A Wide Spectrum of Genetic Disorders Causing Severe Childhood Epilepsy in Taiwan: A Case Series of Ultrarare Genetic Cause and Novel Mutation Analysis in a Pilot Study

Abstract

Background: Pediatric epileptic encephalopathy and severe neurological disorders comprise a group of heterogenous diseases. We used whole-exome sequencing (WES) to identify genetic defects in pediatric patients. Methods: Patients with refractory seizures using ≥2 antiepileptic drugs (AEDs) receiving one AED and having neurodevelopmental regression or having severe neurological or neuromuscular disorders with unidentified causes were enrolled, of which 54 patients fulfilled the inclusion criteria, were enrolled, and underwent WES. Results: Genetic diagnoses were confirmed in 24 patients. In the seizure group, KCNQ2, SCN1A, TBCID 24, GRIN1, IRF2BPL, MECP2, OSGEP, PACS1, PIGA, PPP1CB, SMARCA4, SUOX, SZT2, UBE3A, 16p13.11 microdeletion, [4p16.3p16.1(68,345–7,739,782)X1, 17q25.1q25.3(73,608,322–81,041,938)X3], and LAMA2 were identified. In the nonseizure group, SCN2A, SPTBN2, DMD, and FBN1 were identified. Ten novel mutations were identified. The recurrent genes included SCN1A, KCNQ2, and TBCID24. Male pediatric patients had a significantly higher (57% vs. 29%; p < 0.05, odds ratio = 3.18) yield than their female counterparts. Seventeen genes were identified from the seizure groups, of which 82% were rare genetic etiologies for childhood seizure and did not appear recurrently in the case series. Conclusions: Wide genetic variation was identified for severe childhood seizures by WES. WES had a high yield, particularly in male infantile patients.

Amplitude Integrated Electroencephalography and Continuous Electroencephalography Monitoring Is Crucial in High-Risk Infants and Their Findings Correlate With Neurodevelopmental Outcomes

“…Notably, the characteristics of different genetic seizures are noteworthy. Neonatal genetic seizures that are heterogeneous in genetic etiology and often associated with ultra-rare genetic causes ( 23 ). The characteristics of EEG findings can be helpful in defining the cause of seizure—either non-genetic or genetic—even associate it with different genes, including KCNQ2, SCN8A, SCN2A , and SCN1A .…”

Galloway–Mowat Syndrome Type 3 Caused by OSGEP Gene Variants: A Case Report and Literature Review

“…We collected the following data from the publications: the history of pregnancy and delivery, sex, gestational age at birth, birth weight, age at onset, leading signs or symptoms at onset, biochemical and imaging findings, genotype and outcomes. A total of 34 patients from 31 families, described in 6 publications (3,9,(13)(14)(15)(16), were included in our study.…”

Whole‐Exome Sequencing of a Saudi Epilepsy Cohort Reveals Association Signals in Known and Potentially Novel Loci

“…Likely pathogenic variants in 12 of these 102 monogenic epilepsy genes were observed in these 44 of these epileptic subjects (CHRNA4, CLN3, CLN8, DEPDC5, KCNJ10, KCNMA1, POLG, PRICKLE1, SCN1A, SCN2A, SCN8A and SCN9A). Of the 18 genes that were not contained in the 30 genes with likely pathogenic variants, a number including SZT2, SCN10A, UBA5 have been reported in whole exome sequencing in epilepsy subjects [19,20]. Only one homozygous mutation, a stop-gain, was observed in single individual, in Potassium Calcium-Activated Channel Subfamily M Alpha 1 (KCNMA), a calcium-sensitive potassium channel gene which has been shown to have a role in general and early-onset epilepsy-related phenotypes [22,23,24,25,26].…”