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

Area of Science:

• Genetics
• Biochemistry
• Newborn Screening

Background:

• Accurate variant classification is vital for newborn screening (NBS) to avoid misdiagnoses.
• The IDUA gene variant c.250G>A (p.Gly84Ser) has conflicting pathogenicity reports for Mucopolysaccharidosis Type I (MPS I).

Purpose of the Study:

• To clarify the clinical significance of the IDUA gene variant c.250G>A (p.Gly84Ser).
• To evaluate the pathogenicity of the IDUA variant in homozygous individuals identified via NBS.

Main Methods:

• Case series of three individuals homozygous for the IDUA c.250G>A (p.Gly84Ser) variant.
• Analysis of alpha-iduronidase (IDUA) enzyme activity and glycosaminoglycans (GAGs) levels.
• Clinical follow-up of patients up to 3.5 years of age.

Main Results:

• All patients exhibited low IDUA enzyme activity but normal or mildly elevated GAGs.
• No patients developed clinical features of MPS I during the follow-up period.
• Functional and population data suggest a pseudodeficiency effect for this variant.

Conclusions:

• Homozygosity for the IDUA c.250G>A (p.Gly84Ser) variant does not cause MPS I symptoms.
• This variant may represent a pseudodeficiency allele, warranting caution in NBS interpretation.
• Avoiding unnecessary interventions reduces psychosocial and economic burdens, especially for the South Asian population.