Expanding the ClinGen Lysosomal Storage Disorder Curation Effort: VCEPs for Mucopolysaccharidosis Type II and IIIA - PROJECT SUMMARY Lysosomal diseases (LDs) are a group of over 70 rare, inherited monogenic disorders caused by deficiencies in lysosomal enzymes, transporters, or related proteins, resulting in progressive accumulation of toxic substrates and multisystem disease. Among LDs, mucopolysaccharidosis type II (MPS II) and type IIIA (MPS IIIA) are particularly severe, characterized by early-onset neurocognitive decline, somatic complications, and premature death. These disorders exemplify the diagnostic and clinical management challenges in LDs: broad phenotypic variability, frequent identification of novel or rare variants, and a high proportion of variants of uncertain significance (VUS) in the associated genes IDS and SGSH. The lack of standardized, expert-reviewed variant classification frameworks delays access to care, and complicates eligibility for emerging therapies and clinical trials. This proposal aims to address these gaps by expanding the scope of the ClinGen Lysosomal Diseases Variant Curation Expert Panel (LD VCEP), co-led by Drs. Filippo Pinto e Vairo, Lorne Clarke, Catherine Rehder, and Jennifer Goldstein to include expert curation of IDS and SGSH. The panel has already demonstrated success by implementing ACMG/AMP-based variant interpretation guidelines for IDUA and GAA, the genes implicated in MPS I and Pompe disease. Building on this foundation, our project will establish gene-specific criteria for IDS and SGSH, curate and classify high-priority variants, and disseminate results through ClinVar and the ClinGen Evidence Repository. Our rationale for prioritizing MPS II and IIIA is threefold: (1) both conditions are clinically devastating and lack curated, standardized variant interpretation resources; (2) MPS II has recently been added to the U.S. Recommended Uniform Screening Panel (RUSP) for newborn screening, and MPS IIIA is being piloted in screening programs; and (3) both disorders are targets for emerging gene and enzyme replacement therapies, making accurate molecular diagnosis critical. These factors create a time-sensitive need for expert variant interpretation to support newborn screening follow-up, clinical decision-making, and therapeutic access. The proposed work will be carried out through three specific aims: (1) expert curation and classification of IDS variants using customized ACMG/AMP criteria; (2) expert curation and classification of SGSH variants, addressing both classical and atypical phenotypes; and (3) establishment of a sustainable model for annual variant reclassification, stakeholder engagement, and dissemination. The project will be led by a multidisciplinary consortium of clinical and molecular geneticists, biochemical geneticists, bioinformaticians, genetic counselors, and patient advocacy partners, supported by strong institutional infrastructure and national and international collaborations. This initiative aligns directly with the goals of PAR-23-199 by advancing expert-driven, transparent, and publicly accessible variant interpretation in clinically actionable genes. In addition to reducing VUS burden and improving diagnostic clarity for MPS II and IIIA, this project will create a scalable framework to support future expansion of the LD VCEP to additional lysosomal disease genes.
