Format

Send to

Choose Destination
Mol Brain. 2018 Sep 5;11(1):48. doi: 10.1186/s13041-018-0392-5.

Novel and de novo mutations in pediatric refractory epilepsy.

Liu J1,2, Tong L1,2, Song S3, Niu Y1,2, Li J1,2, Wu X1,2, Zhang J4, Zai CC5, Luo F4, Wu J4, Li H5, Wong AHC5, Sun R1,2, Liu F2,5, Li B6,7.

Author information

1
Department of Pediatrics, Qilu Hospital of Shandong University, Jinan, Shandong, People's Republic of China.
2
Shandong University, Jinan, Shandong, People's Republic of China.
3
Qilu Children's hospital of Shandong University, Jinan, Shandong, People's Republic of China.
4
MyGenostics Inc., Beijing, People's Republic of China.
5
Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, University of Toronto, Toronto, ON, Canada.
6
Department of Pediatrics, Qilu Hospital of Shandong University, Jinan, Shandong, People's Republic of China. 198962000693@sdu.edu.cn.
7
Shandong University, Jinan, Shandong, People's Republic of China. 198962000693@sdu.edu.cn.

Abstract

Pediatric refractory epilepsy is a broad phenotypic spectrum with great genetic heterogeneity. Next-generation sequencing (NGS) combined with Sanger sequencing could help to understand the genetic diversity and underlying disease mechanisms in pediatric epilepsy. Here, we report sequencing results from a cohort of 172 refractory epilepsy patients aged 0-14 years. The pathogenicity of identified variants was evaluated in accordance with the American College of Medical Genetics and Genomics (ACMG) criteria. We identified 43 pathogenic or likely pathogenic variants in 40 patients (23.3%). Among these variants, 74.4% mutations (32/43) were de novo and 60.5% mutations (26/43) were novel. Patients with onset age of seizures ≤12 months had higher yields of deleterious variants compared to those with onset age of seizures > 12 months (P = 0.006). Variants in ion channel genes accounted for the greatest functional gene category (55.8%), with SCN1A coming first (16/43). 81.25% (13/16) of SCN1A mutations were de novo and 68.8% (11/16) were novel in Dravet syndrome. Pathogenic or likely pathogenic variants were found in the KCNQ2, STXBP1, SCN2A genes in Ohtahara syndrome. Novel deleterious variants were also found in West syndrome, Doose syndrome and glucose transporter type 1 deficiency syndrome patients. One de novo MECP2 mutation were found in a Rett syndrome patient. TSC1/TSC2 variants were found in 60% patients with tuberous sclerosis complex patients. Other novel mutations detected in unclassified epilepsy patients involve the SCN8A, CACNA1A, GABRB3, GABRA1, IQSEC2, TSC1, VRK2, ATP1A2, PCDH19, SLC9A6 and CHD2 genes. Our study provides novel insights into the genetic origins of pediatric epilepsy and represents a starting-point for further investigations into the molecular pathophysiology of pediatric epilepsy that could eventually lead to better treatments.

KEYWORDS:

ACMG scoring; Next-generation sequencing; Refractory epilepsy

PMID:
30185235
PMCID:
PMC6125990
DOI:
10.1186/s13041-018-0392-5
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for BioMed Central Icon for PubMed Central
Loading ...
Support Center