PHENOTYPIC DISCORDANCE AMONG SIBLINGS, TWINS, AND FAMILIAL CASES WITH GAUCHER DISEASE: A SYSTEMATIC REVIEW OF GENETIC AND EPIGENETIC DISEASE MODIFIERS

Joseph Miguel A. Abringe.; Ma. Paula V. Bergado.; Mhyk Edrian Evasco.; and Gecelene C. Estorico

doi:10.5281/zenodo.21297338

Abstract

This systematic review integrates data from peer-reviewed studies to characterize the extreme phenotypic heterogeneity of Gaucher disease (GD) within familial clusters. Analysis of identical twins and siblings reveals that identical GBA1genotypes often result in discordant clinical trajectories, ranging from treatment-resistant visceral infiltration to severe skeletal complications. The synthesis identifies that 6.2% of patients with atypical GD presentations harbor concurrent genetic disorders, such as Familial Mediterranean Fever, which significantly modify disease progression and therapeutic needs. Furthermore, results from sibling pairs discordant for Parkinsonism suggest that penetrance is likely driven by modifiers of protein homeostasis and molecular chaperones rather than enzyme activity levels alone. These findings support the implementation of a precision medicine framework that integrates longitudinal deep phenotyping with multi-locus genomic evaluation to optimize individualized care for affected families.

Keywords

Gaucher disease, phenotypic heterogeneity, familial clusters, GBA1 variants, Parkinsonism

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