epileptic encephalopathies. EIEE is rare; it is estimated to affect 1/100,000 to 1/50,000 live births (orphanet).

Identifying the molecular basis of a patient’s epilepsy may provide valuable information to inform prognosis, recurrence risk, and treatment.  In particular, targeted therapy of genetic epilepsies is an area of rapid change and great promise (see table below). Some patients may benefit from drugs that target a specific pathway, gene product, or functional change to a specific protein (Musto et al. 2020. PubMed ID: 31889633; Reif et al. 2017. PubMed ID: 27781560).

EIEE is genetically heterogeneous; over 100 genes are involved in disease pathogenesis (Lemke et al. 2012. PubMed ID: 22612257). Structural brain abnormalities and inborn errors of metabolism are among the most common comorbidities. However, seizures may be idiopathic or associated with trauma (Sharma and Prasad 2013. PubMed ID: 23250121; Wilmshurst et al. 2015. PubMed ID: 26122601). An increasing fraction of EIEE can be attributed to a genetic cause.  Many EIEE cases are sporadic, occurring in families with no prior history of seizure (Allen et al. 2013. PubMed ID: 23934111). Sporadic cases of EIEE may be inherited by autosomal recessive transmission, but are more commonly caused by dominant, de novo, pathogenic variants in neuronally-expressed genes. De novo pathogenic missense variants are especially common among genetic epilepsies. For example, missense variants in ion channels (channelopathies) may modify gating kinetics, ion permeability, voltage sensitivity or ligand-binding imparting both gain- or loss-of-function effects (Kullmann. 2002. PubMed ID: 12023309). In addition, a large number of epilepsy-related genes are sensitive to null mutation and chain-terminating variants that are well-documented to be pathogenic (Human Gene Mutation Database). Finally, rare cases of EIEE have been attributed to copy number changes involving epilepsy-related genes (ARHGEF9, ARX, CDKL5, CHD2, DNM1, FOXG1, GABRA1, GABRB3, GABRG2, GRIN2A, MBD5, MECP2, MEF2C, PCDH19, PLCB1, PRRT2, SCN1A, SCN2A, SCN8A, SLC2A1, SLC9A6, SPTAN1, STX1B, STXBP1, TSC1 and TSC2). This test includes CNV analysis.  

In this panel, we sequence a total of 117 genes. Among them, over 20 genes have been associated with precision therapy in gene-drug studies. These include ALDH7A1, BCKDK, CHRNA4, DEPDC5, FOLR1, GAMT, GRIN2A, KCNQ2, KCNQ3, KCNT1, PCDH19, PNPO, POLG, PRRT2, SCN1A, SCN2A, SCN8A, SLC19A3, SLC2A1, STXBP1, TSC1 and TSC2 (see the table below). The panel includes 66 genes listed in OMIM in the phenotypic series of EIEE. Additionally, several genes on this panel are included based on their association with well-characterized syndromes in which infantile seizures are a predominant feature (Ottman et al. 2010. PubMed ID: 20100225; Wilmshurst et al. 2015. PubMed ID: 26122601). Examples of related epilepsy syndromes include:

Tuberous Sclerosis: TSC1 and TSC2

Infantile Spasm: ADSL, ARX, CDKL5, PNPO, MEF2C, SCN1A, SCN2A, STXBP1, TSC1, and TSC2

Dravet Syndrome: SCN1A, SCN1B, GABRG2, SCN2A, SCN9A, PCDH19, GABRA1, STXBP1, and CHD2

Ohtahara Syndrome: ARX, STXBP1, SCN2A, KCNQ2, KCNT1, SLC25A22, CDKL5, PNKP, and SPTAN1

Generalized (or genetic) Epilepsy with Febrile Seizures Plus (GEFS+): SCN1A, SCN1B, SCN2A, SCN9A, GABRG2, and STX1B

Benign Familial Neonatal or Infantile Seizures: KCNQ2, KCNQ3, and PRRT2

Early-onset Absence Epilepsy: SLC2A1

Rett Syndrome: MECP2, CDKL5, and FOXG1

Selected metabolic disorders: FOLR1, GAMT, ALDH7A1, PNPO, and SLC19A3

Selected mitochondrial disease: POLG, FARS2, and SLC25A22

See individual gene summaries for more information about molecular biology of gene products and spectra of pathogenic variants. 

This panel includes genes causative for autosomal dominant, autosomal recessive and X-linked early infantile epileptic encephalopathy. Extrapolating from previously published studies of next generation sequencing in large cohorts of patients with EIEE, we predict that our EIEE Panel will identify pathogenic variants in more than 37% of EIEE cases with unknown cause (Lemke et al. 2012. PubMed ID: 22612257; Kodera et al. 2013. PubMed ID: 23662938; Carvill et al. 2013. PubMed ID: 23708187; Della Mina et al. 2015. PubMed ID: 24848745; Wang et al. 2014. PubMed ID:24818677; Ream and Mikati. 2014. PubMed ID:25108116).

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel typically provides 99.6% coverage of all coding exons of the genes plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define coverage as ≥20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).