Frequency of iduronate-2-sulfatase gene variants detected in newborn screening for mucopolysaccharidoses type Ⅱ in Japan

Background: Mucopolysaccharidosis II (MPS II; Hunter syndrome) is an X-linked recessive inborn metabolic disorder caused by a defect in iduronate-2-sulfatase (IDS). MPS II is a systemic disease affecting multiple organs. In Japan, the area where NBS for MPS II has been performed has been expanding in recent years because MPS II is the most common MPS disease in Japan and effective ERTs have been approved. We have conducted NBS for MPS II since December 2016, the earliest in Japan. Here, we report and discuss the frequencies of MPS II and the IDS gene variants detected in NBS.
Material and Method: A total of 197,700 newborns participated in this study between April 2019 and July 2022. Dried blood spot (DBS) samples were prepared as part of a routine public health program using a heel-prick procedure 3–6 days after birth. IDS activity was assayed in DBS samples. Newborns whose IDS activity was still below the cutoff level were referred to the hospital for clinical assessment, and physical examination and biochemical assays were performed to detect MPS II symptoms. The IDS gene of the newborns was sequenced to confirm the diagnosis.
Result: 197,700 newborns were screened for IDS activity. A total of 157 newborns (0.08%) were recalled and 122 showed impaired IDS activity in the second IDS activity measurement. 112 newborns underwent IDS gene analysis. One newborn with MPS II was hemizygous for a novel pathogenic variant (c.1003C>A) with high urinary GAG levels. The frequency of patients with MPS II at the time of screening was 1 in 197,700.
Conclusion: In this study, 197,700 newborns were screened and 122 showed decreased IDS activity in DBSs. One newborn with a novel variant of c.1003C>A (p.His335Asn) was diagnosed with MPS II using a combination of IDS genetic and urinary GAG analyses. The remaining 111 were considered false positives. As pseudodeficiency variants or VOUS are frequently detected in Japan, it is necessary to introduce GAG measurements in DBSs.