New genotype-phenotype correlations and management recommendations for individuals with RERE variants

Purpose To define the phenotypic spectrum and genotype-phenotype correlations associated with pathogenic RERE variants and inform clinical management and genetic counseling for neurodevelopmental disorder with or without anomalies of the brain, eye, or heart (NEDBEH). Methods We assembled a cohort of 54 individuals with heterozygous pathogenic, likely pathogenic, and variants of uncertain significance in RERE , including 30 previously unreported cases. Individuals were classified into 5 subcohorts based on variant type and location: loss-of-function, missense variants inside and outside a specific histidine-rich region (HRR), and HRR in-frame deletions and duplications. Phenotypic features were analyzed and compared across groups. Protein modeling was performed to assess potential structural effects. Results Developmental delay, intellectual disability, and/or autism spectrum disorder were prevalent across all groups. Loss-of-function variants are associated with fewer multisystem anomalies than missense variants and are more likely to be inherited from a mildly symptomatic or asymptomatic parent. In contrast, HRR-associated missense variants and in-frame HRR duplications were associated with more multisystem phenotypes and usually arise de novo. HRR missense variants were structurally stabilizing, suggesting a gain-of-function or dominant-negative mechanism. Conclusion These findings expand the clinical spectrum of RERE -related disorders, refine genotype-phenotype correlations, and support variant-specific approaches to management and genetic counseling.