Reclassifying IDUA c.250G>A (p.Gly84Ser): Evidence for a Possible Pseudodeficiency Allele

Accurate variant classification is crucial for newborn screening (NBS) to prevent missed diagnoses or unnecessary interventions. The IDUA gene variant denoted as c.250G>A (p.Gly84Ser) has been identified in individuals with positive NBS for Mucopolysaccharidosis Type I (MPS I). This variant has conflicting pathogenicity reports including one publication classifying this variant as associated with a severe MPS I phenotype; therefore, we aim to clarify the clinical significance of this variant by presenting a case series describing three individuals, each homozygous for c.250G>A (p.Gly84Ser), identified in Michigan and California. All patients in this case series had low alpha-iduronidase (IDUA) enzyme activity with normal or mildly elevated glycosaminoglycans (GAGs) in blood or urine not falling into the range or pattern seen for affected individuals. None of these patients have developed clinical features of MPS I during follow-up ranging up to 3.5 years of age. Review of functional and population data supports a pseudodeficiency effect, resulting in no need for treatment. Based on our experience with three patients all homozygous for c.250G>A (p.Gly84Ser), despite causing low in vitro IDUA activity, homozygosity for the IDUA gene variant denoted as c.250G>A (p.Gly84Ser), does not cause symptoms of MPS I and may represent a pseudodeficiency allele. Caution should be exercised in newborns with this variant to help reduce unnecessary interventions and alleviate the psychosocial and economic consequences of false-positive NBS results, particularly for the South Asian population.