Deciphering the role of MYC Gene Variants in Childhood Cerebral Adrenoleukodystrophy (ccALD) using Integrative Transcriptomic and Variant Analysis

¹ Department of Biotechnology, Jaypee Institute ofInformation Technology, A-10, Sector 62 Noida, Uttar Pradesh, India- 201309
² Department of Biomedical Sciences, Humanitas University, Milan, Italy
³ Tumor Microenvironment Unit, IRCCS Humanitas Research Hospital, Milan, Italy

^* Corresponding author: This email address is being protected from spambots. You need JavaScript enabled to view it. , This email address is being protected from spambots. You need JavaScript enabled to view it.

Abstract

Objective: Childhood cerebral adrenoleukodystrophy (ccALD) is a severe neurodegenerative disorder characterized by rapid demyelination and disruption of the blood-brain barrier (BBB). Although mutations in the ABCD1 gene are the primary cause of the disease, the downstream molecular mechanisms contributing to disease progression remain poorly understood. This study aimed to identify key regulatory genes and functionally relevant variants associated with ccALD using an integrative transcriptomic and variant analysis approach.

Methods: RNA sequencing (RNA-seq) data derived from brain microvascular endothelial cells (BMECs) of ccALD patients and healthy controls were analyzed to identify differentially expressed genes (DEGs). Gene interaction networks were constructed using Cytoscape to identify hub genes. Variant calling was performed following the GATK Best Practices pipeline, including read preprocessing, alignment, base quality score recalibration, variant calling, filtering, and functional annotation using GATK Funcotator.

Results: Differential expression analysis identified 1,039 upregulated and 744 downregulated genes in ccALD BMECs compared with controls. Network analysis revealed MYC as the top hub gene, indicating its central role in disease- associated molecular networks. Variant analysis identified two rare variants within the MYC gene: rs2130098148 (C>A), a missense mutation, and rs2130107263 (A>T), a stop-gain mutation. Both variants were associated with pathways related to MAPK signaling, suggesting potential functional consequences for MYC-mediated cellular regulation.

Conclusion: This integrative transcriptomic and variant analysis demonstrates disruption of MYC at both the expression and genetic levels in ccALD. These findings suggest that MYC may act as a modifier gene contributing to BBB dysfunction and neuroinflammation in ccALD. The study highlights the value of integrative multi-omics approaches in uncovering molecular mechanisms underlying rare neurodegenerative diseases and identifies MYC as a potential candidate for further functional investigation.