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Lineage Tracing and Clonal Analysis in Developing Cerebral Cortex Using Mosaic Analysis with Double Markers MADM
Published on: May 8, 2020
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Somatic Mosaicism Patterns Define Clinical-Surgical Subtypes of Focal Cortical Dysplasia Through Cell-Type-Specific
Camila Araújo Bernardino Garcia1, Muhammad Zubair2, Xincen Xi2
1Department of Surgery and Anatomy, Ribeirão Preto Medical School, University of São Paulo (USP), Ribeirao Preto, SP, Brazil.
Medrxiv : the Preprint Server for Health Sciences
|November 24, 2025
Summary
Mosaic variants in Focal Cortical Dysplasia Type II (FCDII) correlate with epilepsy severity. High mosaic fractions (MF > 40%) predict successful focal resection, while low MF (<5%) suggests diffuse network dysfunction requiring broader surgery.
Area of Science:
- Neuroscience
- Genetics
- Oncology
Background:
- Focal Cortical Dysplasia Type II (FCDII) is a leading cause of pediatric drug-resistant epilepsy.
- The genetic underpinnings and clinical implications of FCDII, particularly regarding surgical outcomes, remain incompletely understood.
- Somatic mosaicism is implicated in FCD, but its role in surgical planning requires further elucidation.
Purpose of the Study:
- To investigate the genetic landscape of FCDII by identifying novel somatic variants.
- To correlate identified genetic variants and their mosaic fractions (MF) with clinical phenotypes and surgical outcomes in FCDII patients.
- To establish MF as a biomarker for predicting surgical success in FCDII.
Main Methods:
- Deep exome sequencing and amplicon validation on surgical biopsies and blood samples from 14 FCDII patients.
- Multiscale pathogenic validation of identified somatic variants.
- Integration of genetic data with single-nucleus RNA sequencing and spatial maps of developing human cortices.
Main Results:
- Novel somatic variants were identified in genes related to neurotransmission, structural regulation, cellular maintenance, and RNA processing.
- High mosaic fractions (MF > 40%) in specific cortical layers (Layers 5 and 6 excitatory neurons) were associated with FCDIIB and successful focal resections (87.5% Engel score I).
- Low mosaic fractions (MF < 5%) with diffuse distribution were linked to FCDIIA, hemispherectomy, and poorer outcomes (Engel score II/III).
Conclusions:
- Mosaic fraction (MF) thresholds serve as high-definition biomarkers for estimating surgical outcomes in FCDII.
- MF > 40% indicates viable focal resection, while MF < 5% suggests network dysfunction necessitating extensive resection.
- Integrating genetic mapping with cellular localization enables precision surgery and translates molecular diagnosis into clinical practice for FCDII.
