Epigenetic dysregulation of the protocadherin gamma cluster links edematous severe acute malnutrition to neurodevelopmental impairment: a comprehensive in silico reanalysis of raw methylation data

Abstract Background Children surviving severe acute malnutrition (SAM), particularly the edematous form (kwashiorkor or ESAM), suffer from profound, long-term neurodevelopmental deficits and cognitive impairment. The molecular mechanisms driving these persistent neurological sequelae remain poorly understood. The protocadherin gamma ( PCDHG ) gene cluster on chromosome 5q31 is strictly regulated by stochastic promoter DNA methylation to orchestrate neuronal self-avoidance, dendritic tiling, and synapse formation. This study aimed to investigate whether ESAM is associated with targeted epigenetic dysregulation of the PCDHG cluster. Results Raw fluorescent intensity files (IDATs) for 374 buccal swab samples (GEO: GSE112893) were processed using the minfi R package with Normal-Exponential Out-Of-Band (Noob) background correction. Differential methylation analysis using limma identified 76 significant differentially methylated positions (DMPs) (false discovery rate < 0.05). Strikingly, 98.7% (75/76) were hypomethylated in ESAM. Genomic annotation revealed that 22 of these DMPs map exclusively to the PCDHG cluster. Pathway enrichment analysis demonstrated highly significant convergence on "homophilic cell-cell adhesion" (p = 2.93 × 10⁻²), "Cadherin signaling" (p = 1.72 × 10⁻¹), and critically, "nervous system development" (p = 4.55 × 10⁻¹⁰). Conclusions ESAM is characterized by a specific, profound hypomethylation of the PCDHG cluster. Given the essential role of proto-cadherins in neural circuit assembly and epithelial barrier integrity, this epigenetic signature provides a novel molecular mechanism linking early-life edematous malnutrition to both the neurodevelopmental sequelae and the physical barrier dysfunction observed in kwashiorkor.