Molecular analysis and prenatal diagnosis of seven Chinese families with genetic epilepsy

Bin Mao; Na Lin; Danhua Guo; Deqin He; Huili Xue; Lingji Chen; Qianqian He; Min Zhang; Meihuan Chen; Hailong Huang; Liangpu Xu

doi:10.3389/fnins.2023.1165601

Molecular analysis and prenatal diagnosis of seven Chinese families with genetic epilepsy

Front Neurosci. 2023 May 12:17:1165601. doi: 10.3389/fnins.2023.1165601. eCollection 2023.

Authors

Bin Mao^#^{1

2}, Na Lin^#^{1

2}, Danhua Guo^#^{1

2}, Deqin He^{1

2}, Huili Xue^{1

2}, Lingji Chen^{1

2}, Qianqian He^{1

2}, Min Zhang^{1

2}, Meihuan Chen^{1

2}, Hailong Huang^{1

2}, Liangpu Xu^{1

2}

Affiliations

¹ Medical Genetic Diagnosis and Therapy Center, Fujian Maternity and Child Health Hospital, College of Clinical Medicine for Obstetrics and Gynecology and Pediatrics, Fujian Medical University, Fuzhou, China.
² Fujian Provincial Key Laboratory of Prenatal Diagnosis and Birth Defect, Fuzhou, China.

^# Contributed equally.

Abstract

Introduction: Genetic epilepsy is a large group of clinically and genetically heterogeneous neurological disorders characterized by recurrent seizures, which have a clear association with genetic defects. In this study, we have recruited seven families from China with neurodevelopmental abnormalities in which epilepsy was a predominant manifestation, aiming to elucidate the underlying causes and make a precise diagnosis for the cases.

Methods: Whole-exome sequencing (WES) combined with Sanger sequencing was used to identify the causative variants associated with the diseases in addition to essential imaging and biomedical examination.

Results: A gross intragenic deletion detected in MFSD8 was investigated via gap-polymerase chain reaction (PCR), real-time quantitative PCR (qPCR), and mRNA sequence analysis. We identified 11 variants in seven genes (ALDH7A1, CDKL5, PCDH19, QARS1, POLG, GRIN2A, and MFSD8) responsible for genetic epilepsy in the seven families, respectively. A total of six variants (c.1408T>G in ALDH7A1, c.1994_1997del in CDKL5, c.794G>A in QARS1, c.2453C>T in GRIN2A, and c.217dup and c.863+995_998+1480del in MFSD8) have not yet been reported to be associated with diseases and were all evaluated to be pathogenic or likely pathogenic according to the American College of Medical Genetics and Genomics (ACMG) guidelines.

Methods: Based on the molecular findings, we have associated the intragenic deletion in MFSD8 with the mutagenesis mechanism of Alu-mediated genomic rearrangements for the first time and provided genetic counseling, medical suggestions, and prenatal diagnosis for the families. In conclusion, molecular diagnosis is crucial to obtain improved medical outcomes and recurrence risk evaluation for genetic epilepsy.

Keywords: Alu elements; genetic epilepsy; molecular analysis; pathogenic variants; prenatal diagnosis.

Grants and funding

This study was supported by the Fujian Maternity and Child Health Hospital Natural Science Foundation (FY YCXY 21-05), Fujian Provincial Natural Science Foundation (2022J05218), Key Project on the Integration of Industry, Education and Research Collaborative Innovation of Fujian Province (2021YZ034011), and Key Project on Science and Technology Program of Fujian Health Commission (2021ZD01002).