Related Experiment Video
Updated: May 21, 2025
In Vivo Functional Study of Disease-associated Rare Human Variants Using Drosophila
Published on: August 20, 2019
De novo TANC2 variants caused developmental and epileptic encephalopathy and epilepsy
Sheng Luo1, Wen-Jun Zhang1, Mi Jiang1
1Department of Neurology, Institute of Neuroscience, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China.
Objective:
The TANC2 gene encodes a scaffolding synaptic protein with essential roles in synaptic transmission. This study aims to explore the association between TANC2 and epilepsy and the mechanism underlying phenotypic variation.
Methods:
Trio-based exome sequencing was performed in patients with epilepsy from the China Epilepsy 1.0 cohort. The association between TANC2 and epilepsy was validated with a Drosophila model. The role of TANC2 in development was investigated by single-cell RNA sequencing in cerebral organoids and spatiotemporal expression across brain regions.
Results:
De novo TANC2 variants were identified in six unrelated cases, including four null and two missense variants. The six variants were classified as "pathogenic"/"likely pathogenic," according to the American College of Medical Genetics and Genomics guidelines. Patients with null variants exhibited severe phenotypes, including three with epilepsy and neurodevelopmental disorders (NDDs) and one with developmental and epileptic encephalopathy (DEE). In contrast, the patients with missense variants presented with only epilepsy. Genotype-phenotype correlation analysis revealed that variants associated with epilepsy and NDD were mostly null variants, whereas the missense variants were associated with NDD or epilepsy. NDD-associated missense variants exhibited more severe damage effects, compared with the epilepsy-associated missense variants. Functional studies in Drosophila suggested that knockdown TANC2 led to increased susceptibility to seizure-like behavior. TANC2 expresses highly in the brain, with three peaks in early fetal, infancy, and adulthood, coinciding with the onset ages of patients. Specifically, TANC2 exhibited the highest expression in the early fetal stage, indicating its vital role in early development. Single-cell RNA sequencing revealed an extensive expression of TANC2 in neurons in 1-month-old cerebral organoids, suggesting its vital role in neurodevelopment.
Significance:
This study suggested TANC2 as a causative gene of epilepsy and DEE. The phenotypic spectrums of TANC2 potentially ranged from early lethality, DEE, epilepsy with NDD, NDD, to mild epilepsy, depending on the damaging effects caused by variants.
More Related Videos
09:37Navigating MARRVEL, a Web-Based Tool that Integrates Human Genomics and Model Organism Genetics Information
Published on: August 15, 2019
08:22A Novel Strategy Combining Array-CGH, Whole-exome Sequencing and In Utero Electroporation in Rodents to Identify Causative Genes for Brain Malformations
Published on: December 1, 2017
Related Concept Videos
01:13Seizures: Classification
Seizures are typically classified into two main categories: focal and generalized seizures.
Focal Seizures
Focal seizures originate from specific regions of the brain. These seizures are further sub-classified into two types:
01:24Arteries of the Lower Limbs
Various factors can trigger epilepsy, including genetic factors, brain damage, metabolic causes, and unknown etiology. Diagnosis of epilepsy involves electroencephalography (EEG), which...
01:20Antiepileptic Drugs: Modulators of Neurotransmitter Release Mediated by SV2A Protein
SV2A is a transmembrane glycoprotein located predominantly in the brain, modulating the release of neurotransmitters for neuronal communication. Both levetiracetam and brivaracetam exhibit a high affinity for...