Variant classification for mucopolysaccharidosis type I; ACMG/AMP specification for IDUA from the ClinGen lysosomal...

With the increasing use of DNA sequencing technologies in healthcare, an accurate understanding of the clinical relevance of genetic variants is vital for the appropriate integration of these results into personalized care. To address this need, the NIH-funded Clinical Genome Resource (ClinGen) Lysosomal Diseases Variant Curation Expert Panel (VCEP) has developed variant classification guidance for IDUA, the gene encoding alpha-L-iduronidase. Deficiency of alpha-L-iduronidase activity causes mucopolysaccharidosis type I (MPS I). IDUA variant interpretation was prioritized by the VCEP following the 2016 inclusion of MPS I in the Recommended Uniform Screening Panel (RUSP) for newborns in the USA, reflecting the critical role of IDUA sequencing in therapeutic decision-making and care of individuals identified through either newborn screening or diagnostic platforms. Furthermore, as genetic testing is increasingly used as a first line test in the diagnosis of lysosomal diseases, accurate variant classification is vital. The LD VCEP's IDUA-specific variant classification guidance is based on the American College of Medical Genetics & Genomics and Association for Molecular Pathology's (ACMG/AMP) variation classification guidelines [1], with criteria tailored specifically to IDUA and MPS I. To date, the LD VCEP has submitted classifications and supporting data for 131 IDUA variants to ClinVar and to the ClinGen Evidence Repository, where this data is publicly available. Here, we discuss the development of the ClinGen LD VCEP's IDUA-specific ACMG/AMP criteria, our results to date, challenges, and plans for future work.