ORIGINAL RESEARCH article
Front. Genet.
Sec. Genetics of Common and Rare Diseases
Volume 16 - 2025 | doi: 10.3389/fgene.2025.1553036
Precision Genomic Profiling in Gaucher Disease: Insights from Atypical Presentations
Provisionally accepted
Armaan Saith
Jiapeng Ruan
Noor Ul Ain
Maniya Kasaiyan
Dhanpat JainGary Israel
Sameet Mehta
Nigel S Bamford
Shiny NairPramod K Mistry*- School of Medicine, Yale University, New Haven, Connecticut, United States
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Background: Gaucher disease (GD) is characterized by significant phenotypic heterogeneity, even among patients with identical GBA1 genotypes, suggesting the role of genetic and/or epigenetic modifiers. The enzymatic defect and pathological accumulation of glucosylceramide (GlcCer) lead to chronic metabolic inflammation, providing ample opportunities for interaction with other biological pathways to influence disease expression. Herein, we developed a model of precision medicine in this prototype single-gene disorder. Methods: This study leveraged a well-characterized, longitudinally followed cohort of GD patients from a major tertiary center, integrating whole exome sequencing (WES) with detailed clinical information. We applied a precision medicine framework centered on four components – clinical reasoning, deep phenotyping, genomic integration, and individualized therapy - to a subset of patients (n=17) who presented with complex phenotypes deviating from the classical GD presentation and/or were a priori suspected of harboring a second genetic disorder. Results: Out of 275 patients, 17 (6.2%) presented with atypical phenotypes not fully explained by GD. WES revealed additional genetic diagnoses, including hereditary hemochromatosis-associated variants (n=5), Familial Mediterranean Fever (n=4), homozygous MSH6 mutation-associated hereditary cancer predisposition (n=2), and autosomal dominant polycystic kidney disease (ADPKD) (n=2). Conclusions: The presence of concurrent genetic disorders in a subset of GD patients has the potential to modify clinical presentation, impact disease trajectory, and introduce additional complexities in clinical management. This study contributes to advancing precision medicine strategies aimed at optimizing patient outcomes. Future research into genetic and epigenetic modifiers of GD will further refine this framework and enhance individualized therapeutic approaches.
Keywords: Gaucher Disease, modifier genes, complex phenotypes, longitudinal deep phenotyping, whole exome sequencing
Received: 02 Jan 2025; Accepted: 01 Oct 2025.
Copyright: © 2025 Saith, Ruan, Ain, Kasaiyan, Jain, Israel, Mehta, Bamford, Nair and Mistry. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Pramod K Mistry, pramod.mistry@yale.edu
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