Expanding the Clinical Spectrum of RERE-Related Disorders: A Case Report of Neurodevelopmental Disorder with Brain Malformations Including Chiari Type I.

INTRODUCTION

Neurodevelopmental disorder with or without anomalies of the brain, eye, or heart (NEDBEH) is a rare genetic condition caused by heterozygous pathogenic variants in the RERE gene, which encodes a transcriptional co-repressor essential for embryonic development. Most reported cases result from de novo variants and show a broad spectrum of neurodevelopmental and structural abnormalities. This report expands the phenotypic spectrum of NEDBEH by describing the first association with a Chiari type I malformation.

CASE PRESENTATION: We report a 26-year-old Colombian male presenting with global developmental delay, progressive spasticity, mild dysmorphic features and a Chiari type I malformation, a finding not previously linked to RERE variants. Whole-exome sequencing identified a heterozygous de novo missense variant in RERE (NM_001042681.3:c.815A>G; p.Tyr272Cys), initially classified as a variant of uncertain significance but supported as likely pathogenic according to ACMG criteria (PP3, PM2). The RERE gene functions as a retinoic acid-dependent transcriptional cofactor, a pathway critical for hindbrain segmentation and morphogenesis, providing a plausible mechanism for the cerebellar anomaly observed.

CONCLUSION

This case broadens the clinical spectrum of RERE-related NEDBEH, suggesting potential cerebellar involvement secondary to disrupted retinoic acid signaling. It emphasizes the importance of genomic testing for patients with neurodevelopmental delay and structural brain malformations, enabling accurate diagnosis, genetic counseling, and deeper understanding of rare developmental disorders.